Clinical trial NCT02333331
Conditions: Sarcopenia
Keywords: Sarcopenia, muscle wasting, elderly, strength, physical function, muscle, gait speed
Sponsor: Novartis Pharmaceuticals
Start date: 2014-12-09; Completion date: 2018-06-28
Enrollment: 217 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to determine the efficacy of repeat dosing with multiple dose levels of bimagrumab on patient physical function, skeletal muscle mass and strength in older adults with sarcopenia. In addition, this study generated data on the safety, tolerability, and pharmacokinetics of bimagrumab in older adults with sarcopenia.

Detailed description:

Arms: arm 1: BYM338 70 mg intravenous infusion arm 2: BYM338 210 mg intravenous infusion arm 3: BYM338 700 mg intravenous infusion arm 4: Placebo intravenous infusion
Interventions: intervention 1: bimagrumab intervention 2: placebo
Intervention descriptions: intervention 1: Bimagrumab will be administered as an intravenous infusion starting on Day 1 until week 21. intervention 2: Placebo will be administered as an intravenous infusion starting on Day 1 until week 21.

Protocol documents:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research 
BYM338/bimagrumab 
Clinical Trial Protocol CBYM338E2202 / NCT02333331
A 28 week, randomized, double-blind, placebo-controlled, 
two-part, multi-center, parallel group dose range finding 
study to assess the effect of monthly doses of bimagrumab 
70, 210, and 700 mg on skeletal muscle strength and 
function in older adults with sarcopenia 
(InvestiGAIT) 
Authors: 
 
Document type: 
Amended Protocol Version 
EudraCT number: 
2014-003482-25 
Version number: 
v03 (Clean) 
Development phase: 
II 
Release date: 
04-Oct-2017
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Notification of serious adverse events 
A serious adverse event (SAE) is any event which is fatal or life-threatening, which requires 
or prolongs hospitalization, which is significantly or permanently disabling or incapacitating, 
which constitutes a congenital anomaly or a birth defect, or which is medically significant, 
may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
Any SAE occurring in a subject from consent until 30 days after stopping the trial/study drug 
must be reported either on the paper SAE report form or via the electronic SAE form within 
the clinical data capture system (where available). 
For SAEs reported using the paper SAE report form, the investigator will ensure that the form 
is completed and faxed by the investigator to the local Novartis Drug Safety and 
Epidemiology Department within 24 hours of learning of the occurrence of the SAE even if 
the SAE does not appear to be drug-related. The original SAE form, together with the fax 
confirmation sheet, must be kept with the case report forms at the study site. 
For SAEs recorded electronically in the Novartis clinical data capture system, information 
should be entered, saved and e-signed within 24 hours of awareness of the SAE. These data 
will automatically be submitted to Novartis Drug Safety & Epidemiology. 
More details in Section 7 of this protocol. 
Fax numbers of local Novartis Drug Safety and Epidemiology Departments 
Australia 
Fax: 
 
North America 
Fax  
        
 
France 
Fax  
 
Germany 
Fax  
 
 
   
 
Denmark 
Fax  
 
Belgium 
Fax  
 
Spain 
Fax  
 
Switzerland 
Fax  
 
Japan 
Fax  
 
Taiwan 
Fax 
 
Czech Republic 
Fax 
 
Russia 
Fax 
  
South Korea 
Fax 
 


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In addition, the investigator will inform the following responsible person(s) of Novartis 
Translational Medicine: 
 
Tel. Business:  
 (direct) 
 
Tel. Mobile phone:  
 
(Sponsor’s medical expert) 
Email: 
 
Any update to the Novartis DS&E or personnel information required during the course of the 
study will be communicated directly to the relevant Investigator site(s); a specific protocol 
amendment should not be required. 


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Table of contents 
Notification of serious adverse events ................................................................................. 2 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 8 
List of figures ...................................................................................................................... 9 
List of abbreviations .......................................................................................................... 10 
 13 
Glossary of terms ............................................................................................................... 14 
Amendment 3 (October 2017) ........................................................................................... 16 
Amendment 2 (September 2016) ....................................................................................... 19 
Amendment 1 (May 2015) ................................................................................................ 28 
Protocol synopsis ............................................................................................................... 31 
Assessment schedule ......................................................................................................... 37 
1 
Introduction ....................................................................................................................... 39 
1.1 
Background ............................................................................................................ 39 
1.1.1 
Relevant data summary ......................................................................... 41 
1.1.2 
Human safety and tolerability data ....................................................... 41 
 
 42 
 
 44 
1.2 
Study purpose ........................................................................................................ 45 
2 
Study objectives ................................................................................................................. 45 
2.1 
Primary objective ................................................................................................... 45 
2.2 
Secondary objective(s) ........................................................................................... 45 
 
 46 
3 
Investigational plan ........................................................................................................... 47 
3.1 
Study design........................................................................................................... 47 
3.1.1 
Part A .................................................................................................... 47 
3.1.2 
Interim Analysis .................................................................................... 48 
3.1.3 
Part B ..................................................................................................... 49 
3.1.4 
Exercise program .................................................................................. 49 
3.1.5 
Drug treatment assignment ................................................................... 50 
3.2 
Rationale for study design ..................................................................................... 54 
3.3 
Rationale for dose/regimen, duration of treatment ................................................ 56 
3.3.1 
Dose and frequency ............................................................................... 56 
3.4 
Rationale for choice of comparator ....................................................................... 58 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 58 


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3.6 
Risks and benefits .................................................................................................. 59 
 
 59 
3.6.2 
Trial-related risks .................................................................................. 62 
4 
Population .......................................................................................................................... 63 
4.1 
Inclusion criteria .................................................................................................... 64 
4.2 
Exclusion criteria ................................................................................................... 64 
5 
Treatment ........................................................................................................................... 68 
5.1 
Protocol requested treatment ................................................................................. 68 
5.1.1 
Investigational treatment ....................................................................... 68 
5.1.2 
Additional study treatment .................................................................... 69 
5.2 
Treatment arms ...................................................................................................... 69 
5.3 
Treatment assignment ............................................................................................ 69 
5.4 
Treatment blinding ................................................................................................. 70 
5.5 
Treating the Patient ................................................................................................ 70 
5.5.1 
Patient numbering ................................................................................. 70 
5.5.2 
Dispensing the study treatment ............................................................. 71 
5.5.3 
Handling of study treatment .................................................................. 71 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 72 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 73 
5.5.6 
Recommended treatment of adverse events .......................................... 73 
5.5.7 
Rescue medication ................................................................................ 73 
5.5.8 
Concomitant treatment .......................................................................... 73 
5.5.9 
Prohibited treatment .............................................................................. 74 
5.5.10 
Discontinuation of study treatment ....................................................... 74 
5.5.11 
Withdrawal of consent .......................................................................... 76 
5.5.12 
Loss to follow-up .................................................................................. 76 
5.5.13 
Emergency breaking of assigned treatment .......................................... 76 
5.5.14 
Study completion and post-study treatment .......................................... 77 
5.5.15 
Early study termination ......................................................................... 77 
6 
Visit assessments ............................................................................................................... 77 
6.1 
Dietary, fluid and other restrictions ....................................................................... 78 
6.2 
Dietary Requirement .............................................................................................. 78 
6.2.1 
Dietary assessment ................................................................................ 78 
6.2.2 
Nutritional supplement .......................................................................... 79 
6.3 
Patient demographics/other baseline characteristics ............................................. 80 
6.3.1 
Demographic Information ..................................................................... 80 


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6.3.2 
Medical History ..................................................................................... 80 
6.3.3 
Cardiovascular and metabolic co-morbidities ....................................... 80 
6.4 
Treatment exposure and compliance ..................................................................... 80 
6.5 
Efficacy / Pharmacodynamic assessments ............................................................. 81 
6.5.1 
Short physical performance battery ...................................................... 81 
6.5.2 
Gait speed .............................................................................................. 82 
6.5.3 
6 minute walk test ................................................................................. 82 
 
 83 
6.5.5 
Total lean body mass and appendicular skeletal mass index (ASMI) 
assessed by DXA................................................................................... 83 
 
 83 
 
 85 
 
 86 
6.6 
Safety ..................................................................................................................... 86 
6.6.1 
Physical examination ............................................................................ 86 
6.6.2 
Vital signs.............................................................................................. 86 
6.6.3 
Height and weight ................................................................................. 87 
6.6.4 
Laboratory evaluations .......................................................................... 87 
6.6.5 
Electrocardiogram (ECG) ..................................................................... 88 
6.6.6 
Pregnancy .............................................................................................. 89 
 
 89 
 
 89 
 
 89 
 
 90 
 
 90 
 
 90 
 
 90 
 
 90 
 
 90 
 
 90 
 
 91 
 
 92 
 
 92 
7 
Safety monitoring .............................................................................................................. 93 
7.1 
Adverse events ....................................................................................................... 93 
7.2 
Serious adverse event reporting ............................................................................. 95 


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7.3 
Liver safety monitoring ......................................................................................... 96 
 
 96 
7.5 
Pregnancy reporting ............................................................................................... 97 
7.6 
Safety monitoring .................................................................................................. 97 
8 
Data review and database management ............................................................................. 98 
8.1 
Site monitoring ...................................................................................................... 98 
8.2 
Data collection ....................................................................................................... 98 
8.3 
Database management and quality control ............................................................ 99 
8.4 
Data Monitoring Committee ................................................................................ 100 
8.5 
Adjudication committee ....................................................................................... 101 
9 
Data analysis .................................................................................................................... 101 
9.1 
Analysis sets ........................................................................................................ 101 
9.2 
Subject demographics and other baseline characteristics .................................... 102 
9.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) .......................................................................................................... 102 
9.3.1 
Study medication ................................................................................. 102 
9.3.2 
Concomitant medications .................................................................... 102 
9.4 
Analysis of the primary variable(s) ..................................................................... 102 
9.4.1 
Variable(s) ........................................................................................... 102 
9.4.2 
Statistical model, hypothesis and method of analysis ......................... 102 
9.4.3 
Handling of missing values/censoring/discontinuations ..................... 105 
9.4.4 
Supportive analyses ............................................................................. 105 
9.5 
Analysis of secondary 
 variables ................................................ 105 
9.5.1 
Efficacy / Pharmacodynamics ............................................................. 105 
9.5.2 
Safety ................................................................................................... 105 
9.5.3 
Vital signs............................................................................................ 106 
9.5.4 
ECG evaluations .................................................................................. 106 
 
 106 
9.5.6 
 / pharmacodynamic interactions .............................. 107 
 
. 107 
 
 107 
 
 107 
9.6 
Sample size calculation ........................................................................................ 108 
9.6.1 
Sample size for primary objective: ..................................................... 108 
9.7 
Power for analysis of key secondary variables .................................................... 110 
9.8 
Interim analyses ................................................................................................... 111 


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10 Ethical considerations ...................................................................................................... 112 
10.1 
Regulatory and ethical compliance ...................................................................... 112 
10.2 
Informed consent procedures ............................................................................... 112 
10.3 
Responsibilities of the investigator and IRB/IEC ................................................ 112 
10.4 
Publication of study protocol and results............................................................. 113 
11 Protocol adherence .......................................................................................................... 113 
11.1 
Protocol Amendments ......................................................................................... 113 
12 References ....................................................................................................................... 114 
13 Appendix 1: Sample log table – all matrices ................................................................... 118 
14 Appendix 2: Liver event definitions and follow-up requirements .................................. 120 
15 Appendix 3: Clinically notable laboratory values ........................................................... 123 
16 Appendix 4:  Blinding and unblinding ............................................................................ 124 
 126 
 
 130 
List of tables 
 
 
 58 
 
 59 
 
 
 60 
 
 74 
 
 96 
Table 9-1 
Standard Deviation of SPPB ............................................................... 108 
Table 9-2 
Power calculation for statistical significance in Part A ...................... 108 
 
 109 
Table 9-4 
Optimal contrasts used for the power calculation ............................... 110 
Table 9-5 
Overall power of Part B taking into consideration Part A outcome ... 110 
 
 
 111 
Table 9-7 
Variability in 6MWT ........................................................................... 111 
 
 
 111 
Table 14-1 
Liver Event Definitions ....................................................................... 120 
Table 14-2 
Liver Event Follow Up Requirements ................................................ 120 


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Table 15-1 
Clinically notable lab values ............................................................... 123 
Table 16-1 
Blinding levels .................................................................................... 124 
List of figures 
 
 43 
 
 
 44 
Figure 3-1 
Study Design: Part A ............................................................................. 47 
Figure 3-2 
Study Flow Diagram ............................................................................. 48 
Figure 3-3 
Study Design: Part B ............................................................................. 49 
 
 104 


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List of abbreviations 
6MWT 
6 minute walk test 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
adverse event 
AICD 
Automated Implantable Cardioverter-Defibrillator 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
ActRIIA/B 
type II activin receptors A and B 
ASMI 
Appendicular skeletal mass/muscle index 
AST 
aspartate aminotransferase 
BMI 
Body Mass Index 
BUN 
blood urea nitrogen 
CD-ROM 
compact disc – read only memory 
CFR 
Code of Federal Regulation 
CK 
creatinine kinase 
CMR 
cardiac magnetic resonance imaging 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EoS 
End of Study 
EoT 
End of Treatment 
EWGSOP 
European Working Group on Sarcopenia in Older People 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 


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FNIH 
Foundation for the National Institutes of Health 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GDF-11 
Growth differentiation factor 11 
γ-GT 
Gamma-glutamyl transferase 
GS 
Gait speed 
h 
hour 
HIV 
human immunodeficiency virus 
IA 
 interim analysis 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
i.v. 
intravenous 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LBM 
lean body mass 
LFT 
Liver function test (raised serum transaminases and/or bilirubin levels) 
LIVI 
liquid in vial 
LLQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities  
mg 
Milligram(s) 
MI 
Myocardial infarction 
ml 
milliliter(s) 
MMSE 
Mini Mental State Examination 
ONS 
Oral Nutritional Supplement 
 
 
PD 
pharmacodynamic(s) 
 
 
 
 
 
 
 
 
PP 
per protocol 


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PRO 
Patient Reported Outcome 
RBC 
red blood cell(s) 
REB 
Research Ethics Board 
RVR 
Rapid ventricular rate / response 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
Statistical analysis plan 
s.c. 
subcutaneous 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SHBG 
Sex hormone-binding globulin 
SI 
Systems International 
sIBM 
Sporadic Inclusion Body Myositis 
SPPB 
Short Physical Performance Battery 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
SVT 
Supraventricular tachycardia 
TBL 
total bilirubin 
TGF-β 
transforming growth factor beta 
TMDD 
target mediated drug disposition 
TMV 
thigh muscle volume 
ULN 
upper limit of normal 
ULOQ 
upper limit of quantification 
WBC 
white blood cell(s) 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
Point/time of subject entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The study 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.  
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. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, 
titration, washout, etc. 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned. 
Randomization number 
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment 
Study phase 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Study completion 
Point/time at which the subject came in for a final evaluation 
visit or when study drug was discontinued whichever is later 
Study drug/treatment 
Any drug (or combination of drugs) administered to the subject 
as part of the required study procedures; includes investigational 
drug, active drug run-ins or background therapy 


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Study drug discontinuation 
Point/time when subject permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
subject withdrawal 
Patient Number 
A number assigned to each subject/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 3 (October 2017)  
Amendment rationale  
The primary purpose of this amendment is to present 
 the 
resultant modifications to the protocol, and to adjust the sample size to enable program 
decision making at the completion of Part A. In addition, editorial revisions were made to 
clarify the terminology of the oral nutritional supplement and to improve understanding in 
other areas of the text. 
 
 
 
 
 
 
 
The results from Part A will be used for strategic decision making within the bimagrumab 
program. To ensure an adequate sample size will be available for the interim analysis 
following Part A, the total number of patients randomized has been increased from 150 to 196. 
The additional patients will increase the predicted power for interpretable results based on the 
original calculation, using estimates of the minimum and maximum variability expected in the 
SPPB data. 
The term “protein supplement” was used in prior versions of the protocol to describe a 
nutritional supplement that contained a certain amount of dietary protein and other macro- and 
micronutrients. In order to eliminate confusion by using more universally understood 
terminology, “protein supplement” has been replaced with “oral nutritional supplement” to 
more accurately reflect the product intended to be consumed by the patient. The actual 
product used should not be changed.  
Changes to the protocol 
Assessment Schedule, Section 3.1 Study design, Section 6 Visit assessments Section 13 
Appendix 1: Sample log table – all matrices,  
• Clinical chemistry samples added at Week 3, 5, and 9. 
Protocol synopsis 
• Updated to reflect changes throughout the protocol. 
Section 3.1 Study design, Section 3.5 Purpose and timing of interim analyses/design 
adaptations, Section 4 Population, Section 5.2 Treatment arms, Section 5.5 Treating the 
patient 
• Total number of patients enrolled until the end of Part A was updated to 196, to 
include 100 patients randomized to BYM338 700 mg and 60 patients randomized to 
placebo. 


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• Total number of patients to be enrolled in Part B and randomization ratio of Part B 
was clarified. 
• Total number of patients to be enrolled in the entire study (Parts A and B) updated to 
339. 
• Study Flow Diagram (Figure 3-2) clarified. 
Section 3.1 Study design 
• Updated to remove reference to electronic diaries. 
Section 3.1.2 Interim Analysis and Section 9.4.2.1 Analysis for part-A 
• The interim analysis may include additional endpoints of safety, efficacy, 
 and 
background treatments. 
Section 3.2 Rationale for study design, Section 4.1 Inclusion criteria, Section 5.1.2 Additional 
study treatment, Section 5.5.3.2 Handling of other study treatments, Section 6.2 Dietary 
Requirement and throughout the protocol 
• Protein supplementation terminology updated to oral nutritional supplementation. 
 
 
 
Section 4.2 Exclusion criteria 
• 
 
 
• Criterion #25 clarified to note that active infection results must be received prior to 
randomization. 
• 
 
Section 5.5.6 Recommended treatment of adverse events 
• 
. 
Section 6.5.7 Mini Mental State Examination (MMSE) 
• Clarified that MMSE is not required at baseline, as per the Assessment Schedule. 
 
 
 
 
 
 
 
Section 9.4.2.1 Analysis for part-A 
• Criterion 1 significant difference updated from one-sided 5% level to one-sided 2.5% 
level. 
• The two-sided confidence interval of treatment vs placebo was updated from 90% to 
95%. 


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Section 9.6 Sample size calculation 
• Sample size calculations for Part A interim analysis updated.  
Section 9.7 Power for analysis of key secondary variables 
• Analysis of power for key secondary variables updated for gait speed and 6-minute 
walk test. 
Section 15 Appendix 3: Clinically notable laboratory values 
• 
 
Section 16 Appendix 4: Blinding and unblinding 
• Footnote added to clarify that if the study is terminated following the interim analysis, 
blinding will follow the final database lock event guidelines.  
Additional administrative clarifications and corrections have been made throughout the 
protocol for clarity. 
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. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  
 


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Amendment 2 (September 2016) 
Amendment rational 
The purpose of this amendment is to align the study design and endpoints with progress made 
in the field of sarcopenia and the bimagrumab program since the original protocol was 
submitted, integrate new safety data from recently completed bimagrumab studies, facilitate 
recruitment, and reduce patient and site burden where possible.  
There are two key design changes in this amendment: change in the primary outcome and 
division of dose evaluations into two parts. The Short Physical Performance Battery (SPPB) 
will replace the 6-Minute Walk Test (6MWT) as the primary outcome, and the 6MWT will 
become a secondary outcome. This change is based on a combination of factors identified 
from the medical literature and observed in discussions with health authorities since the 
original protocol was written. The measurement properties of the SPPB are supported by an 
extensive history and body of literature that show a strong link between declining lower 
extremity functional status and adverse, clinically relevant outcomes in older adults, including 
falls, hospitalizations, incident disability and death (Guralnik et al 1994, Guralnik et al 1995, 
Guralnik et al 2000, Studenski et al 2011). The 6MWT was chosen originally as the primary 
outcome based on the large, clinically relevant improvement observed in the sarcopenia proof 
of concept study (CBYM338X2201, unpublished data), where the SPPB was not included. In 
contrast to the SPPB, the 6MWT assesses mobility and is more clinically relevant in other 
patient populations, such as those with cardiovascular or pulmonary disease or multiple 
sclerosis (Morris et al 2014; ATS 2002; Brown and Simnad 2016). 
The SPPB score and 4-meter gait speed have emerged as the predominant characteristics that 
define inadequate lower extremity function in older adults in general and in those with 
sarcopenia and frailty in particular (Studenski et al 2014). The SPPB has been used recently as 
the primary outcome variable in intervention trials examining functional recovery following 
hip fracture (Latham et al 2014, Prestmo et al 2015). In a large US based study (LIFE Study) 
evaluating an exercise and diet intervention in older adults, the SPPB was a key outcome that 
demonstrated an improvement of ≥1 point was associated with a significant reduction in falls 
and the baseline score predicted onset of mobility disability (Pahor et al 2014). 
The original four arm parallel design with three dose levels will become a two part study, to 
reduce the number of patients exposed to an experimental therapy until data are obtained that 
demonstrate the efficaciousness of bimagrumab to improve functional status in patients with 
sarcopenia, as assessed by the SPPB. This study is the first to assess the SPPB in patients with 
sarcopenia administered bimagrumab. Therefore, Part A will determine the effect of the 
highest dose level (700 mg) of bimagrumab on total SPPB score compared to placebo in this 
population. 
 
 
 


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Intensive (monthly) monitoring of certain safety parameters (physical exam, ECG, 
hematology, clinical chemistry, cardiac panel, vitamin D level, coagulation and urinalysis) is 
being replaced with a frequency aligned with standard clinical care, based on the absence of 
safety signals in the clinical program. As an example, coagulation monitoring, originally 
included because of observations of epistaxis with a competitor molecule using a different 
mechanism of action, is being reduced due to the absence of bleeding associated adverse 
events reported in the bimagrumab program. 
 
 
 
 
 Echocardiography has 
been used in studies with healthy volunteers and patients to monitor changes in cardiac 
structure and function in response to preclinical findings of a compensatory hypertrophy. 
 
 
 
 
 
 
 
 
 
 
 
Requirement for adjudication of orthopedic complications has also been removed from the 
protocol. This adjudication process was designed for a parallel indication (hip fracture) and 
the events to be adjudicated do not apply to a sarcopenia population. 
While adequate nutrition and body weight stability remain important, comprehensive diet 
assessment beyond qualification will only be required if there is an indication of malnutrition 
from another assessment or if there is a change in body weight of ±5% from baseline. 
Revisions to the inclusion and exclusion criteria should broaden participant eligibility without 
compromising safety. Minimum body weight will be lowered from 40 kg to 35 kg to 
accommodate the normal lower body weight of older adults in Asian countries. Particular 
conditions often seen in older adults (e.g., depression) that are well-managed may be 
considered if the patient is able to comply with all study procedures. In addition, the Mini 
Mental State Examination (MMSE) score for inclusion into the study has been lowered from 
24 to 21 to include patients with mild cognitive impairment who are able to comply with 
study activities and to accommodate a limitation of the instrument in people with lower 
education levels, experienced in several countries. Other criteria that were overlapping or not 
clearly described have been clarified. 


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In line with 
decreasing the study burden for patients, the frequency of efficacy 
 assessments has 
also been reduced. 
 
 
 
At the time of this amendment, approximately 65 patients have been enrolled in the study. 
All patients enrolled in the study prior to this amendment will continue on the treatment arm 
they were randomized to, but will be switched to the new assessment schedule at their next 
study visit (assessment schedule for Parts A and B are the same). Patients who have 
undergone a baseline echocardiogram under a prior version of the protocol will have a follow 
up assessment at study end of treatment (EOT). All patients who receive study drug will be 
included in the safety and efficacy analyses as described in the analysis plan in this protocol.  
Changes to the protocol 
Title Page 
• Study branding (InvestiGAIT) added to study title. 
• Removal of ‘parallel group’ in line with the new study design. 
Protocol Synopsis 
• Amended to reflect changes throughout the protocol. 
Assessment Schedule 
• Elimination of the following assessments: 
o Echocardiography (will only be performed at EOT for patients enrolled prior to 
this amendment who have received a baseline scan). A footnote (#12) has been 
added to specify the same. 
o FSH, LH and Sex hormone-binding globulin (SHBG) 
o Coagulation parameters 
o 
 
o 
 
o 
 
o 
 


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• Reduction in frequency of the following assessments: 
o Physical examination (removed at visits 102, 103, 105 and 106). 
o Height (removed at EOS). 
o Body temperature, blood pressure / pulse rate removed at visit 101 in order to 
avoid duplication where visits are combined. 
o Electrocardiogram (removed at visits 101, 102, 103, 105, 106 and EOS). 
o Hematology and clinical chemistry (removed at visits 101, 103, 105 and 106 
but added at visit 104). 
o Testosterone and urinalysis (now only performed at screening (visit 1) for 
eligibility). 
o Cardiac panel (removed at visits 101, 102 and 103). 
o Vitamin D quantification (removed at visits 103, 105 and EOS but added at 
visit 104). 
o 6 minute walk test (removed at visits 102, 103, 105, 106 and EOS). 
o 
 
o SPPB (removed at visits 102, 105 and EOS). 
o 
 
o 
 
 
 
o Diet assessment (removed at visits 102, 103, 104, 105 and 106 unless 
malnutrition is indicated or a change in weight of ±5% occurs). A footnote 
(#11) has been added to specify this. 
o 
 
o 
 
o 
 
o 
 
o 
 
 
• Footnote #9 added to state that visits 2 & 3 (run-in) and visits 5 & 101 (baseline and 
Day 1) may be combined where feasible and considered safe for the patient, in order to 
reduce the study burden for patients. 
Introduction (Background) 
• Human safety and tolerability data updated with latest information. 
• Human pharmacodynamic data with latest information. 
Objectives 
• Primary objective amended to SPPB and 6MWT moved to secondary objectives. 
• 
 
• Minor changes or clarifications to other objectives. 


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Section 3.1 Study design 
• Amended to provide details of Parts A and B purpose and design. 
• Details of interim analysis added. 
• Study design diagrams amended. 
• Drug treatment assignment updated to include Parts A and B. 
• Removal of reference to timing of specific assessments throughout to simplify and 
avoid inconsistencies with other protocol sections. 
• Text added to state that visits 2 & 3 (run-in) and visits 5 & 101 (baseline and Day 1) 
may be combined. 
• Adjustment of requirement for observation following dosing. 
Section 3.2 Rationale for study design 
• Updated with rationale for changes to population, 2-part study design and study 
outcomes. 
Section 3.3 Rationale for dose/regimen, duration of treatment 
• Updated with rationale for dose levels and changes in body weight requirements. 
Section 3.5 Purpose and timing of interim analyses/design adaptations 
• Added information on the purpose and details of the planned IA. 
Section 3.6 Risks and benefits 
• Updated risks in line with new study data, including readouts from 
 
 and hormone safety study (CBYM338X2108). 
Section 4.1 Inclusion Criteria 
• Inclusion criteria #4: clarification that Appendicular skeletal muscle index (ASMI) 
eligibility should be based on the central reading and update to allow possibility of 
other Asian countries in addition to the ones previously considered. 
• Addition of inclusion criterion #5: SPPB score of ≤9 at screening, to reduce the risk of 
a ceiling effect on this endpoint. 
• Inclusion criterion #6 (previously #5):   
o lower weight limit reduced to 35.0 kg based on feedback from sites in Japan 
and in order to align this criterion throughout the bimagrumab program.   
o BMI lower limit is reduced to 15.0 kg/m2 based on feedback from sites in 
Japan and in order to align this criterion throughout the bimagrumab program. 
o BMI upper limit is raised to 32.0 kg/m2 based on feedback from investigators. 
Section 4.2 Exclusion Criteria 
• Addition of statement allowing repeat of out of range values once prior to run-in and 
clarification that laboratory parameters are assessed centrally. 
• 
 
• Exclusion criterion #1: clarified to ensure that subjects with well managed 
musculoskeletal pain are not excluded. 


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• Exclusion criterion #2: clarified that subjects with adequately treated depression are 
not excluded. 
• Exclusion criterion #4 modified to incorporate muscle diseases from exclusion 
criterion #11 (e.g., myopathy), and exclusion #11 deleted. 
• Exclusion criterion #6: addition of Systems International (SI) units 
• Exclusion criterion #7:  lower limit for hemoglobin at screening changed to 10.0 g/dL 
for women, to account for the difference in normal ranges between men and women 
and additional of SI units. 
• 
 
• Exclusion criteria #11 (previously #13): clarified that subjects with well managed 
gastrointestinal diseases may be included. 
• Exclusion criterion #14 (previously #17): amended to remove hypertrophic 
cardiomyopathy based on latest data on cardiac safety. 
• 
 
• Exclusion criterion #15, 16, 17 and 18 (previously #’s 18, 19, 20 and 22): amended 
cardiac exclusions to reflect the latest safety information and to align with the most 
recent exclusion criteria in the bimagrumab program.  
• Exclusion criterion #21 has been removed. This criterion had been utilized as a 
standard exclusion in healthy volunteer studies.
 
 
• 
 
 
• Exclusion criteria #29 (previously #34): clarification that only regular (e.g. daily) 
assistance with basic activities of daily living (ADL) is excluded and that assistance 
with instrumental ADL is permitted. 
• Exclusion criterion #30 (previously #36) amended to lower the MMSE cutoff to 21. 
• Exclusion criteria #33 (previously #39): amended text to clarify that only systemic 
corticosteroids are excluded. 
• 
 
 
• 
 
Section 5.1.2 Additional study treatment 
• Updated to clarify that nutritional supplements are required for the study. 
Section 5.2 Treatment arms 
• Updated with details of Parts A and B. 
Section 5.3 Treatment assignment 
• Clarification that the randomization number is for internal use only. 


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Section 5.4 Treatment blinding 
• Clarification of a fourth method to maintain the blind in the study, i.e. any potentially 
unblinding parameters will not be made available to the patient, site or study team. 
Section 5.5.1 Patient numbering 
• Amendment of randomization number text in line with the actual IRT process in use 
for the study. 
• Addition of details on randomization schemes prior to amendment, and following 
amendment (Parts A and B). 
Section 5.5.2 Dispensing the study treatment 
• Updated to align with other bimagrumab studies and to remove duplication of text. 
Section 5.5.3.2 Handling of other study treatments 
• Added clarification of vitamin D supplementation 
• 
 
Section 5.5.6 Recommended treatment of adverse events 
• The recommendation for the treatment of acute allergic reactions has been moved to 
Section 5.5.6 (previously included in Section 5.5.7). 
Section 5.5.8 Concomitant treatment 
• Updated in line with the latest protocol template language 
 
 
 
 
Section 5.5.10 Discontinuation of study treatment 
• Update of study stopping rules to remove hypersensitivity reaction in alignment with 
other bimagrumab studies and to avoid overlap with the second stopping criteria. 
• Update of individual subject withdrawal rules:
 
 
Section 6 Visit assessments 
• Expansion of the visit windows based on feedback from sites and in line with other 
studies in the bimagrumab program. 
• Text added to state that visits 2 & 3 (run-in) and visits 5 & 101 (baseline and Day 1) 
may be combined. 
• Order of assessments updated according to new assessment schedule. 
Section 6.1 Dietary, fluid and other restrictions 
• Removal of restriction on alcohol during the study as this is primarily a requirement in 
healthy volunteer studies. 
• Removal of requirement for fluid intake due to reduced need for urine collection. 


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Section 6.2 Dietary Requirement 
• Adjustment of the requirements for nutritional assessment and counselling – this will 
now only be required if a change in weight of ±5% is observed. 
• 
 
Section 6.5 Efficacy / Pharmacodynamic assessments 
• Re-ordering of sections to reflect change in study outcomes. 
 
 
 
Section 6.5.5 (previously Section 6.5.6) Total lean body mass and appendicular skeletal mass 
index (ASMI) assessed by DXA 
• Clarification that the images acquired will be independently reviewed by a central 
reading vendor. 
 
 
 
 
 
 
 
 
Section 6.5.7 Mini Mental State Examination (MMSE) 
• Adjustment of the score required for eligibility to 21 
 
 
 
Section 6.6.4 Laboratory evaluations 
• Removal of coagulation parameters 
• Removal of FSH, LH and SHBG from hormone panel 
Section 6.6.6 Echocardiography 
• Removal of section 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 7.1 Adverse events 
• Addition of new field on AE eCRF documenting the AE classification. 
• Addition of text regarding collection of information on adverse events of special 
interest. 
Section 8.4 Data Monitoring Committee 
• Amendment of language due to new fully unblinded review of data by DMC. 
Section 8.5 Adjudication Committee 
• Removal of requirement for orthopedic adjudication which does not make sense in this 
population. 
Section 9 Data analysis 
• All sections updated in line with new study outcomes and associated analyses. 
Section 12 References 
• Addition of 19 new references 
Appendix 1: Sample log table – all matrices 
• 
 
 
• Removal of urinalysis sampling at V4, 101, 103, 105, EOT and EOS. 
• 
 
• 
 
Appendix 3: Clinically notable laboratory values 
• Addition of this new appendix to define the criteria to be used as a guidance for 
notable abnormalities of key laboratory tests. 
 
 
 
Minor changes have been made throughout the protocol to improve clarity. 
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. 
A copy of this amended protocol will be sent to the participating Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent Form (ICF) that takes into account the changes 
described in this protocol amendment. Novartis will provide an updated model ICF to sites.  


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Amendment 1 (May 2015) 
Amendment rationale 
The purpose of this amendment is to correct minor inconsistencies identified during health 
authority and ethics committee reviews, and to provide some clarifications on study 
assessments. 
At the time of implementing this amendment, 3 patients had begun treatment; none were 
affected by changes made to the protocol.  The changes described in this amendment do not 
affect the objectives of the study, impact the safety of the subjects or change the analysis of 
the study data.  Some adjustments have been made to inclusion and exclusion criteria as a 
result of experience so far with the population required for this study. 
Changes to the protocol 
Protocol Synopsis 
• Amended to reflect changes throughout the protocol 
Assessment Schedule 
• Addition of visit windows. 
• Addition of Informed Consent to assessment schedule (already present in protocol but 
previously omitted from assessment schedule). 
• 
 
• 
 
• Amendments due to change in follow-up period for patients continuing to the 
extension: 
• Movement of height measurement and 
 from EoS visit to 
EoT visit to provide data for extension study baseline. 
• Removal of footnote for prematurely discontinuing patients to only return for EoS 
visit. 
• Addition of footnotes stating that EoT visit will occur 4 weeks after last dose and 
will be the last visit for patients continuing to the extension study, and EoS visit 
will occur 4 weeks after EoT visit except for patients continuing to the extension 
study. 
• ‘Study Completion information’ changed to ‘Phase Completion’ and assessment 
added at Baseline V2 and EoT to be in compliance with current database requirements. 
Section 3.1 Study design 
• Correction to add follow-up period to the diagram. 
• Correction to assessments at Day 1 due to inconsistency with the Assessment 
Schedule. 
• Addition of information on observation period following dosing on ‘Other Dosing 
Visits – Days 29, 57, 85, 113 and 141’. 


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• Explanation that patients continuing to the extension study will move directly from 
EoT visit to Visit 1 of the extension. 
• Clarification that EoS visit will occur only for those patients discontinuing from the 
study prematurely or those not continuing to the extension study. 
• Addition of information on planned extension study. 
Section 3.6.1 BYM-related risks 
• Text describing a standardized dermatology assessment removed. This is no longer 
needed as adverse event recording is sufficient. 
Section 4.1 Inclusion criteria: 
• Inclusion criterion #6:  Dietary criteria to apply only at baseline, allowing correction 
of nutritional deficiency during screening period if appropriate. 
Section 4.2 Exclusion criteria: 
• Exclusion criterion #5:  Amendment to state that intraocular surgery or intraocular 
laser procedures for refractive corrections are excluded. 
• Exclusion criterion #6:  Vitamin D criteria to apply only at baseline, allowing 
correction of low vitamin D levels at screening if appropriate. 
• Exclusion criterion #11:  Addition of inclusion body myositis in the examples for 
exclusion. 
• Exclusion criterion #12:  Addition of other systemic autoimmune disease requiring 
immunosuppressive therapy or corticosteroids to exclusion. 
• Exclusion criterion #35:  Amendment to allow patients receiving testosterone 
replacement therapy. 
• Exclusion criterion #39:  Clarification that medication exclusion applies prior to 
screening. 
• Exclusion criterion #40:  Clarification to exclude patients taking a systemic VEGF 
inhibitor and the acceptability of intravitreal use. 
Section 5.5.1 Patient numbering 
• Correction and clarification of randomization process with IRT system. 
Section 5.5.3 Handling of study treatment 
• Adjustment of concomitant vitamin D requirements to allow for sourcing in all 
countries. 
 
 
 
 
Section 5.5.10 Discontinuation of study treatment 
• Amendment of study completion requirements for patients who discontinue treatment 
early to ensure compliance with required safety follow-up timelines and consistency 
with the planned extension study. 


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Section 6.2.2 Nutritional supplement 
• Adjustment of concomitant vitamin D requirements to allow for sourcing in all 
countries. 
• Addition of low vitamin D correction with a loading dose. 
Section 6.5.3 6 minute walk test 
• Text added to clarify the conditions under which a test could be repeated. 
Section 6.5.6 Patient Reported Outcomes 
• Clarifications of PRO terminology 
• 
 
Section 6.6.2 Vital signs 
• Clarification that vital signs should be measured on the same arm at each visit where 
possible. 
Section 6.6.4 Laboratory evaluations 
• Clarification of situations where repeat assessments can be performed. 
• Addition of creatinine to the chemistry panel to support the evaluation of eGFR for 
inclusion/exclusion. 
Section 6.6.7 Pregnancy 
• Removal of requirement for sexually active men to use a condom during the course of 
the study in alignment with the rest of the bimagrumab program, as there is no 
associated risk with this antibody. 
 
 
 
Section 8.5 Adjudication committee 
• Addition of orthopedic event adjudication 
Section 10.2 Informed consent procedures 
• 
 
 
Appendix 1: Sample log table 
• Corrections to blood volumes following final setup and reconciliation with the central 
lab, and correcting an error which occurred during insertion of the table.  
 
 
• 
 
 


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Protocol synopsis 
Protocol number 
CBYM338E2202 
Title 
A 28 week, randomized, double-blind, placebo-controlled, two-part, multi-
center, parallel group dose range finding study to assess the effect of 
monthly doses of bimagrumab 70, 210, and 700 mg on skeletal muscle 
strength and function in older adults with sarcopenia (InvestiGAIT). 
Brief title 
Dose range finding study to assess multiple doses and evaluate safety and 
tolerability of bimagrumab in patients with sarcopenia. 
Sponsor and Clinical 
Phase 
Novartis  
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to determine the efficacy of repeat dosing with 
multiple dose levels of bimagrumab on patient function, skeletal muscle mass 
and strength in older adults with sarcopenia. In addition, this study will 
generate data on the safety, tolerability, 
 of 
bimagrumab in older adults with sarcopenia. 
The randomized, parallel group, placebo-controlled design will allow an 
unbiased comparison between 3 different dose regimens of bimagrumab and 
placebo on changes in muscle quantity and patient physical function in a 
population of older adults with sarcopenia 
Primary Objective(s) 
• 
To assess the effect of 24-weeks of bimagrumab treatment on 
patient physical function assessed by a change in the Short Physical 
Performance Battery (SPPB) total score from baseline to week 25 
relative to placebo in older adults with sarcopenia. 
Secondary Objectives 
• 
To assess the effect of multiple doses of bimagrumab on the safety 
and tolerability of bimagrumab administered over 24 weeks as 
measured by vital signs, clinical laboratory values, 
electrocardiogram (ECG), echocardiogram (in a limited number of 
patients), and adverse events (AE) compared to placebo in older 
adults with sarcopenia.  
• 
To assess the effect of bimagrumab compared to placebo on 
improvement in physical performance as measured by change from 
baseline to week 25 in the 6-Minute Walk Test (6MWT) distance in 
older adults with sarcopenia.  
• 
To assess the effect of bimagrumab compared to placebo on 
improvement in mobility as measured by change from baseline to 
week 25 in usual gait speed (GS) over 4 meters in older adults with 
sarcopenia. 
• 
To assess the effect of bimagrumab on total lean body mass and 
appendicular skeletal muscle index (ASMI) measured by DXA, 
assessed by the change from baseline to week 25 compared to 
placebo in older adults with sarcopenia. 


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Study design 
A two-part, randomized, double-blind, placebo-controlled, parallel group 
study design with approximately 339 older adults with sarcopenia assigned to 
one of four treatment groups: placebo, bimagrumab 70 mg, bimagrumab 
210 mg, or bimagrumab 700 mg. 
The study will consist of a 20-day screening period followed by a 28-day run-
in period, and a 24-week treatment period followed by a 4-week follow-up 
period. During the run-in period, all subjects will be introduced to a 3 times 
per week exercise program, daily vitamin D and oral nutritional 
supplementation, and the performance-based endpoints. Towards the end of 
the run-in period, subjects will be re-assessed for eligibility (utilizing the 
baseline eligibility criteria) and qualified subjects will enter the treatment 
phase to receive six monthly doses of assigned study drug. 
Population 
The study population will be community-dwelling men and women ages 70 
years and older meeting the criteria for sarcopenia as defined by the 
European Working Group on Sarcopenia in Older People (EWGSOP)  
(Cruz-Jentoft et al 2010) and Asian Working Group for Sarcopenia 
(Chen et al 2014). 
Inclusion criteria 
1. Written informed consent must be obtained before any assessment is 
performed; 
2. Men and postmenopausal women aged 70 years or older at screening 
with self-reported mobility limitations such as difficulty standing up from a 
chair, walking for longer than 10 minutes on a flat surface or climbing a 
flight of stairs; 
• 
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. 
3. Gait speed over 4 meters of <0.8 m/s but ≥0.3 m/s at screening and 
baseline; 
4. Appendicular skeletal muscle index (skeletal muscle in kg/ height in m2) 
by DXA based on central reading: 
• 
≤ 7.26 kg/m2 for men and ≤ 5.5 kg/m2 for women to be assessed 
during screening.   
• 
ASIAN COUNTRIES ONLY: ≤ 7.0 kg/m2 for men and ≤ 5.4 kg/m2 for 
women to be assessed during screening; 
5. Total SPPB score of ≤9 at screening and baseline; 
6. Weigh at least 35.0 kg to participate in the study and have a body mass 
index (BMI) within the range of 15.0 – 32.0 kg/m2;  
7. Usual dietary intake ≥ 20 kcal/kg body weight and ≥ 0.8 g protein/kg per 
day over the 4 weeks prior to baseline estimated by an established 
method of diet assessment (i.e. 24 hour recalls, food records or similar) 


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Exclusion criteria 
Medical conditions limiting performance of physical assessments 
1. History of a lower limb fracture (e.g. femur, tibia) within the past 6 months 
with persistent negative impact on lower extremity function or any 
significant impairment or disease adversely impacting gait (e.g. 
intermittent claudication in advanced peripheral vascular disease, spinal 
stenosis, or severe osteoarthritis of the knee or hip with joint pain not 
controlled with medication/injections that adversely impacts mobility); 
2. Confirmed diagnosis of significant psychiatric disease (e.g. 
dementia/Alzheimer's disease, schizophrenia, depression or bipolar disorder). 
Individuals with adequately treated depression are eligible for enrollment; 
3. A Patient Health Questionnaire – 9 (PHQ-9) score ≥ 10 at screening; 
4. Neurological injury/disorder with significant persistent functional deficit 
(e.g. stroke with hemiparesis, spinal cord injury, muscular dystrophy, 
polymyositis, dermatomyositis, myopathy/myositides, myasthenia gravis, 
Parkinson’s disease, peripheral polyneuropathy); 
5. Intraocular surgery and laser procedures for refractive correction within 
6 months prior to screening; 
6. Vitamin D deficiency defined as 25-OH-vitamin D levels < 12.0 ng/mL 
(30nmol/L) at baseline; 
7. Hemoglobin concentration below 11.0 g/dL (110g/L) for men or below 
10.0 g/dL (100g/L) for women at screening. 
Medical conditions associated with muscle loss  
8. Chronic kidney disease [estimated glomerular filtration rate (GFR)  
< 30 mL/min]; 
9. History of confirmed chronic obstructive pulmonary disease with a 
severity grade > 2 on the Medical Research Council Dyspnea Scale; 
10. Confirmed rheumatoid arthritis or other systemic autoimmune disease 
requiring immunosuppressive therapy or corticosteroids > 10mg/d 
prednisone equivalent, acquired immunodeficiency syndrome (AIDS), or 
type 1 diabetes mellitus; 
11. History of or ongoing gastrointestinal diseases known to cause 
malabsorption of protein or energy, such as inflammatory bowel disease, 
celiac disease, short bowel syndrome, pancreatic insufficiency. 
Individuals in which the disease is well controlled with 
medication/enzyme supplements (e.g., pancreatic insufficiency) or dietary 
modification (e.g., celiac disease) are eligible for enrollment; 
Liver 
 related conditions 
12. Abnormal liver function tests such as SGOT (AST), SGPT (ALT), alkaline 
phosphatase, or serum bilirubin (except Gilbert’s Disease), 
 
. The investigator 
should be guided by the following criteria: 
• 
Any single transaminase may not exceed 3x the upper limit of normal 
(ULN). A single parameter elevated up to and including 3x ULN 
should be re-checked as soon as possible, and always prior to 
enrollment/randomization, to rule out any lab error. 
• 
If the total bilirubin concentration is increased above the ULN, total 
bilirubin should be differentiated into the direct and indirect reacting 
bilirubin. In any case, serum bilirubin should not exceed the value of 
1.6 mg/dL (27μmol/L). 
• 
 
 


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13. Known history or presence of severe active 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); 
Cardiovascular conditions 
14. Confirmed diagnosis of heart failure classified as New York Heart 
Association Class III and IV (e.g. dilated cardiomyopathy); 
15. Myocardial infarction, coronary artery bypass graft surgery, percutaneous 
coronary intervention (e.g. angioplasty or stent placement), or deep vein 
thrombosis/pulmonary embolism within 12 weeks of screening. Patients 
with current/active unstable angina are excluded; 
16. Severe cardiac valve disorders or defects (e.g. aortic or mitral stenosis); 
17. Severe pulmonary hypertension uncontrolled with medication; 
18.  Clinically significant cardiac arrhythmia requiring medical intervention in 
the past 3 months (e.g.  SVT, atrial fibrillation with RVR, AICD with 
discharge ); 
Other medical or living conditions 
19. History of hypersensitivity to therapeutically administered antibodies. 
20. Chest pain, severe shortness of breath, or occurrence of other safety 
concerns during the screening or baseline assessments. 
21. Lack of peripheral venous access 
22. Active cancer (i.e., under current treatment), or cancer requiring 
treatment in the last 5 years excluding nonmelanoma skin cancers or 
cancers with excellent prognosis (e.g., early stage prostate or breast 
cancer, carcinoma in situ of the uterine cervix); 
23. Significant coagulopathy, platelet count less than 75,000/mm3; 
24. Active systemic infection requiring hospitalization or treatment with i.v. 
anti-infectives or antibiotics within 4 weeks of screening; 
25. Any chronic active infection (e.g., HIV, hepatitis B or C, tuberculosis, etc), 
to be confirmed prior to randomization. Subjects receiving 
chemoprophylaxis for latent tuberculosis infection are eligible for the 
study; 
26. Active alcohol/drug abuse, or alcohol/drug treatment < 12 months prior to 
screening; subjects having successfully completed an alcohol/drug 
treatment program >12 months prior to screening with sustained 
abstinence are eligible; 
27. Subject has any medical condition or laboratory finding during screening 
(e.g. an unexplained or clinically significant lab result), which, in the 
opinion of the investigator may interfere with participation in the study, 
might confound the results of the study, or pose an additional safety risk 
in administering bimagrumab; 
28. Subject plans to move out of the study area within 12 months or be out of 
study area for > 4 weeks continuously; 
29. Individuals who require routine and regular (e.g., daily) assistance from 
another person to complete one or more basic activities of daily living 
(basic ADL; bathing, dressing, toileting, feeding, grooming) regardless of 
where they reside. Assistance with instrumental ADL (i.e., shopping, 
meal preparation, housework) is permitted; 


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30. Subjects with a Mini Mental State Examination score < 21 at screening; 
Prohibited medication 
Investigational and 
reference therapy 
Placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg 
Efficacy assessments 
• 
Short Physical Performance Battery (SPPB) to assess functional 
status 
• 
6 minute walk test (6MWT) to assess functional status 
• 
 


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• 
Gait speed (GS) to assess functional status 
• 
Total lean body mass (LBM) and appendicular skeletal mass index 
(ASMI) assessed by DXA to measure lean body mass and skeletal 
muscle mass of the arms and legs, respectively. 
• 
Patient reported outcome questionnaires 
Safety assessments 
• 
Physical examination 
• 
Vital signs (heart rate, blood pressure) 
• 
Height and weight 
• 
Laboratory evaluations 
• 
Urinalysis 
• 
ECG 
• 
Echocardiography (at EOT only for patients enrolled prior to this 
amendment who have a baseline scan) 
• 
 
• 
 
• 
 
Other assessments 
• 
 
• 
 
Data analysis 
 
 
 
 
This is a two part study. Part-A will investigate the presence of a positive 
effect of maximum bimagrumab dose  (700 mg) over placebo in change from 
baseline SPPB score at week 25. A positive effect of bimagrumab will be 
defined as a statistically significant effect over placebo and a clinically 
relevant improvement of ≥ 1 unit increase from baseline compared to week 
25. 
 
 
 
 
 
 
Key words 
Dose range finding study, effect, safety and tolerability, bimagrumab, 
sarcopenia, muscle, physical function 


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Assessment schedule 
 


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1 
Introduction 
1.1 
Background 
Muscle regulation and the ActRII Receptors 
Several members of the transforming growth factor beta (TGF-β) superfamily, including 
myostatin, activin A, and growth differentiation factor 11 (GDF11), negatively regulate 
skeletal muscle mass in animals and humans throughout the lifecycle. Ligand signaling occurs 
via type II activin receptors (both ActRIIA and B; and the Smad 2/3 pathway), to inhibit 
muscle protein synthesis and myocyte differentiation and proliferation. The absence of any of 
these ligands in developing animals and humans results in a hypermuscular phenotype with an 
increased number and size of muscle fibers. A postpartum reduction of myostatin levels 
results in the hypertrophy of skeletal muscle due to an increase in the size of existing 
myofibers (Lee et al 2005; Lee et al 2010; Trendelenburg et al 2012). Thus, the capacity for 
modulating muscle growth by perturbing this signaling pathway at the receptor level is much 
more substantial than previously appreciated by direct anti-myostatin approaches.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scientific rationale 
Sarcopenia, the age-associated loss of skeletal muscle mass and physical function 
(Cruz-Jentoft et al 2010; Fielding et al 2011), affects approximately 30% of American men 
and women over the age of 60 and 50% older than 80 years (Baumgartner et al 1998). 
Sarcopenia is thought to result in mobility disability in 2-5% of elderly adults 
(Dam et al 2014). Loss of skeletal muscle mass and strength are common consequences of 
many chronic diseases, hospitalizations and normal aging and are strongly associated with 
morbidity, disability, mortality and loss of independence (Janssen et al 2004). A decline in 
muscle mass and strength in the elderly often manifests as reduced physical functional 


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capacity leading to lower quality of life and an increased risk of adverse health events (e.g., 
falls and fractures subsequent to falls). Currently, there is no standard treatment for the loss of 
skeletal muscle mass and function seen with aging. 
Multiple consensus groups have proposed definitions for sarcopenia based upon changes in 
muscle mass and strength and physical function. Thus, diagnosis depends on documentation 
of low muscle mass plus low muscle strength or the presence of low physical performance 
(Cruz-Jentoft et al 2010; Muscaritoli et al 2010; Fielding et al 2011; Studenski et al 2014). 
The European Working Group on Sarcopenia in Older People (EWGSOP) recommended 
thresholds for defining sarcopenia that were based on the mean muscle mass in a normative 
healthy young adult population, with cutoff points calculated as two standard deviations 
below the mean reference value. This threshold is operationalized using an ASMI (skeletal 
muscle of the upper and lower limbs in kg/height in m2) by dual energy X-ray absorptiometry 
(DXA) of ≤ 7.26 kg/m2 for men and ≤ 5.5 kg/m2 for women. A similar consensus definition on 
sarcopenia was recently published from five other collaborative special interest groups – 
“Cachexia-anorexia in chronic wasting diseases”, “International Working Group on 
Sarcopenia”, “Nutrition in Geriatrics”, the “Asian Working Group for Sarcopenia” and the 
Foundation for the National Institutes of Health Sarcopenia Project – that recommended low 
muscle mass plus usual gait speed as the preferred measure of physical function 
(Muscaritoli et al 2010; Fielding et al 2011; Chen et al 2014; Studenski et al 2014).  
The Short Physical Performance Battery (SPPB) is a series of six activities involving three 
domains of physical function – balance, usual walking speed and rising from a chair – and 
commonly used globally to assess and quantify (score 0-12) lower extremity function. 
The SPPB has been shown to predict future adverse health events. The SPPB has been 
translated into many languages in Europe and Asia and has been administered more than 
30,000 times throughout the world with no known serious adverse consequences. Recently, 
the SPPB has emerged as an outcome of interest to health authorities and others as a means to 
assess the efficacy of drugs to improve physical function in populations of older adults. 
The quantitative properties of the SPPB are supported by a long history and large body of 
literature.  Substantial data documents test-retest reliability (Studenski et al 2003, 
Freire et al 2012); construct validity (Guralnik et al 1994, Latham et al 2008); predictive 
validity for mortality (Guralnik et al 1994, Perera et al 2005), incident disability  
(Guralnik et al 1995, Guralnik et al 2000, Gill 2010), institutionalization and hospitalization 
(Guralnik et al 1994, Studenski 2009), functional decline after hospital discharge 
(Corsonello et al 2011); and sensitivity to clinically important change (Ostir et al 2002, 
Latham et al  2008, Perera et l 2006, Perera et al  2014).  The SPPB has been used as the 
primary (Pahor et al 2006, McAuley et al 2013, Latham et al 2014, Prestmo et al 2015) and 
key secondary (Pahor et al 2014) outcome in a number of randomized clinical trials. 
Easy to perform in both clinical and research environments, gait speed  is a component of the 
SPPB and commonly included in comprehensive geriatric assessment and care in many 
countries. There is a substantial body of epidemiologic and intervention based literature 
demonstrating a strong association between slowed and declining gait speed and future adverse 
physical status and health outcomes, including mortality (Studenski et al 2011). In addition, a gait 
speed of <0.8 m/s categorizes a person as “mobility impaired.” (Studenski et al 2014). The two 
gait speed cutoff points recommended in the consensus statements for the diagnosis of sarcopenia 


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are < 0.8 m/s and 1.0 m/s in the 4 m walking test to include patients at increased risk of functional 
decline (Cruz-Jentoft et al 2010; Fielding et al 2011). The largest analysis to date, of 
26,000 patients in observational data from multiple studies, further supports the 0.8 m/s cutoff 
to define the population at increased risk for adverse health events (Dam et al 2014). 
 
 
1.1.1 
Relevant data summary 
All information currently available on pharmacology, toxicology, 
, and 
pharmacodynamics has been obtained from in vitro experiments, animal trials, toxicology 
studies, and previous human studies. To date, bimagrumab has been generally safe and well 
tolerated and efficacious at increasing muscle mass in adults 19-86 years of age. Findings and 
relevant data from prior studies are briefly described below and detailed in the bimagrumab 
Investigator’s Brochure (Investigator’s Brochure). 
1.1.2 
Human safety and tolerability data 
 
 
 
 
 
 
 
 
Study results to date indicate that bimagrumab is safe and well tolerated. The current safety 
profile is favorable, with adverse events limited to several minor, transient clinical symptoms. 
Transient cases of episodic, involuntary muscle contractions (referred to as “cramps or 
spasms”), acne and diarrhea of mostly mild intensity have been observed in study participants 
 
 
However, no one in the Proof of Concept 
(PoC) study (CBYM338X2201) in participants with sarcopenia and mobility limitations dropped 
out due to an AE. 
Based on preclinical, toxicology and clinical findings to date the benefit-risk profile remains 
positive and supports continued development in patients with skeletal muscle loss who would 
benefit from increased lean tissue. The reference safety information for bimagrumab can be 
found in the Investigator’s Brochure. 


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1.2 
Study purpose 
The purpose of this study is to determine the efficacy of repeat dosing with multiple dose 
levels of bimagrumab on patient physical function, skeletal muscle mass and strength in older 
adults with sarcopenia. In addition, this study will generate data on the safety, tolerability, 
 
 of bimagrumab in this patient population. 
2 
Study objectives 
2.1 
Primary objective 
The primary objective is to assess the effect of 24-weeks of bimagrumab treatment on patient 
physical function assessed by a change in the Short Physical Performance Battery (SPPB) 
total score from baseline to week 25 relative to placebo in older adults with sarcopenia.  
2.2 
Secondary objective(s) 
• To assess the effect of bimagrumab compared to placebo on the safety and tolerability of 
multiple doses of bimagrumab administered over 24-weeks as measured by vital signs, 
clinical laboratory values, electrocardiogram (ECG), echocardiogram (in a limited number 
of patients), and adverse events (AE) in older adults with sarcopenia.  
• To assess the effect of bimagrumab compared to placebo on improvement in physical 
function as measured by a change from baseline to week 25 in the 6 minute walk test 
(6MWT) distance in older adults with sarcopenia. 
• To assess the effect of bimagrumab compared to placebo on improvement in mobility as 
measured by change from baseline to week 25 in usual gait speed (GS) over 4 meters in 
older adults with sarcopenia. 
• To assess the effect of bimagrumab on total lean body mass and appendicular skeletal 
muscle index (ASMI) measured by DXA, assessed by the change from baseline to week 
25 compared to placebo in older adults with sarcopenia. 


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3 
Investigational plan 
3.1 
Study design 
This Phase IIb study is a two-part, randomized, double-blind, placebo-controlled study design 
with approximately 339 older adults with sarcopenia assigned to one of four treatment groups: 
placebo, bimagrumab 70mg, bimagrumab 210mg, or bimagrumab 700mg,  
The study will consist of a 20-day screening period followed by a 28-day run-in period, and a 
24-week treatment period followed by a 4 week follow-up period. During the run-in period, 
all patients will be introduced to 
 
the performance-based endpoints. Towards the 
end of the run-in period, patients will be re-assessed for eligibility (utilizing the baseline 
eligibility criteria) and qualified patients will enter the treatment phase to receive six monthly 
doses of assigned study drug. Patients randomized prior to implementation of protocol 
amendment v02 will remain on their assigned treatment, but will be switched to the new 
assessment schedule at their next scheduled visit. 
 
 
 
3.1.1 
Part A 
Patients will be enrolled and randomized to receive either bimagrumab 700 mg or placebo 
(see Figure 3-1), until approximately 100 patients will have been enrolled in the bimagrumab 
arm and 60 patients in the placebo arm.  At this point, recruitment into the study will be 
paused until Part A is completed and an interim analysis conducted. 
Figure 3-1 
Study Design: Part A 
 


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3.1.2 
Interim Analysis 
An interim analysis will be performed on the bimagrumab 700mg and placebo groups at the 
completion of Part A to determine treatment efficacy. 
 
 
 
 
 
Primary analysis: To support the primary objective, the change in the Short Physical 
Performance Battery (SPPB) total score from baseline to week 25 will be compared between 
treatment groups.  
Following criteria will be evaluated at the end of Part-A 
• 
 
• 
 
 
 
  
Based on the planned use of Part A data for decision making, additional endpoints of safety 
(e.g., AEs, lab values, ECG), 
 background treatments (e.g., exercise, Vitamin D, diet), and 
efficacy (e.g., gait speed, 6MWT, 
, 
, LBM and ASMI by DXA, 
) may be included in the interim analysis.  
Figure 3-2 
Study Flow Diagram 
 


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3.1.3 
Part B 
 
 
 
 
 
 
Figure 3-3 
Study Design: Part B 
 
Assessments performed under Part A and Part B are the same (see Assessment Schedule). 
3.1.4 
Exercise program 
During screening, the ability of patients to perform the exercise program will be determined 
by a trained study staff member, to ensure patients have the ability to perform the required 
physical movements. 
 
 
 
 
 
 


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3.1.5 
Drug treatment assignment 
Part A: At the conclusion of the baseline period (Visit 5), newly recruited eligible patients will 
be randomized in a 
 ratio to receive i.v. doses of bimagrumab 700mg or placebo every 4 
weeks until Week 21 for a total of 6 doses. 
 
 End of infusion will be considered as the time of the end of 
the line flush. All times stated within this protocol are from the start of study drug 
administration (unless otherwise stated). The assessments that will be carried out at each 
visit are presented in the study Assessment schedule. 
 
 
 
 


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Study Phases 
Screening 
Visit 1 - Day -50 to -30 
Patients will be required to attend the investigator center for the screening visit (for logistical 
reasons more than 1 visit may be planned) where qualification for the study will be assessed 
by the investigator. Informed consent will be obtained prior to implementing any study 
specific procedures. 
Patients not meeting the minimum vitamin D or nutritional requirements at initial evaluation 
can be offered dietary counseling and/or receive vitamin D supplementation through their 
physician. If they are able to achieve required levels by the baseline visit, they may be 
enrolled, otherwise they will be listed as a screen failure and may be re-screened at a later 
time.  
The ability and willingness of the patient to perform the exercise program should be evaluated 
by the investigator or a team member during this visit. 
 
 
 
 
 
 
  
Only patients who meet the inclusion/exclusion criteria at screening will be eligible to 
proceed to the run-in period of the study. However: 
• Central laboratory assessments or ECG interpretations which fall outside of the 
protocol-specified range at screening can be repeated once at an unscheduled visit 
during the screening period to confirm patient eligibility prior to run-in. 
• Patients excluded for one of the temporary medical conditions listed in section 4.2 
may be rescreened after a period that is considered clinically relevant by the 
investigator.  
For a full list of assessments, please refer to the Assessment schedule. 
Run-in Period 
Visits 2-5 - Day -29 to -1  
Patients are requested to visit the clinical site in the morning, under fasted conditions for the 
blood collections. 
 
 
  
As reported above,
 
 


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. Dietary supplements will be initiated during the run-in period as well. 
 based 
on the Investigators judgement 
, 
Visits 2 and 3 may be combined and performed on one day.  Each visit will be recorded 
separately in the eCRF with the same visit date. 
For a complete list of assessments, please refer to the Assessment schedule. 
Baseline 
Visits 4 and 5 - Day -15 to -1 
These Baseline visits will occur towards the end of the run-in period. Patient eligibility will be 
rechecked, including current medical conditions and medications.  
 
  
Patient eligibility must be confirmed by the investigator via repeat evaluation of the 
inclusion/exclusion criteria prior to randomization and progression into the treatment 
period. 
 
 
All other baseline assessments should be performed during the final week of the run-in period. 
For a complete list of assessments, please refer to the Assessment schedule. 
Where the investigator deems it safe to do so, visits 5 (baseline) and 101 (Day 1) may be 
combined and performed on one day after the completion of the run-in period.  All visit 5 
(baseline) assessments must be performed pre-dose. Each visit will be recorded separately in 
the eCRF with the same visit date. 
Treatment Period 
First dosing Visit – Day 1  
Once all blood draws have occurred at this visit, the subjects can be given breakfast (if the 
patient has not already eaten).
 
The above mentioned assessments must be performed prior to administration of the first dose 
of bimagrumab. This visit may be combined with the previous visit (Visit 5). 
Time of dosing will be collected in the eCRF and appropriate documentation of the patient 
specific dispensing process must be maintained. Wherever possible, it is recommended that 
infusions occur at approximately the same time of day at each dosing visit (e.g., morning or 
afternoon). 
 
 


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Following dose administration, patients should be observed for a period of time to ensure they 
are feeling well enough to be discharged from the study site. The duration of observation can 
be approximately 10-20 minutes or longer at the discretion of the investigator. 
For a complete list of assessments, please refer to the Assessment schedule. 
Non-dosing Visit – Day 15 
Subjects should return to the clinic site for collection of clinical chemistry labs as per the 
Assessment Schedule. 
Other Dosing Visits – Days 29, 57, 85, 113, and 141 
Dosing visits must occur on the day ± the visit window specified in Section 6.  
All assessments 
 should be performed prior to dosing. 
Please refer to Section 6 and the Outcomes Manual for more details regarding the sequence of 
assessments. 
Time of dosing will be collected in the eCRF and appropriate documentation of the patient 
specific dispensing process must be maintained. Infusions should occur at approximately the 
same time of day at each dosing visit. 
 
 
 
Following dose administration, patients should be observed for a period of time to ensure they 
are feeling well enough to be discharged from the study site. The duration of observation can 
be approximately 10-20 minutes or longer at the discretion of the investigator. 
For a complete and detailed list of assessments, please refer to the Assessment schedule. 
End of Treatment (EoT) 
Day 169  
This visit will take place approximately 4 weeks after the last study drug administration and 
must occur on the day ± the visit window specified in Section 6. 
For a complete list of assessments, please refer to the Assessment schedule. 
Patients participating in the extension study will move immediately to Visit 1 of the 
extension trial following this End of Treatment visit. 
End of study (EOS) 
Day 197 
This is the last planned visit in the study. The visit will take place approximately 8 weeks after 
the last dose for patients who discontinue from the study prematurely or who are not 
continuing to the extension study, and must occur on the day ± the visit window specified in 
Section 6. 


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Patients will be discharged from the study if they are in good general health as assessed by the 
Investigator. If deemed not appropriate for discharge, the Investigator (or the responsible 
medical delegate) will arrange for transfer of medical care to the patient’s primary physician 
or another appropriately qualified medical practitioner. For a complete list of assessments, 
please refer to the Assessment schedule. 
Study Extension 
An extension trial to evaluate the durability of effect of bimagrumab upon discontinuation of 
drug treatment is currently on-going. At the completion of this study, in participating sites, 
eligible patients may be invited to join the extension trial to evaluate the durability of effect of 
bimagrumab. 
3.2 
Rationale for study design 
The two-part, randomized, double-blind, placebo-controlled design of this phase IIb study will 
allow a comparison of repeat dosing of three dose regimens of bimagrumab and placebo on 
changes in muscle quantity and patient physical function in a population of older adults with 
sarcopenia.  
Patient population 
The study population will be comprised of men and women aged 70 years or older with 
sarcopenia and muscle-associated slow gait speed (GS). The population enrolled in this study 
should reflect the general heterogeneity of elderly people with low skeletal muscle mass and 
mobility limitation with regard to co-morbidities, polypharmacy, physical functional status, 
physiological reserve, and physical activity patterns. Data on drug safety, tolerability, 
 and pharmacodynamics from this design and population, should provide an 
assessment of possible beneficial or adverse effects of bimagrumab in the larger global 
population of elderly adults with similar co-morbidities, functional status and mobility 
limitations. The exclusion criteria aim to omit individuals whose health condition(s) or status 
could put them at unwarranted safety risk from participation in study activities; those patients 
in whom their muscle related dysfunction is not the primary reason for low functional 
capacity; patients likely not to improve due to non-muscle issues, e.g. unmanaged 
osteoarthritis pain; or patients with conditions that could confound the study objectives. 
To better clarify the potential effects of bimagrumab and to minimize within and between 
country differences in standard of care of older adults with mobility limitations, all study 
participants will receive oral nutritional supplements (ONS) and vitamin D and participate in 
a personalized exercise program. 
Design 
A randomized, placebo-controlled, double-blind design will be used to ensure the comparison 
of active vs. placebo treatments. Due to the subjective and effort-based nature of many study 
endpoints (e.g., AEs, SPPB, 6MWT, 
, 
), randomization to treatment and 
investigator and patient blinding will minimize the potential bias of patients and assessment 
personnel on key safety and performance-based endpoints.  


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The original four arm parallel design with three dose levels will become a two part study as of 
protocol amendment v02, to better address key study goals and to reduce the number of 
patients potentially exposed to an ineffective therapy until there is more evidence that 
bimagrumab is useful in treating sarcopenia. This study is the first to assess the SPPB in 
patients with sarcopenia administered bimagrumab. Therefore, Part A will determine the 
effect of the highest dose level (700 mg) of bimagrumab on total SPPB score compared to 
placebo in this population. At the completion of Part A, an interim analysis will be performed 
to determine efficacy and a sample size re-estimation to confirm original enrollment plan. 
 
 
 Patients randomized to 70 mg and 210 mg 
bimagrumab before amendment v02 
 will complete the study 
following the assessment schedule of this amendment and their data will be combined with 
other patients who receive the same dose level in Part B. Completion of Parts A and B will 
achieve the same objectives as the original design, just in a staggered manner. 
Randomization will be used to account for the expected heterogeneity of the geriatric sample 
population and to minimize selection, age, gender and baseline differences between groups. It 
is expected that patients administered bimagrumab will demonstrate a greater increase in 
muscle mass (LBM and ASMI) after receiving the drug compared to patients receiving 
placebo and that this increase in muscle will translate into an increase in physical function seen 
as an improvement in the SPPB score and other outcomes. 
Outcome variables 
A key design change in this amendment is that the SPPB will become the primary outcome. 
This switch of the SPPB from a key secondary outcome in earlier versions of the protocol and 
the change of 6MWT distance from the primary to a key secondary outcome is based on a 
combination of factors identified from the medical literature and observed in discussions with 
health authorities since the original protocol was written. Created to assess physical function 
in longitudinal aging studies in the 1970’s, the measurement properties of the SPPB are 
supported by an extensive history and body of literature. These data show a strong link of 
declining lower extremity functional status to adverse, clinically relevant outcomes in older 
adults, including falls, hospitalizations, institutionalization, incident disability and death 
(Guralnik et al 1994, Guralnik et al 1995, Studenski et al 2011, Perera et al 2006). 
Comparatively, the 6MWT is more clinically relevant in other patient populations, such as 
congestive heart failure, pulmonary disease and multiple sclerosis (Morris et al 2014; 
ATS 2002; Brown and Simnad 2016).  
The SPPB score and 4-meter gait speed have emerged as the predominant characteristics that 
define impaired lower extremity function in older adults in general and in those with 
sarcopenia and frailty (Studenski et al 2014). The SPPB has been used as the primary outcome 
variable in two recent intervention trials examining functional recovery following hip fracture 
(Latham et al 2014, Prestmo et al 2015). In addition, the SPPB was a key outcome in a large 
US based study (LIFE Study), evaluating an exercise and diet intervention in older adults that 
demonstrated an improvement of ≥1 point on the SPPB score was associated with a 
significant reduction in falls, and the baseline score predicted onset of mobility disability. 


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Health authorities have identified the SPPB as a candidate for a registration endpoint. 
Novartis is collaborating with the FDA and the American Federation for Aging Research to 
validate the SPPB as a regulatory outcome.  
 
 
 
To standardize the exercise program across all patients, the schedule of 2-3 exercise sessions 
per week will be maintained throughout the study. 
The 6MWT, 
 
 will provide data to assess the potentially broader clinical impact of a 
change in muscle quantity on improvements in patient perceived functional status 
(see Section 6.5). 
 
 
 
 
 
 
 
3.3 
Rationale for dose/regimen, duration of treatment 
3.3.1 
Dose and frequency 
Part A of the study will evaluate the fixed i.v. dose of 700 mg bimagrumab administered 
every 4 weeks over a 20-week period for a total of six doses. 
Part B of the study will evaluate fixed i.v. doses of 70 mg, 210 mg, or 700 mg bimagrumab 
every 4 weeks over a 21-week period for a total of six doses. 
 
 
 
 
 
 
 
 
 
  
Fixed i.v. dosing rather than body weight based dosing will be used in the current study 
 
, allowing the exploration 
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subsequent clinical development of bimagrumab for patients with sarcopenia. Based on the 
definition of sarcopenia and experience in this and prior studies, the lower limit of body 
weight has been lowered by 5 kg to 35 kg to be more inclusive of older adults in Asian 
counties. It is unlikely that a person will weigh more than 100 kg based on the limits of ASMI 
and BMI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Exposure to bimagrumab for 6 monthly doses is expected to be safe and well tolerated based 
on the experience from earlier clinical studies.
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 However, future clinical experience with bimagrumab 
may clarify more precisely where the limits of efficacy and tolerability are. Therefore, this 
study proposes to investigate a wider rather than narrower range of bimagrumab exposures by 
administering a fixed dose of 700 mg, 210 mg and 70 mg. 
Six doses will be used to evaluate the durability of treatment on the expected improvement in 
physical function and the time course for multiple performance assessments and to avoid 


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being misled by early changes that are not maintained with continued dosing 
(Papanicolaou et al 2013). 
3.4 
Rationale for choice of comparator 
A placebo infusion will be used as the comparator in this placebo-controlled study; no drug 
comparator will be used. A placebo is used because several of the outcome measures are 
behavioral in nature and dependent on a patient’s or observer’s beliefs and perceptions. 
Therefore, knowing treatment assignment may bias outcome measures and other important 
results (i.e., AEs). In addition, placebo-controlled studies provide the optimal situation to 
distinguish adverse events caused by a drug from those resulting from underlying conditions 
or “background noise”. As there is no approved pharmacotherapy for sarcopenia and it is not 
known if bimagrumab is efficacious, the use of placebo is ethically appropriate. 
3.5 
Purpose and timing of interim analyses/design adaptations 
An interim analysis is planned to evaluate the efficacy and safety of multiple doses of 
bimagrumab in patients with sarcopenia.
 
 
  The analysis will 
assess the effect of bimagrumab by the change from baseline to week 25 for efficacy in SPPB 
total and component scores, 6MWT distance and 
. Safety will also be examined 
based on the incidence of adverse events and clinically relevant changes in certain clinical 
laboratory variables. 
 
 
 
 
Further information is described in Section 9.8. 


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3.6 
Risks and benefits 
Target related risks and selection of participants 
A paucity of human data limits the ability to predict the short and long-term risk of reducing 
the activity of myostatin and other ActRII ligands in older adults. However, the risk to 
patients in this trial will be minimized by adherence to the inclusion/exclusion criteria and 
close clinical monitoring. 
 
 
 
 
 


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An external Data Monitoring Committee (DMC) will monitor safety data from the study and 
currently monitors the entire bimagrumab program for potential safety concerns 
(see Section 8.4).
 
 
 
 
 


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3.6.2 
Trial-related risks 
Infusion 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 should be 
discontinued and appropriate therapy initiated. Although not expected, an acute allergic reaction 
should be treated as needed using conventional counter measure therapies as indicated 
(including but not limited to epinephrine, antihistamine, corticosteroid, intravenous supplies, 
crystalloid, an oral airway, bag and mask, and supplemental oxygen). In the case of a serious 
adverse event in which decreasing the systemic concentration of bimagrumab may be of 
clinical benefit, the investigator should consider plasmapheresis. Study sites should not feel 
constrained in any way from providing necessary medical intervention. 
Blood draw risks 
During the collection of blood samples, subjects may experience pain and/or bruising at the 
insertion site of the needle/catheter. Although rare, localized clot formation, infections and 


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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 
replenish the blood volume removed. 
Imaging risks 
This clinical study involves exposure to radiation from a DXA total body scan. The radiation 
exposure by DXA is not necessary for medical care but is intended for research purposes only.  
The total amount of radiation exposure per subject from DXA will be about 25 µSv. 
This amount of radiation is equivalent to approximately 3.6 days of background exposure 
(approx. 0.3 µSv per hour at sea level). For effective radiation doses under 3 mSv (300 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 2009). DXA 
measures are also described as having no observable or biological effect and are similar to 
natural background levels of radiation in most countries. Therefore, DXA scans within the 
study period need not be limited from a safety perspective. 
Exercise-related injuries 
From the beginning of the run-in period to EOS, the patients will be required to perform a 
prescribed set of exercises two to three times each week. 
 
 
 
Some people participating in an exercise program may experience transient muscle soreness 
due to an increase in the volume and intensity of associated muscle contractions beyond their 
usual daily level. This risk of temporary muscle soreness is most commonly observed in 
individuals who are inexperienced with exercise and who are sedentary in their daily lives at 
the time of enrollment.
 
 
 
 
4 
Population 
The study population will be community-dwelling men and women ages 70 years and older 
meeting the criteria for sarcopenia as defined by the European Working Group on Sarcopenia 
in Older People (EWGSOP) (Cruz-Jentoft et al 2010). A modification in the criterion for 
appendicular lean mass will be made for patients from countries in Asia to account for the 
population difference in normal levels of lean body mass (Chen et al 2014). This study 
population should reflect the general heterogeneity of older adults with sarcopenia with regard 
to co-morbidities, physical functional status, physiological reserve, polypharmacy, and 
physical activity patterns.
 
 


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 The investigator must ensure that all patients being considered for the study meet the 
eligibility criteria prior to randomization. No additional exclusions should be applied by the 
investigator. Patient selection is to be established by checking through all inclusion/exclusion 
criteria at screening and baseline as stated in the protocol. A relevant record (e.g. checklist) 
must be stored with the source documentation at the study site. Deviation from any entry 
criterion excludes a patient from enrollment into the study. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria at 
screening. In addition, several of the criteria must be confirmed at baseline, as documented 
below: 
1. Written informed consent must be obtained before any assessment is performed; 
2. Men and postmenopausal women aged 70 years or older at screening, with self-reported 
mobility limitations such as difficulty standing up from a chair, walking for longer than 10 
minutes on a flat surface or climbing a flight of stairs; 
• 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. 
3. Gait speed over 4 meters of <0.8 m/s but ≥0.3 m/s at screening and baseline; 
4. Appendicular skeletal muscle index (skeletal muscle of arms and legs in kg/ height in m2) 
by DXA based on central reading: 
• ≤ 7.26 kg/m2 for men and ≤ 5.5 kg/m2 for women to be assessed during screening. 
• ASIAN COUNTRIES: ≤ 7.0 kg/m2 for men and ≤ 5.4 kg/m2 for women to be 
assessed during screening (Chen et al 2014); 
5. Total SPPB score of ≤9 at screening and baseline; 
6. Weigh at least 35.0 kg and have a body mass index (BMI) within the range of 15.0 – 32.0 
kg/m2;  
7. Usual dietary intake ≥ 20 kcal/kg body weight and ≥ 0.8 g protein/kg per day over the 4 
weeks prior to baseline estimated by an established method of diet assessment (i.e. 24 
hour recalls, food records or similar); 
8. Be able to communicate well with the investigator and to understand and comply with the 
exercise program, oral nutritional supplements (ONS), visit schedule and other requirements of 
the study. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
Central laboratory assessments or ECG interpretations which fall outside of the protocol-
specified range at screening can be repeated once at an unscheduled visit during the 
screening period to confirm patient eligibility prior to run-in. 


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Medical conditions limiting performance of physical assessments 
1. History of a lower limb fracture (e.g. femur, tibia) within the past 6 months with persistent 
negative impact on lower extremity function or any significant impairment or disease 
adversely impacting gait (e.g. intermittent claudication in advanced peripheral vascular 
disease, spinal stenosis, or severe osteoarthritis of the knee or hip with joint pain not 
controlled with medication/injections that adversely impacts mobility); 
2. Confirmed diagnosis of significant psychiatric disease (e.g. dementia/Alzheimer's disease, 
schizophrenia, depression or bipolar disorder). Individuals with adequately treated 
depression are eligible for enrollment; 
3. A Patient Health Questionnaire – 9 (PHQ-9) score ≥ 10 at screening;  
4. Neurological injury/disorder with significant persistent functional deficit (e.g. stroke with 
hemiparesis, spinal cord injury, muscular dystrophy, polymyositis, dermatomyositis, 
myopathy/myositides, myasthenia gravis, Parkinson’s disease, peripheral polyneuropathy); 
5. Intraocular surgery or intraocular laser procedures for refractive corrections within 6 
months prior to screening; 
6. Vitamin D deficiency defined as 25-OH-vitamin D levels < 12.0 ng/mL (30 nmol/L) at 
baseline: 
• In patients with 25-OH vitamin D level of <12.0 ng/mL at screening and with no 
symptoms of osteomalacia or low serum calcium, administration of a loading dose of 
oral vitamin D (recommended minimum 50 000 IU of vitamin D3, but according to 
local guidance) will be allowed. (Different formulations of vitamin D3 are allowed 
based on the approved therapy in the patient’s country. Vitamin D2 is permitted 
where D3 is not available); 
7. Hemoglobin concentration below 11.0 g/dL (110 g/L) for men or below 10.0 g/dL (100 
g/L) for women at screening. 
Medical conditions associated with muscle loss  
8. Chronic kidney disease [estimated glomerular filtration rate (GFR) < 30 mL/min]; 
9. History of confirmed chronic obstructive pulmonary disease with a severity grade > 2 on 
the Medical Research Council Dyspnea Scale; 
10. Confirmed rheumatoid arthritis or other systemic autoimmune disease requiring 
immunosuppressive therapy or corticosteroids > 10 mg/d prednisone equivalent, acquired 
immunodeficiency syndrome (AIDS), or type 1 diabetes mellitus; 
11. History of or ongoing gastrointestinal diseases known to cause malabsorption of protein or 
energy, such as inflammatory bowel disease, celiac disease, short bowel syndrome, 
pancreatic insufficiency. Individuals in which the disease is well controlled with 
medication/enzyme supplements (e.g., pancreatic insufficiency) or dietary modification 
(e.g., celiac disease) are eligible for enrollment; 
Liver 
 related conditions 
12. Abnormal liver function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, 
or serum bilirubin (except Gilbert’s Disease), 
 
. The investigator should be guided by the following criteria: 


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• Any single transaminase may not exceed 3x the upper limit of normal (ULN). A 
single parameter elevated up to and including 3x ULN should be re-checked as soon 
as possible, and always prior to enrollment/randomization, to rule out any lab error. 
• If the total bilirubin concentration is increased above the ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. In any case, serum 
bilirubin should not exceed the value of 1.6 mg/dL (27μmol/L). 
• 
 
 
13. Known history or presence of severe active 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); 
Cardiovascular conditions 
14. Confirmed diagnosis of heart failure classified as New York Heart Association Class III 
and IV (e.g. dilated cardiomyopathy); 
15. Myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary 
intervention (e.g. angioplasty or stent placement), or deep vein thrombosis/pulmonary 
embolism within 12 weeks of screening. Patients with current/active unstable angina are 
excluded; 
16. Severe cardiac valve disorders or defects (e.g. aortic or mitral stenosis); 
17. Severe pulmonary hypertension uncontrolled with medication; 
18. Clinically significant cardiac arrhythmia requiring medical intervention in the past 3 
months (e.g. SVT, atrial fibrillation with RVR, AICD with discharge); 
Other medical or living conditions 
19. History of hypersensitivity to therapeutically administered antibodies. 
20. Chest pain, severe shortness of breath, or occurrence of other safety concerns during the 
screening or baseline assessments. 
21. Lack of peripheral venous access 
22. Active cancer (i.e., under current treatment), or cancer requiring treatment in the last 
5 years excluding nonmelanoma skin cancers or cancers with excellent prognosis 
(e.g., early stage prostate or breast cancer, carcinoma in situ of the uterine cervix); 
23. Significant coagulopathy, platelet count less than 75,000/mm3; 
24. Active systemic infection requiring hospitalization or treatment with i.v. anti-infectives or 
antibiotics within 4 weeks of screening; 
25. Any chronic active infection (e.g., HIV, hepatitis B or C, tuberculosis, etc), to be 
confirmed prior to randomization. Patients receiving chemoprophylaxis for latent tuberculosis 
infection are eligible for the study; 
26. Active alcohol/drug abuse, or alcohol/drug treatment < 12 months prior to screening; 
subjects having successfully completed an alcohol/drug treatment program >12 months 
prior to screening with sustained abstinence are eligible; 


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27. Patient has any medical condition or laboratory finding during screening (e.g. an 
unexplained or clinically significant lab result), which, in the opinion of the investigator 
may interfere with participation in the study, might confound the results of the study, or 
pose an additional safety risk in administering bimagrumab; 
28. Patient plans to move out of the study area within 12 months or be out of study area 
for > 4 weeks continuously; 
29. Individuals who require routine and regular (e.g., daily) assistance from another person to 
complete one or more basic activities of daily living (basic ADL bathing, dressing, 
toileting, feeding, grooming) regardless of where they reside.  Assistance with 
instrumental ADL (i.e., shopping, meal preparation, housework) is permitted; 
30. Patients with a Mini Mental State Examination score < 21 at screening; 
 
 
 
 
 
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No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients, within and across study sites. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
 
 
 
Placebo will be a Dextrose 5% in water (D5W) infusion supplied by the site. 
Study drugs must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secure location to which only the Investigator and 
designated staff have access. Upon receipt, the study drugs should be stored according to the 
instructions specified on the drug labels. Storage conditions must be adequately monitored 
and appropriate temperature logs maintained as source data. Appropriate documentation of the 
subject specific dispensing process must be maintained. Bulk medication labels will be in the 
local language, will comply with the legal requirements of each country, and will include 
storage conditions for the drug but no information about the patient. 
Note: To maintain the blind, the investigational treatments will be prepared by an unblinded 
pharmacist/designee, 
 and the investigational 
treatment will only be administered by study personnel blinded to patient treatment 
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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 Investigator must not destroy any drug labels, 
or any partly used or unused drug supply. Only after receiving a written authorization by 
Novartis, the Investigator/designee will send all the unused and partly used drug supplies as 
well as the empty containers to the address provided at the time of authorization for 
destruction. 
5.1.2 
Additional study treatment 
Dietary counseling will be performed to support daily intake levels of at least 0.8 g protein/kg 
and 20 kcals/kg of body weight and to ensure daily supplementation with Vitamin D 
throughout the study and ONS during the run-in period
 
 
If it is determined to be necessary from one of the planned 
diet assessments, patients will be instructed to consume ONS as needed to ensure adequate 
protein intake (see Section 5.5.3.2 and Section 6.2). 
5.2 
Treatment arms 
In part A, patients will be assigned in a ratio of 
 (700mg bimagrumab: placebo). 
In Part B, patients will be assigned in a ratio of 
 (210mg bimagrumab:70mg 
bimagrumab: placebo:700 mg bimagrumab). 
By the end of the study, patients will have been assigned to one of the following 4 treatment 
arms to receive i.v. doses of the following: 
1. Bimagrumab 70 mg 6 doses 
2. Bimagrumab 210 mg 6 doses  
3. Bimagrumab 700 mg 6 doses  
4. Placebo 6 doses  
5.3 
Treatment assignment 
Treatment / randomization numbers will be assigned in ascending, sequential order to eligible 
subjects (see Section 5.5.1 for details). 
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 Interactive Response Technology (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. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will then 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm. The randomization number is for internal use only and will not be 
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5.4 
Treatment blinding 
Randomized patients will remain blinded to treatment allocation from the time of 
randomization until database lock. Investigator staff, persons administering the assessments, 
and the Novartis clinical team will also remain blinded to treatment allocations throughout the study. 
The following methods will be used to maintain the blind: (1) Randomization data are kept 
strictly confidential until the time of un-blinding and will not be accessible by anyone else 
involved in the study except for the un-blinded pharmacist 
 
(see specifications provided in Appendix 4). (2)
 
 (3) To the best extent possible the order of 
assessments will match the one used at each dosing visit, thus normalizing the process to all 
patients, (4) Any potentially unblinding parameters will not be available to the patient, site or 
study team, e.g. DXA results, FSH or Activin A. Randomization data are strictly confidential 
and will be accessible only to authorized personnel until unblinding of the trial after database 
lock (see Appendix 4 for details).
 
 Both the unblinded pharmacist 
and 
 will keep treatment allocation information confidential until clinical database 
lock. Un-blinding will only occur in the case of patient emergencies (see Section 5.5.13) and 
at the conclusion of the study. 
IMPORTANT: Due to the difference in preparation methods between the active and placebo 
treatments, an unblinded pharmacist or other qualified trained personnel who is independent 
of the study team will be required. This unblinded pharmacist will receive the appropriate 
treatment allocation numbers. Appropriate measures must be taken by the unblinded 
pharmacist to ensure that the study team remains blinded throughout the course of dose 
administrations and the remainder of the study. 
5.5 
Treating the Patient 
5.5.1 
Patient numbering 
Patient number 
Each patient screened is assigned a unique patient number. The screening number is a 
combination of a four digit center number, which is provided by Novartis, and a three digit 
sequential number allocated by the investigator, starting with 001. Therefore, if the center 
number is 1001, the patient numbers will be assigned such as 1001001, 1001002, etc. in 
ascending order. If the center number is 1002, the patient numbers will be assigned such as 
1002001, 1002002, etc. 
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. 
Patients can be re-screened and should be assigned a new patient number. 


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Randomization number 
If the patient is deemed eligible for the study following Baseline and will commence the 
dosing, a randomization number will be assigned using an interactive response technology 
(IRT) system. Once assigned to a patient, a randomization number will not be reused. 
5.5.1.1 
Randomization scheme before protocol amendment v02:  
All eligible patients were randomized 
 (bimagrumab 700mg : bimagrumab 210mg : 
bimagrumab 70mg : Placebo) ratio in 4 treatment arms.
 
 
5.5.1.2 
Randomization scheme for Part A: 
Following protocol amendment 02, for Part A, patients will be randomized into bimagrumab 
700 mg and placebo using a 
 scheme. 
 
 
No randomization into lower dose groups (bimagrumab 70mg 
and bimagrumab 210 mg) will occur in Part A. 
5.5.2 
Dispensing the study treatment 
The packaging of the investigational treatment will be open-label. Once prepared, 
bimagrumab will not be identical in appearance to placebo. 
Refer to the Pharmacist Instruction Manual for details on dispensing, preparing and 
administering study treatment. 
The unblinded pharmacist/designee will NOT administer the study drug to the subject. 
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received at the study site by a designated person, handled 
and stored safely and properly, and kept in a secured location to which only the Investigator 
and designated staff have access. Upon receipt, the study drugs 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 respective 
Novartis CPO Quality Assurance representative. Storage conditions must be adequately 
monitored and appropriate temperature logs maintained as Source data. 


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The Investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the unblinded 
Monitor during site visits and/or at the completion of the trial. 
All drug supplies are to be used only for this protocol and not for any other purpose. 
Unless specifically instructed by Novartis, the Investigator must not destroy any drug labels, 
or any used, partly used or unused drug supply. 
At the conclusion of the study, and, if allowed during the course of the study (e.g. the 
unblinded monitor), the Investigator will provide a copy of the drug accountability ledger to 
the Monitor. 
Only after receiving a written authorization by Novartis, the Investigator/designee will send 
all the unused and partly used drug supplies as well as the empty containers to the address 
provided at the time of authorization for destruction or have the unused and partly used drug 
supplies as well as the empty containers destroyed by the site’s pharmacist, providing a drug 
destruction certificate (appropriate local SOP must be in place). 
5.5.3.2 
Handling of other study treatments 
Patients with vitamin D deficiency (< 12.0 ng/mL) at baseline are ineligible for this study, but 
may be rescreened following successful replenishment treatment. To ensure sufficient 
Vitamin D levels during the study, all patients will receive vitamin D supplementation from the start 
of the run-in period to the EOS. The vitamin D supplements should be locally sourced. 
- 
daily administration of 800 IU  to 4000 IU vitamin D3 (or D2 if D3 is not available) 
(dose and form of vitamin D should be chosen by the site based on patient need and 
country standard); or, 
- 
equivalent weekly or monthly formulation if deemed to be of advantage for the 
individual patient’s compliance. 
Similarly the minimum baseline nutritional intake for participating in this study is an average 
of at least 20 kcal/kg body weight/day and 0.8 g protein per kg of body weight per day as 
estimated by an established method of dietary assessment such as 24-hour recall or food 
records. 
 
 
 
 
 
For more details refer to Section 6.2. 
5.5.4 
Instructions for prescribing and taking study treatment 
 
Infusions will 
occur every 4 weeks, after all pre-dose assessments have been performed. Six doses will be 
administered during the course of the study (see Section 3.1). 
Only the materials (infusion bag, administration set and filter) specified in the pharmacy 
manual should be used for administration of the study medication. 


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All dosages prescribed and dispensed to the patient during the study must be recorded on the 
Dosage Administration Record eCRF page.  
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Study drug 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. 
 
 
5.5.6 
Recommended treatment of adverse events 
 
 
 
 
 
 
  
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies eCRF. 
Although not expected, any acute allergic reactions should be treated as needed using 
conventional counter measure therapies as indicated (including but not limited to epinephrine, 
antihistamine, corticosteroid, intravenous supplies, crystalloid, an oral airway, bag and mask, 
and supplemental oxygen). In the case of a serious adverse event in which decreasing the 
systemic concentration of bimagrumab may be of clinical benefit, the investigator should 
consider plasmapheresis. Study sites should not feel constrained in any way from providing 
necessary medical intervention. 
 
5.5.7 
Rescue medication 
Not applicable, as there are no approved pharmacotherapies for sarcopenia.  
5.5.8 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study. All prescription medications, over-the-counter drugs 
and significant non-drug therapies (including physical therapy and blood transfusions) 
administered or taken within the timeframe defined in the entry criteria prior to the start of the 
study and during the study, must be recorded on the Concomitant medications eCRF or 
Surgical and Medical procedures eCRF. 
 
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assessed against all exclusion criteria/prohibited medication. If in doubt, the investigator 
should contact Novartis before randomizing a patient or, if the patient is already enrolled, to 
determine if the patient should continue participation in the study. 
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy. 
5.5.9 
Prohibited treatment 
Any investigational treatment on a different protocol is forbidden at the time of enrollment or 
within 5 half-lives of the investigational treatment prior to enrollment. 
 
 
 
 
 
5.5.10 
Discontinuation of study treatment 
Study “Stopping rules” 
An external Data Monitoring Committee (DMC) will monitor unblinded safety data from a 
bimagrumab program perspective, including this study, for potential safety concerns 
(see Section 8.4). If the Committee views the benefit-risk to change adversely at any time, a 
decision could be made to stop and re-evaluate the protocol or continue the study. In addition, 


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if any of the following situations occur, the study may be placed on hold and, upon review of 
study data by the clinical trial team and the safety team and discussion with the investigators, 
may be terminated or a dose level re-evaluated:   
• The investigators and Novartis consider that the number and/or severity of adverse 
events justify discontinuation of the study 
• The sponsor unilaterally requests it.  
The study may be terminated at any time for any reason by Novartis. Should this be necessary 
the Investigator will be informed of the procedures to be followed to assure that adequate 
consideration is given to the protection of the patient’s interests. The Investigator will be 
responsible for informing their IEC / IRB of the early termination of the trial. 
Individual subject withdrawal 
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the person’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 1 or Appendix 2 
• Death  
• Withdrawal of consent  
• Sponsor decision to terminate (part of) the study 
Investigational treatment may be discontinued under the following circumstances:  
• 
 
• Emergence of one or more adverse events that in the judgment of the investigator, taking 
into account the patient’s overall status, prevent the patient from safely continuing 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 safely continuing in the study  
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent (see Section 5.5.11). They should return 
approximately 4 weeks after their last dose for the EoT visit.  The EoS visit should be 
scheduled 4 weeks after EoT. If they fail to return for these assessments for unknown reasons, 
every effort should be made to contact them as specified in Section 5.5.12. 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit, including a final contact at the 30-day point. Documentation of attempts to 
contact the patient should be recorded in the source documentation.  


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5.5.11 
Withdrawal of consent 
Patients may voluntarily withdraw consent and cease to participate in the study for any reason 
at any time. 
Withdrawal of consent occurs only when (1) a subject does not want to participate in the study 
anymore and (2) does not want to participate in any further visits or assessments and (3) does 
not want any further study related contacts and (4) 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 eCRF. Study 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 and must be destroyed. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
5.5.12 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue, the investigator should show "due diligence" by documenting in 
the source documents steps taken to contact the subject, 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. 
Patients who are discontinued from the study for any reason will not be replaced. 
5.5.13 
Emergency breaking of assigned treatment 
Emergency unblinding should only be undertaken when it is essential to treat the patient 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency code breaks are performed using the IRT system. When the 
investigator contacts the system to unblind a patient, he/she must provide the requested patient 
identifying information and confirm the necessity to unblind the patient. The investigator will 
then receive details of the 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 Clinical Trial Leader that the code has been broken.  
The unblinded treatment code should not be recorded on the eCRF.  
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. If appropriate, the investigator will inform the patient how to 
contact his/her backup in cases of emergency when he/she is unavailable. The investigator 
will provide protocol number, study drug name, patient number, and instructions for 
contacting the local Novartis CPO (or any entity to which it has delegated responsibility for 
emergency code breaks) to the patient in case emergency unblinding is required at a time 
when the investigator and backup are unavailable.  


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Study drug must be discontinued after emergency unblinding. Study drug must also be 
discontinued for any patient whose treatment code has been inadvertently broken or for any 
non-emergency reason (see Section 5.5.10). 
5.5.14 
Study completion and post-study treatment 
Each patient will be required to complete the study in its entirety. The study will complete 
when the last patient completes his/her Study Completion visit, and any repeat assessments 
associated with this visit have been documented and followed-up appropriately by the 
Investigator, or when the last patient has completed his/her End of Treatment visit and has 
transferred to the extension study. 
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.  
5.5.15 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and treated as a prematurely discontinued 
subject. 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 subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial. 
6 
Visit assessments 
The full Assessment schedule is presented before Section 1. 
Recommended visit windows: 
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. If any visits are delayed or missed, the 
site personnel should ensure alignment of future visits according to the originally planned 
visit schedule, and should also ensure that consecutive infusions are performed at least 14 
days apart: 
• Randomization / Day 1: + 2 days 
• Week 3: +/- 2 days 
• Weeks 5-13: +/- 4 days 
• Weeks 17-29: +/- 7 days 
Visits 2 and 3 (early run-in visits) and Visits 5 and 101 (Final baseline and Day 1 dosing) may 
be combined 
 
and where it is deemed safe by the 
investigator. 
 
 
Assessments for a particular visit may be split over more than one day (as long as within the 
required visit window), however the order of assessments should be preserved. 


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Below are guidelines for organizing and performing the study assessments. 
• Assessments should be performed sequentially in the morning as follows: ECG collection, 
vital signs, blood sampling. 
• After blood sampling, patients may be offered breakfast. 
• 
 
 
• Physical performance measures should be performed in the order outlined in the 
Outcomes Manual. Please refer to this manual for more information. 
• After assessment of the physical performance measures and any other protocol-specified 
pre-dose assessment, patients can be dosed. 
• 
 
 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent (see Section 5.5.11). They should return for the 
assessments indicated by an asterisk (*) in the Assessment Table. If they fail to return for 
these assessments for unknown reasons, every effort should be made to contact them as 
specified in Section 5.5.12. 
At a minimum, patients will be contacted for reporting and follow-up of serious adverse 
events during the 30 days following the last study visit, including a final contact at the 30-day 
point. Documentation of attempts to contact the patient should be recorded in the source 
documentation. 
6.1 
Dietary, fluid and other restrictions 
At any visit where required, patients will fast (i.e. no food and liquid except water) for at least 
8 hours prior to the blood draws. Breakfast will be offered after the blood draws and prior to 
performing the performance measures.  
6.2 
Dietary Requirement 
6.2.1 
Dietary assessment 
It is important that patients eat a sufficient amount of calories and protein to allow a muscle 
anabolic therapy to be effective. The minimum nutritional intake for participating in this study 
is an average over the past four weeks of at least 20 kcal/kg body weight/day and 0.8 g protein 
per kg of body weight/day as estimated by an established method of dietary assessment (see 
Section 4.1). This assessment must be administered through a face to face meeting with a 
dietician or comparably trained professional using an established method of dietary 
assessment, (e.g., three serial 24-hour recalls, 3-day dietary record, or similar). Patients not 
meeting the minimum requirement at baseline can be offered dietary counseling and can be 
re-screened after 4-5 weeks. 
At visits after randomization, the nutritional status of patients may be evaluated using an 
interview format diet assessment if the investigator deems it necessary based on a review of 
the patient’s status.  In particular, if a weight increase or decrease of 5% or more compared to 


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baseline is seen, a comprehensive diet assessment using repeated 24-hour recalls or food 
records should be conducted by the dietitian. 
Patients should be encouraged at each clinic visit to consume adequate dietary calories and 
protein. Patients who report low protein intake at screening (less than 0.8 g/kg/day) or at any 
time during the study should be provided nutritional counseling on ways to increase dietary 
protein and other nutrient intake through food or supplementation
 
 
 
 
Similarly, potential patients who are noted to have vitamin D deficiency at the screening visit 
(less than 12.0 ng/dl) should be advised to discuss this deficiency with their primary physician, 
and if appropriate, recommended Vitamin D supplementation (as per Section 6.2.2). If the 
investigator feels that an individual is a good study candidate, the person may be re-screened 
at least four weeks later to ensure that corrective measures have been taken and the patient’s 
protein and/or vitamin D deficiency has been adequately addressed in order to fulfill the 
inclusion criteria. 
Nutritional status and subsequent actions taken (e.g. dietary counseling) will be entered into 
the Nutritional Status eCRF. 
6.2.2 
Nutritional supplement 
An oral Vitamin D supplement will be provided to all study patients throughout the study. 
• In patients with 25-OH vitamin D level of ≥12.0 ng/mL at screening: 
- 
daily administration of vitamin D (800 IU  to 4000 IU, D3 preferable but D2 also 
acceptable per local availability); or, 
- 
equivalent weekly or monthly formulation if deemed to be of advantage for the 
individual patient’s compliance. 
• In patients with 25-OH vitamin D level of <12.0 ng/mL at screening and with no 
symptoms of osteomalacia or low serum calcium: 
- 
administration of loading dose of oral vitamin D (recommended minimum 50 000 IU 
of vitamin D3, but according to local guidance) will be allowed. 
(Different formulations of vitamin D3 are allowed based on the approved therapy in 
the patient’s country. Vitamin D2 is permitted where D3 is not available) Per the 
exclusion criteria, patients must have a 25-OH-vitamin D level ≥ 12.0 ng/mL at 
baseline. 
 


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6.3 
Patient demographics/other baseline characteristics 
6.3.1 
Demographic Information 
Patient demographic and baseline characteristic data to be collected on all subjects include: 
date of birth, age, sex, race, predominant ethnicity. 
6.3.2 
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.  
Fall History will be reported separately on the Falls History eCRF page. 
6.3.3 
Cardiovascular and metabolic co-morbidities 
Information on cardiovascular co-morbidities will be collected. Following conditions will be 
recorded in the eCRF if met by the study subject: 
• Cardiomyopathy 
• Hyperthyroidism 
• Valvular Heart Disease 
• Diabetes (with and without complications) 
• Hypertension 
• Dyslipidemia/Hyperlipidemia 
• Myocardial infarction 
• Peripheral arterial disease 
• Prior stroke (hemorrhagic, ischemic, or unspecified) 
• Prior transient ischemic attack 
• Atrial fibrillation 
The cardiovascular and metabolic history will be recorded in the Cardiovascular History 
eCRF, before randomization. 
6.4 
Treatment exposure and compliance 
Patients will receive all study medication at the Investigator site. Study medication will be 
administered by site personnel, compliance will be ensured by appropriate training of site 
personnel. The date and time of administration of study drug will be recorded in the dosage 
administration record section of the eCRF. 
Every effort will be made to follow each patient; 
 should be made 
wherever possible on non-visit weeks to assess for the presence of AEs, 
 
 and to keep patients engaged in the study. 


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Throughout the study, patients will be required to participate in an exercise program with 
defined minimum requirements (see Section 3.1).
 
6.5 
Efficacy / Pharmacodynamic assessments 
Pharmacodynamic assessments are detailed below. 
Efficacy measurements in the study will include:  
• Short physical performance battery (SPPB) to assess physical function 
• Gait Speed (GS is a component of SPPB) to assess physical function 
• 6 minute walk test (6MWT) to assess physical function 
• 
 
• Total lean body mass (LBM) and appendicular skeletal mass index (ASMI) assessed by 
DXA to measure lean body mass and skeletal muscle mass of the arms and legs, 
respectively. 
• 
 
 
 
6.5.1 
Short physical performance battery 
The Short Physical Performance Battery (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. Collectively, SPPB is considered to be a 
nonspecific but highly sensitive indicator of global health status reflecting several underlying 
physiological impairments.  
The SPPB evaluates lower extremity status by measuring three domains of physical function: 
maintenance of standing balance, usual gait speed and lower extremity strength and power. 
The corresponding tasks include three static positions with decreasing base of support to 
challenge balance, walking at usual speed over 4-meters and, the ability to rise from a chair 
without the use of the arms once and then five times consecutively. The final score is a 
composite of the three groups of tasks and uses a standardized scale of 0-12, with the higher 
score reflecting a higher level of function. A change of 1.0 on the SPPB score is considered 
clinically relevant (Perera et al 2006, Pahor et al 2014). Complete details of test 
administration, equipment and recording into the eCRF are described in the CBYM338E2202 
Outcomes Manual. 


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6.5.2 
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. This test 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 down a hallway).  
Usual gait speed represents one of the most clinically relevant physical performance measures 
to evaluate older persons. Gait speed is associated with physical activity levels, changes in 
strength of lower extremity muscles, frailty and falls (Newman et al 2003, Chandler et al 1998, 
Cesari et al 2005). 
Gait speed is a well-established measure of physical function, it has shown to predict future 
disability in diverse community-dwelling elderly populations and is sensitive to changes in 
physical status in response to an intervention (e.g. physical activity and rehabilitation) 
(Barthuly et al 2012). Poor functional performance as measured by slow or declining gait 
speed is related to an increased risk of mobility 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 been suggested as a key 
indicator of overall health in the geriatric population. 
Complete details of test administration, equipment and recording into the eCRF are described 
as part of the SPPB protocol listed in the CBYM338E2202 Outcomes Manual. 
6.5.3 
6 minute walk test 
The 6 minute walk test (6MWT) is a simple test that measures how many meters a person can 
walk in 6 minutes. Repeated measurement of the 6MWT over time has been used in studying 
numerous musculoskeletal, pulmonary, and cardiovascular conditions and is a validated 
outcome in investigational drug trials.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
Complete details of course set-up, test administration, equipment and recording into the eCRF 
are described in the CBYM338E2202 Outcomes Manual. 


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6.5.5 
Total lean body mass and appendicular skeletal mass index (ASMI) 
assessed by DXA 
Dual energy X-ray absorptiometry (DXA) will be used to assess changes in total lean body 
mass (LBM) and appendicular skeletal mass index (ASMI). DXA instruments use an x-ray 
source that generates and is split into two energies to measure bone mineral mass and soft 
tissue from which fat and fat-free mass (or lean body mass) are estimated. The exam is quick 
(~5-6 min), precise (0.5-1%) and non-invasive. DXA scanners have the precision required to 
detect changes in muscle mass as small as 5%. 
Radiation exposure from DXA scans is minimal. The National Council of Radiation 
Protection and Measurements (NCRP) has recommended the annual effective dose limit for 
infrequent exposure of the general population is 5,000 µSv and that an annual effective dose 
of 10 µSv be considered a Negligible Individual Dose. The effective dose of a DXA whole 
body scan on an adult is 5 µSv. The total amount of radiation exposure per subject from DXA 
in this study will be about 25 µSv. This amount of radiation is equivalent to approximately 
3.6 days of background exposure (approx. 0.3 µSv per hour at sea level). 
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 
consistent 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. 
The images will be transmitted to a central reading vendor for independent review. Sites will 
receive appropriate training for data transfer as well as a DXA manual that will include 
detailed instructions and data transfer procedures. 


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6.6 
Safety 
6.6.1 
Physical examination 
A complete physical examination will include the examination of general appearance, skin 
(including special attention to telangectasias of the skin or nail-folds and acne), neck 
(including thyroid gland, 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 and neurological parameters. Only if indicated based on medical 
history and/or symptoms, should rectal, external genitalia, breast, and/or pelvic exams be performed. 
Skin-related issues will be assessed by the investigator or assigned clinician at each physical 
exam time point. 
 
 
 
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 and will not be recorded in the eCRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History eCRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event 
must be appropriately recorded on the Adverse Event eCRF. 
6.6.2 
Vital signs 
Vital signs include blood pressure (BP) and pulse measurements. After the patient has been 
resting for 3 minutes in a seated position, systolic and diastolic BP will be measured using an 
automated validated device, with an appropriately sized cuff. In case the cuff sizes available 
are not large enough for the patient's arm circumference, a manual sphygmomanometer with 
an appropriately sized cuff may be used. 
If vital signs are out-of-range, the Investigator may obtain two additional readings, so that a 
total of up to three consecutive assessments are made, with the subject seated quietly for 
approximately five minutes preceding each repeat assessment. The last reading must be within 
range at screening and baseline in order for the subject to qualify. All readings should be 
recorded on the eCRF. 
Whenever possible, at each visit, vital signs should be measured using the same arm. 


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6.6.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured.  
Body mass index (BMI) will be calculated using the following formula: 
• BMI = Body weight (kg) / [Height (m)]2 
6.6.4 
Laboratory evaluations 
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening or at baseline and there is a reason to 
believe the result is an anomaly, the assessment may be repeated once prior to randomization. 
If the repeat value remains outside of protocol-specified ranges, the subject is excluded from 
the study. 
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator and shall 
be based, in part, upon the nature and degree of the observed abnormality. The assessment 
may be repeated prior to randomization. 
In all cases, the Investigator must document in the source documents, the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the subject to continue in the study. 
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and may be discussed with Novartis personnel. The results should 
be evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted. 
6.6.4.1 
Hematology 
The following tests will be measured centrally: Hemoglobin, hematocrit, white cell count 
(WBC) with differential as percentage or absolute value (e.g. neutrophils, basophils, 
eosinophils, monocytes, lymphocytes), red cell count (RBC), reticulocyte count and platelet 
count will be measured.  
6.6.4.2 
Clinical chemistry 
The following tests will be measured centrally: Albumin, aldolase, alkaline phosphatase, 
bicarbonate, total bilirubin (note: if the total bilirubin concentration is increased above 
1.5 times the upper limit of normal, direct and indirect reacting bilirubin should be 
differentiated), calcium, chloride, cholesterol, C-reactive protein (CRP), creatinine, γ-GT, 
glucose (fasting), HgbA1c, phosphate, lipase, amylase, potassium, total protein, AST, ALT, 
sodium, magnesium, triglycerides, urea/BUN, uric acid, and vitamin D. 
25-OH Vitamin D is part of the clinical chemistry panel, but listed separately in the 
Assessment schedule because of its importance for eligibility. 


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6.6.4.3 
Cardiac Biomarker Panel 
The following tests will be measured centrally: creatine kinase (CK), CK-MB and CK-MM, 
and troponin T. 
6.6.4.4 
Hormone panel 
The following hormones will be measured centrally at screening only: testosterone and 
thyroid stimulating hormone (TSH). If TSH is abnormal, free thyroxine (free T4 - not total T4) 
should be reported. 
Hormones are listed per assessment frequency in the Assessment schedule.  
6.6.4.5 
Urinalysis 
The following tests will be measured centrally at screening only: A midstream urine sample 
(approx 30 mL) will be obtained, in order to avoid contamination with epithelial cells and 
sediments, and allow proper assessments. 
This analysis will comprise of specific gravity, pH, semi-quantitative “dipstick” evaluation of 
glucose, protein, nitrites, bilirubin, ketones, leukocytes and blood. A microscopic examination 
including RBC, WBC, bacteria and casts will be performed only when dipstick evaluation is 
positive for WBC, or proteins, or blood.   
6.6.5 
Electrocardiogram (ECG) 
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. 
A standard local 12 lead ECG will be performed supine. Interpretation of the tracing must be 
made by a qualified physician locally and documented on the ECG / in the ECG section of the 
eCRF. Each ECG tracing should be labeled with the 
• study number 
• subject initials 
• subject number 
• date and time 
ECG tracings will be dated and signed by the person who makes the interpretation and kept in 
the source documents at the study site. The clock on the ECG machine should be 
synchronized with the central clock on a daily basis. For any ECGs with patient safety 
concerns, two additional ECGs should be performed to confirm the safety finding. 
Clinically significant abnormalities should be recorded on the relevant medical 
history/Current medical conditions eCRF page prior to informed consent signature and on the 
Adverse Events page thereafter (see Section 7.1 and Section 7.2). Clinically significant 
findings must be discussed with the sponsor.  


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The CRF will contain: 
• date and time of ECG 
• heart rate 
• PR interval 
• QT interval uncorrected 
• QTcF  
• QRS duration 
Original ECG tracings, appropriately signed, will be archived at study site. 
6.6.6 
Pregnancy 
Only postmenopausal women aged 70 or older are included in this study. No pregnancy 
testing will be performed as pregnancy is a very low risk in this study. 


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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 subject or 
clinical investigation subject. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
All patients who have signed informed consent and are entered into the study will have all 
adverse events occurring after informed consent is signed recorded on the Adverse Event 
eCRF. 
Pre-existing medical conditions/diseases (i.e. Medical History) are considered AEs if they 
worsen after providing written informed consent. Abnormal laboratory values or test results 
constitute AEs only if they induce clinical signs or symptoms, or are considered clinically 
significant, or they require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, or 
other assessments. 
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 patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver related events are included in 
Appendix 2.  
Adverse events must be recorded on the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information: 
1. the severity grade (mild, moderate, severe) 
• mild:  
usually transient in nature and generally not interfering with normal 
 
 
activities 
• moderate: 
sufficiently discomforting to interfere with normal activities 
• severe: 
prevents normal activities 
2. its relationship to the study treatment (no/yes), or investigational treatment (no/yes), or 
other study treatment (non-investigational) (no/yes), or both or indistinguishable, 
3. its outcome, or if the event is ongoing an outcome of not recovered/not resolved should be 
reported. 
4. whether it constitutes a serious adverse event (SAE) 
5. action taken regarding study treatment 
6. its relationship to study treatment 
7. its duration (e.g. start and end date) 
8. whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 


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9. the classification of the AE (general, heart failure, implant related events, cardiomyopathy, 
ischemic heart disease cardiac rhythm disturbances, spontaneous muscle contraction, bone 
related event, soft tissue related event, diarrhea) 
An SAE is defined as any AE 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: 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o 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 form 
o 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  
o social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given. The action taken to treat the 
adverse event should be recorded on the Adverse Event eCRF. 
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 drug, 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 informed consent 
and should be discussed with the subject during the study as needed. 
In this study, investigators will be asked to provide additional details on selected adverse 
events of special interest 
 
 
 


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7.2 
Serious adverse event reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last 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. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form. Study site personnel must also 
inform the Novartis Medical Expert and/or Clinical Trial Leader (according to page 2 of this 
protocol). 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) should be faxed within 24 hours of awareness of the SAE to the 
local Novartis Drug Safety and Epidemiology Department and also a copy to the Novartis 
Medical Expert and/or Clinical Trial Leader (according to page 2). The telephone and fax 
numbers of the contact persons in the local Drug Safety and Epidemiology department, 
specific to the site, are listed on page 2 of this protocol and/or in the investigator folder 
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. 
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 
subject 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 and 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. 


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7.3 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
Liver events are divided into two categories: 
• Liver events of special interest (AESI) which consist of elevated transaminases and/or 
bilirubin (elevated liver function tests (LFTs)). 
• Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and / or pre-specified adverse events. 
Please refer to Table 14-1-Appendix 2 for complete definitions of liver events.  
Any liver event which meets the criteria for a “medically significant” event should follow the 
standard procedures for SAE reporting as described in Section 7.2.  
Every liver event as defined in Table 14-1-Appendix 2 should be followed up by the 
investigator or designated personal at the trial site, as summarized below and detailed in  
Table 14-2-Appendix 2. 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the subject 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 as appropriate in the CRF. 


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7.5 
Pregnancy reporting 
Based on the inclusion of only postmenopausal women and the age range of patients, 
pregnancy is a very low risk in this study. 
In the unexpected event of a pregnancy occurring while the patient is on study treatment, 
Novartis must be notified within 24 hours of learning of the pregnancy. All activities 
associated with the pregnancy will be reviewed with the site as needed. 
7.6 
Safety monitoring 
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented above. 
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner. 


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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 eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
subject records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study drug 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 subject 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 eCRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
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 subjects will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF) using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Novartis or the CRO working on behalf of Novartis. 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 a CD-ROM or paper copies of the 
subject data for archiving at the investigational site. 
All data captured for this study will have an external originating source (either written or 
electronic), the eCRF is not considered as source. 


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8.3 
Database management and quality control 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Novartis staff review the data entered into the eCRFs 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 who will 
make the correction to the database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions 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). 
The imaging CRO will collect all imaging data (DXA and echocardiography) from sites and 
send for quantitative analysis to a blinded expert reader. The analysis results are then 
collected by the imaging CRO and then transformed into a format according to a Novartis 
data transfer specification. The transformed output will then be sent to Novartis data 
management for incorporation into the CSR. The imaging CRO will be responsible for all 
image data clarification forms and missing data at all sites. 
Subject questionnaires will be entered into an electronic device by the subject. 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). 
Randomization codes 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. 
The occurrence of any 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 by joint written agreement between the 
Global Head of Clinical Information Sciences and the Clinical Franchise Head. 


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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 of toxicity 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 is to independently review and evaluate the unblinded safety data 
generated during the study as defined in this protocol. The DMC ensures that study 
participants are not exposed to unnecessary or unreasonable risks and that the study is 
conducted with high scientific and ethical standards. As needed, the DMC makes 
recommendations to the Sponsor on actions to be taken regarding 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 or semi-blinded 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).  


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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: 
• Generation of unblinded outputs for the DMC (Treatment A or Treatment B), including 
tables, figures, and listings, as required. 
• Preparation of any other reports requested by the DMC during the closed session. 
• Review of the semi-blinded 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 
Independent adjudication committees will be used to monitor specific safety events. 
Events will be blindly reviewed as they occur during the trial to confirm that they have been 
evaluated appropriately and diagnosed correctly. Details regarding the adjudication process 
will be available in the relevant bimagrumab Adjudication Committee charter. The committee 
members will remain blinded to treatment assignment and may provide expert reports at the 
end of the study.  
The clinical database will be searched by Data Management for targeted adverse events 
including but potentially not limited to the following categories: 
• Cardiac safety events 
When an adverse event in this category 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, imaging studies (e.g., 
radiographs), ECGs, operative and pathology reports, hospital discharge summaries. In addition, 
an interview with the patient may be needed (in person or via telephone) 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 
9.1 
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 after randomization and 
had at least one post-dose efficacy assessment. Patients who are randomized due to erroneous 
use of the IRT system will be excluded. Patients will be analyzed according to the treatment 
they were assigned to at randomization.  
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.  


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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 population will be identified and finalized based on blinded review of the data, prior 
to the final database lock. 
9.2 
Subject demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject. 
9.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
Analyses in this section will use the safety analysis set. 
9.3.1 
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 will be taken to be the number of calendar days between the 
first and last infusion date plus 28 days.  
9.3.2 
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 defined as a concomitant medication. 
This includes those that were first administered 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 reported administration. If it cannot be established with certainty that the use 
of a prior medication has ended prior to the first dose of investigational treatment, then it will 
be considered concomitant. 
9.4 
Analysis of the primary variable(s) 
9.4.1 
Variable(s) 
The primary variable is Short Physical Performance Battery (SPPB) test score. 
9.4.2 
Statistical model, hypothesis and method of analysis 
This study is planned to be conducted in two parts. 


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9.4.2.1 
Analysis for part-A 
Part-A is focused on proof of concept of BYM338 on SPPB change from baseline score in 
older adults with sarcopenia. In this part maximum dose of BYM338 (700mg) will be 
compared with placebo to establish the following criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
In addition to the primary objective, additional endpoints of safety (e.g., AEs, lab values, 
ECG), 
 background treatments (e.g., exercise, Vitamin D, diet), and efficacy (e.g., gait 
speed, 6MWT, 
, 
, LBM and ASMI by DXA, 
 
) may be included in the interim analysis.  


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9.4.4 
Supportive analyses 
 
 
 
 
 The last measurement of SPPB obtained 
during the run-in phase, but prior to the double-blinded treatment will be included as covariate. 
Three two-sided significance tests for the treatment to placebo comparison (70 mg vs. placebo, 
210 mg vs. placebo, 700 mg vs. placebo) at the 25 week time point will be computed. 
No adjustment for multiplicity will be done. If convergence problems are noted due to a 
sparse number of Japanese subjects, then the analysis may be redone while omitting this 
covariate.   
 
 
 
 
The primary and secondary analyses will be done for the PP population as well.   
9.5 
Analysis of secondary 
 variables 
For Part B, gait speed over 4 meters and 6MWT will both be analyzed in the same way as 
mentioned in Section 9.4.2. 
 
  
 
9.5.1 
Efficacy / Pharmacodynamics 
Not applicable 
9.5.2 
Safety  
All safety analyses will be performed on the Safety Analysis Set.  
9.5.2.1 
Cardiac Toxicity Analysis 
The relative risk (to placebo) of one or more confirmed cardiac toxicity event will be reported 
with 95% confidence intervals for each of the bimagrumab treated groups. 


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9.5.2.2 
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.  
Separate summaries will be performed for study medication related events, death, serious 
adverse events, adverse events leading to discontinuation of study medication or dose 
adjustment, and other adverse events of interest. 
9.5.2.3 
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 and shift tables will be provided 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. 
 
In addition, all laboratory data will be listed by treatment, patient, and visit and if ranges are 
available abnormalities will be flagged.  
9.5.3 Vital signs 
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time. 
9.5.4 ECG evaluations 
All ECG data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time. 


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9.5.6 
 / pharmacodynamic interactions 
Not Applicable. 


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9.6 
Sample size calculation 
9.6.1 Sample size for primary objective: 
Assumptions for part-A: 
Decision criteria for part-A is based on the maximum BYM338 dose group (700 mg) and 
placebo. 
 
 
 
For SPPB, several relevant references are available for judging the standard deviation of 
SPPB between two time points. 
Table 9-1 
Standard Deviation of SPPB 
Reference 
Study description 
SD 
Perera et al (2006) 
N=492 community dwelling adults 
1.42 
Kwon et al. (2009) 
N=424 older sedentary adults 
0.46  
Papanicolau et al (2013) 
N=120 sarcopenic elderly women 
1.6 
Based on these references, we consider an SD of 1.5 for the change in SPPB from baseline to 
6 months to be a realistic estimate while 2.0 is a conservative estimate. Table 9-2 evaluates 
the power of the comparison between the BYM338 700 mg and placebo groups
 
 
  
Table 9-2 
Power calculation for statistical significance in Part A 
Standard Deviation             
(SPPB points) 
Treatment Effect: BYM338 – 
Placebo (SPPB Points) 
Power 
1.50 
1.1 
0.98 
1.2 
0.99 
1.3 
1.00 
1.4 
1.00 
1.5 
1.00 
1.75 
1.1 
0.94 
1.2 
0.97 
1.3 
0.99 
1.4 
0.99 
1.5 
1.00 
2.00 
1.1 
0.87 
1.2 
0.92 
1.3 
0.95 
1.4 
0.97 
1.5 
0.99 
 


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Table 9-3 below shows the probability of passing both criteria; that is, achieving significance 
as well as a point estimate at or exceeding 1 SPPB point. 
Table 9-3 
Probability of passing dual criteria in Part A 
Standard Deviation             
(SPPB points) 
Treatment Effect: BYM338 – 
Placebo (SPPB Points) 
Power 
1.50 
1.1 
0.64 
1.2 
0.77 
1.3 
0.87 
1.4 
0.93 
1.5 
0.98 
1.75 
1.1 
0.62 
1.2 
0.73 
1.3 
0.83 
1.4 
0.90 
1.5 
0.95 
2.00 
1.1 
0.62 
1.2 
0.72 
1.3 
0.80 
1.4 
0.87 
1.5 
0.92 


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Table 9-4 
Optimal contrasts used for the power calculation 
Dose (mg) 
Linear Model (𝐶𝐶1) 
Emax Model (𝐶𝐶2) 
Exponential Model (𝐶𝐶3) 
0 
-0.4168 
-0.7009 
-0.3308 
70 
-0.3155 
-0.1622 
-0.3043 
210 
-0.1128 
0.1969 
-0.2285 
700 
0.845 
0.6661 
0.8636 
 
 
9.7 
Power for analysis of key secondary variables 
For secondary endpoints no power calculation is performed for part A. Therefore, the 
numbers in Table 9-6 and Table 9-8 are prediction of success rates for final analysis 
conducted at end of part-B. 
As to Gait Speed, from references within-subject standard deviation in the range of, respectively, 
0.15-0.16 m/Sec (Perera et al 2006) and 0.15-0.18 m/Sec (Papanicolaou et al 2013). 
A treatment effect in the range 0.10-0.20 m/Sec has been deemed to be a clinically 
meaningful difference. In addition, Table 9-6 below shows the power to detect a dose-
response by the MCP-MOD procedure. 


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Table 9-6 
Power to detect a significant dose-response trend by MCP-MOD 
(using a monotonic increasing alternative at 2.5% level) for GS 
endpoint 
Treatment Effect 
(m/sec) 
                                       Standard Deviation (m/sec) 
0.15 
0.2 
0.25 
0.2 
1.00 
1.00 
1.00 
0.15 
1.00 
0.99 
0.94 
0.12 
1.00 
0.94 
0.81 
0.1 
0.98 
0.84 
0.65 
The following information is available for judging the variability in 6MWT: 
Table 9-7 
Variability in 6MWT 
 
Remarks 
Estimated standard deviation (m) 
IA of PoC study 
CBYM338X2201 
30 sarcopenic elderly subjects treated with one 
dose of bimagrumab 30 mg/kg. SD of change 
to 16 weeks.  
69 (SD of baseline scores) 
65 (by ancova analysis) 
Perera et al. (2006) 
100 elderly subjects with mild to moderate 
mobility limitations. SD of 3 month change in 
stable subjects 
45-53 (SD of baseline scores) 
A change in 6MWT distance of 50 m is considered a substantial clinically meaningful change 
(Perera et al 2006). 
Table 9-8 
Power to detect a significant dose-response trend by MCP-MOD 
(using a monotonic increasing alternative at 2.5% level) for 6MWT 
endpoint 
Treatment Effect 
(m) 
                                                  Standard Deviation (m) 
50 
60 
70 
80 
90 
30 
0.94 
0.84 
0.71 
0.59 
0.49 
40 
1.00 
0.98 
0.92 
0.84 
0.74 
50 
1.00 
1.00 
0.99 
0.96 
0.91 
60 
1.00 
1.00 
1.00 
0.99 
0.98 
70 
1.00 
1.00 
1.00 
1.00 
1.00 
The dose response shapes are essentially assumed to be same for 6MWT and GS as 
considered in for primary endpoint. However the minimum power from three candidate 
shapes is represented in Table 9-6and Table 9-8. 
9.8 
Interim analyses 
Interim analysis is planned at the end of Part A. An unblinded interim analysis will be 
performed 
. This interim analysis will be conducted 
by an independent study team and the core study team will remain blinded to individual 
treatment data until final database lock. 
 
 
 


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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 Code of Federal Regulations 
Title 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 subjects 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 subject. 
In cases where the subject’s representative gives consent, the subject should be informed 
about the study to the extent possible given his/her understanding. If the subject 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 subject 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. 
 
 
 
 
 
 
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be obtained. 
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, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to subjects. 
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 


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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 subjects 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. 
Novartis does not grant protocol deviations. Under no circumstances should the investigator 
contact Novartis or its agents to request approval of a protocol deviation. If the 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/REB it cannot be implemented. All significant protocol deviations will be 
recorded and reported in the CSR. 
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 subject safety may be implemented prior to 
IRB/IEC/REB 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 subject 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 Health Authorities 
(where required) and the IRB/IEC/REB at the study site should be informed within 
10 working days or less, if required by local regulation. 


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12 
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People. Age and Ageing; 39: 412–423. 
Dam T-T, Peters KW, Fragala M, et al (2014) An evidence-based comparison of operational 
criteria for the presence of sarcopenia.  J Gerontol Med Sci 69: 584-590. 
Dunning T, Sinclair A, Colagiuri S (2014) New IDF Guideline for managing type 2 diabetes 
in older people. Diabetes Res Clin Pract. Mar;103(3):538-40. 
Fielding R, Vellas B, Evans W, et al (2011) Sarcopenia: An Undiagnosed Condition in Older 
Adults. Current Consensus Definition: Prevalence, Etiology, and Consequences. International 
Working Group on Sarcopenia. J Am Med Dir Assoc;12: 249–256.  
Freire AN, Guerra RO, Alvarado B, et al (2012) Validity and reliability of the Short Physical 
Performance Battery in two diverse older adult populations in Quebec and Brazil J Aging 
Health 24:863-78.  


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Gill TM. (2010) Assessment of function and disability in longitudinal studies; Journal of the 
American Geriatrics Society, 58:S308-12. 
Gottdiener JS, Bednarz J, Devereux R, et al (2004) American Society of Echocardiography 
Recommendations for Use of Echocardiography in Clinical Trials.  J Am Soc Echocardiogr; 
17:1086-1119. 
Guralnik JM, Simonsick EM, Ferrucci L, et al (1994) A short physical performance battery 
assessing lower extremity function: Association with self-reported disability and prediction of 
mortality and nursing home admission. Journal of Gerontology, 49:M85-94. 
Guralnik JM. Ferrucci L, Simonsick EM, et al (1995). Lower-extremity function in persons 
over the age of 70 years as a predictor of subsequent disability. The New England Journal of 
Medicine, 332:556-62. 
Guralnik JM, Ferrucci L, Pieper CF, et al (2000) Lower extremity function and subsequent 
disability: consistency across studies, predictive models, and value of gait speed alone 
compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci; 
55(4):M221-31. 
Hardy SE, Perera S, Roumani YF, et al (2007) Improvement in usual gait speed predicts better 
survival in older adults.  J Am Geriatr Soc; 55(11):1727-34. 
Janssen I, Shepard DS, Katzmarzyk PT, et al (2004) The healthcare costs of sarcopenia in the 
United States. J Am Geriatr Soc. Jan;52(1):80-5. 
Kwon S, Perera S, Pahor M, et al (2009) What is a meaningful change in physical 
performance? Findings from a clinical trial in older adults (the LIFE-P study). J Nutr Health 
Aging. 2009 Jun;13(6):538-44. 
Latham NK, Mehta V, Nguyen AM, et al (2008) Performance-based or self-report measures 
of physical function: which should be used in clinical trials of hip fracture patients? Arch Phys 
Med Rehabil. 89:2146-55. 
Latham NK, Harris BA, Bean JF, et al (2014) Effect of a home-based exercise program on 
functional recovery following rehabilitation after hip fracture: a randomized clinical trial. 
JAMA 311:700-8. 
Lee SJ, Lee YS, Zimmers TA, et al (2010) Regulation of muscle mass by follistatin and 
activins. Mol.Endocrinol.; 24 (10):1998-2008. 
Lee SJ, Reed LA, Davies MV, et al (2005) Regulation of muscle growth by multiple ligands 
signaling through activin type II receptors. Proc.Natl.Acad.Sci.U.S.A; 102 (50):18117-18122. 
McAuley E, Wójcicki TR, Gothe NP, et al (2013) Effects of a DVD-delivered exercise 
intervention on physical function in older adults. J Gerontol:Med Sci; 68:1076-82.  
Morris DR, Rodriguez AJ, Moxon JV, et al (2014) Association of lower extremity 
performance with cardiovascular and all-cause mortality in patients with peripheral artery 
disease: a systematic review and meta-analysis. J Am Heart Assoc. 3(4):1-11. 
Muscaritoli M, Anker SD, Argilés J, et al (2010) Consensus definition of sarcopenia, cachexia 
and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-
anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clin Nutr. Apr;29(2):154-9. 
doi: 10.1016/j.clnu.2009.12.004. 


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Newman AB, Haggerty CL, Kritchevsky SB, et al; Health ABC Collaborative Research 
Group (2003). Walking performance and cardiovascular response: associations with age and 
morbidity--the Health, Aging and Body Composition Study. J Gerontol A Biol Sci Med Sci; 
Aug; 58(8):715-20. 
Ostir GV, Volpato S, Fried LP, et al (2002) Reliability and sensitivity to change assessed for a 
summary measure of lower body function: Results from the Women's Health and Aging Study 
JClinical Epidemiology; 55:916-921. 
Papanicolaou DA, Ather SN, Zhu H, et al (2013) A phase IIA randomized, placebo-controlled 
clinical trial to study the efficacy and safety of the selective androgen receptor modulator 
(SARM), MK-0773 in female participants with sarcopenia. J Nutr Health Aging. 
2013;17(6):533-43 
Pahor M, Blair SN, Espeland M, et al (2006) Effects of a physical activity intervention on 
measures of physical performance: Results of the lifestyle interventions and independence for 
Elders Pilot (LIFE-P) study. Journals of Gerontology: Medical Sciences; 61:1157-65. 
Pahor M, Guralnick JM, Ambrosius WT, et al (2014) Effect of structured physical activity on 
prevention of major mobility disability in older adults: the LIFE study randomized clinical 
trial. JAMA. 311(23):2387-96 
Perera S, Studenski S, Chandler J, et al (2005) Magnitude and patterns of decline in health 
and function in 1 year affect subsequent 5-­year survival. JGerontology: Medical Sciences; 
60:894-900. 
Perera, S, Moody SH, Woodman, RC, et al (2006) Meaningful change and responsiveness in 
common physical performance measures in older adults. J Am Geriatr Soc. May;54(5):743-9 
Pinheiro JC, Bornkamp B. and Bretz F (2006) Design and analysis of dose finding studies 
combining multiple comparisons and modeling procedures, Journal of Biopharmaceutical 
Statistics, 16, 639–656  
Prestmo A, Hagen G, Sletvold O, et al (2015) Comprehensive geriatric care for patients with 
hip fractures: a prospective, randomised, controlled trial; Lancet 385:1623-33. 
Rosow I, Breslau N (1966) A Guttman health scale for the aged. J Gerontology. Oct; 
21(4):556-9. 
Simonsick EM, Gardner AW, and Poehlman ET (2000) Assessment of physical function and 
exercise tolerance in older adults: reproducibility and comparability of five measures. Aging 
(Milano). Aug;12(4):274-80 
Stabin MG (2009); Nuclear Medicine Radiation Risks. J Nucl Med. Feb 17. 
Studenski, S. (2009) What are the outcomes of treatment among patients with sarcopenia? 
Journal Nutrition, Health Aging; 13(8), 733-36. 
Studenski S, Perera S, Patel K, et al (2011) Gait speed and survival in older adults. JAMA; 
305(1):50-8.  
Studenski S, Perera S, Wallace D, et al (2003) Physical performance measures in the clinical 
setting. J Am Geriatr Soc; 51(3):314-22. 


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Studenski SA, Peters KW, Alley DE, et al (2014) The FNIH Sarcopenia Project: Rationale, 
study description, conference recommendations, and final estimates. J Gerontol A Biol Sci 
Med Sci.69(5):547-558. 
Tomlinson B, Cruickshank JM, Hayes Y, et al (1990) Selective beta-adrenocceptor partial 
agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatinine 
kinase changes in healthy subjects. Brj J Pharmac; 30: 665-672. 
Trendelenburg AU, Meyer A, Jacobi C, et al (2012) TAK -1/p38/nNFkB signaling inhibits 
myoblast differentiation by increasing levels of Activin A. Skeletal Muscle; 2(1):3. 
Upton PD, Davies RJ, Trembath RC, et al (2009) Bone Morphogenetic Protein (BMP) and 
Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-
1 in Human Pulmonary Artery Endothelial Cells. J Biol Chem. 284(23): 15794-804. 


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Appendix 1: Sample log table – all matrices 
Sample Log (all matrices): 
Time schedule for sampling for safety bloods and urine, 
, pharmacodynamic (PD), 
 
 
 


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14 
Appendix 2: Liver event definitions and follow-up 
requirements 
Table 14-1 
Liver Event Definitions 
 
Definition/ threshold 
Adverse event of special interest 
 
Laboratory values 
ALT or AST > 3 x ULN 
 
ALP > 2 x ULN 
 
TBL > 1.5 x ULN 
Medically significant event 
(SAE) 
 
Laboratory values 
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction]) 
 
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction]) 
 
TBL > 3 x ULN 
 
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and 
TBL > 2 x ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 x ULN) 
Adverse events 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders – severe events only”* or any “Hy’s law case” PT 
* 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 
Liver Event Follow Up Requirements 
Criteria 
Event type 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
OR 
ALT or 
AST >3xULN and 
INR >1.5 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize, if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
 
ALT or AST 
> 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 


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Criteria 
Event type 
Actions required 
Follow-up monitoring 
> 5 to ≤ 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
Report to Novartis as an SAE 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 x ULN 
accompanied by 
symptomsb 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 x ULN  
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Investigator & Novartis 
Repeat LFT once or twice in the 
week 
If elevation persists, establish 
causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 3 x ULN 
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
ALP (isolated) 
> 5 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, report to 
Novartis as an SAE 
Establish causality 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
> 2 to ≤5 x ULN 
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Investigator & Novartis 
Repeat LFT once or twice in the 
week. If elevation persists, establish 
causality 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 2 x ULN 
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 


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Criteria 
Event type 
Actions required 
Follow-up monitoring 
TBL (isolated) 
> 3 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 3 x ULN 
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Novartis 
Repeat LFT once or twice in the 
week. If elevation persists, 
establish causality 
investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 1.5 x ULN 
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
Preferred terms 
Jaundice 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize the patient 
Report to Novartis as an SAE 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
“Drug-related 
hepatic 
disorders - severe 
events only” SMQ 
AE 
Medically 
significant 
Discontinue the study drug  
hospitalization if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
Complete liver CRF 
Investigator discretion 
a Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN 
b General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia 
c 
Resolution is defined as an outcome of one of the following: return to baseline values, stable 
values at three subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a 
maximum of 6 months, liver transplantation, and death. 


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15 
Appendix 3: Clinically notable laboratory values 
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 15-1 
Clinically notable lab values 
Laboratory Variable 
Notable Criteria 
 
 
 
 
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 
 


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16 
Appendix 4:  Blinding and unblinding 
Randomization data are kept strictly confidential. Prior to final clinical database lock, 
unblinding is allowed only for authorized personnel as described in the table below. 
Table 16-1 
Blinding levels 
 
 
Time or Event 
Role 
1 
2 
3 
4 
5 
6* 
7 
Drug Supply 
UI 
UI 
UI 
UI 
UI 
UI 
UI 
Randomization Office 
UI 
UI 
UI 
UI 
UI 
UI 
UI 
Data Monitoring Committee 
B 
UI 
UI 
UI 
UI 
UI 
UI 
Subject 
B 
B 
B 
B 
UI 
B 
B 
Treating Physician 
B 
B 
B 
B 
UI 
B 
B 
Primary Investigator  
B 
B 
B 
B 
UI 
B 
B 
Blinded Study Monitor 
B 
B 
B 
B 
UI 
B 
B 
Unblinded Study Monitor 
B 
UI 
UI 
UI 
UI 
B 
UI 
Clinical Trial Leader 
B 
B 
B 
B 
UI 
UG 
UI 
Data Manager 
B 
B 
B 
B 
UI 
B 
B 
 
B 
UI 
UI 
UI 
UI 
UG 
UI 
 
B 
B 
B 
B 
UI 
UG 
UI 
Statistician 
B 
B 
B 
B 
UI 
UG 
UI 
Translational Medicine Expert 
B 
B 
B 
B 
UI 
UG 
UI 
Independent Trial Leader 
B 
B 
B 
B 
B 
UI 
UI 
Independent Translational Medical Expert 
B 
B 
B 
B 
B 
UI 
UI 
Independent Statistician 
B 
B 
B 
B 
B 
UI 
UI 
Independent Data Manager 
B 
B 
B 
B 
B 
UI 
UI 
Independent Programmer 
B 
B 
B 
B 
B 
UI 
UI 
Modeler 
B 
B 
B 
B 
UI 
UI 
UI 
Programmer  
B 
B 
B 
B 
UI 
UI 
UI 
*In the event the study is terminated with the Interim Analysis, then all interim data will be treated as final 
database lock (event 7). 
UG Allowed to be unblinded on treatment group level  
UI Allowed to be unblinded on individual patient level 
B Remains blinded 
1 Generation of randomization list, QC and lock randomization list 
2 Patient allocation to treatment 
3 Single-blinded treatment administration 
4 Double-blinded treatment administration 
5 Safety emergency event (unblinding of a single subject) 


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6 Interim Analysis 
7 Database lock  
 
 
 
 


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SAP_000.pdf: 
Clinical Development 
BYM338/Bimagrumab 
CBYM338E2202 / NCT02333331
A 28 week, randomized, double-blind, placebo-controlled, 
two-part, multi-center, parallel group dose range finding 
study to assess the effect of monthly doses of bimagrumab 
70, 210, and 700 mg on skeletal muscle strength and 
function in older adults with sarcopenia (InvestiGAIT) 
Author(s): 
 (Trial Statistician) 
Document type: 
SAP: Statistical Analysis Plan 
Document status: 
Draft 
Release date: 
16-Jul-18
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Clinical Development .......................................................................................................... 1 
Table of contents ................................................................................................................. 2 
1 
Introduction to SAP documentation .................................................................................... 4 
1.1 
Scope ........................................................................................................................ 4 
1.2 
Changes to SAP documentation .............................................................................. 4 
2 
Study objectives and design ................................................................................................ 7 
2.1 
Study objectives ....................................................................................................... 7 
2.1.1 
Primary objective .................................................................................... 7 
2.1.2 
Secondary objective(s) ............................................................................ 7 
 
 7 
2.2 
Study design and treatment ...................................................................................... 8 
2.2.1 
Part A ...................................................................................................... 9 
2.2.2 
Part B ....................................................................................................... 9 
3 
First interpretable results (FIR) ......................................................................................... 11 
3.1 
Interim FIR ............................................................................................................ 11 
4 
Interim analyses ................................................................................................................. 12 
5 
Subgroups .......................................................................................................................... 12 
6 
Protocol deviations ............................................................................................................ 13 
7 
Statistical methods: Analysis sets ...................................................................................... 14 
7.1 
Recommended visit windows: ............................................................................... 15 
7.2 
Patient disposition, background and demographic characteristics ........................ 15 
7.2.1 
Patient disposition ................................................................................. 15 
7.2.2 
Patient demographics and other baseline characteristics ...................... 15 
7.3 
Efficacy/ Pharmacodynamic assessments .............................................................. 17 
 
 21 
7.5 
Other Assessments ................................................................................................. 22 
8 
Treatments (study drug, other concomitant therapies, compliance) .................................. 23 
8.1 
Study drug administration ...................................................................................... 23 
8.2 
Prior and concomitant medications ....................................................................... 23 
 
 24 
10 Statistical methods for Pharmacodynamic (PD) parameters ............................................. 24 
Table 10-1 
Analysis set to be used for different endpoints ..................................... 24 
10.1 
Analysis of the primary variable(s) ....................................................................... 25 
10.1.1 
Variable ................................................................................................. 25 
10.1.2 
Descriptive statistics .............................................................................. 26 
10.1.3 
Statistical model, hypothesis and method of analysis ........................... 26 


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10.1.4 
Sensitivity analysis ................................................................................ 29 
10.1.5 
Handling of missing values/censoring/discontinuations ....................... 29 
10.2 
Analysis of secondary 
 variables .................................................. 29 
10.2.1 
Secondary variables .............................................................................. 29 
 
 30 
10.2.3 
Additional analysis ................................................................................ 34 
11 Safety analysis ................................................................................................................... 35 
11.1 
Cardiac toxicity – cardiomyopathy analysis .......................................................... 35 
11.2 
Adverse events ....................................................................................................... 36 
11.3 
Deaths .................................................................................................................... 37 
11.4 
Laboratory data ...................................................................................................... 38 
11.5 
Vital signs .............................................................................................................. 39 
11.6 
ECG ....................................................................................................................... 40 
11.7 
Echocardiography .................................................................................................. 40 
11.8 
Other safety variables ............................................................................................ 41 
 41 
13 Clinical Study Report - Appendix 16.1.9 Documentation of statistical methods .......... 42 
13.1 
Introduction ............................................................................................................ 42 
13.2 
Precision and summary statistics ........................................................................... 42 
13.3 
Study Day 1 and other study days ......................................................................... 43 
13.4 
Definition of Baseline and post-baseline measurements ....................................... 43 
13.5 
Protocol-defined visits ........................................................................................... 44 
13.6 
Analysis visits ........................................................................................................ 44 
13.6.1 
Visit naming .......................................................................................... 44 
13.6.2 
Early discontinuation visit remapping .................................................. 45 
13.7 
Handling of missing values/censoring/discontinuations ....................................... 45 
13.8 
Imputation of missing and incomplete dates ......................................................... 45 
 
 45 
 
 45 
 
 48 
14 References ......................................................................................................................... 49 
 


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1 
Introduction to SAP documentation 
1.1 
Scope 
The SAP document contains detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CBYM338E2202”.  
SAP provides the description of the statistical methodology used to analyze the data, TFL 
(Table figure and listing)  details the presentation of the data, including shells of summary 
tables, figures and listings, and PDS (Programming data specification) contains programming 
specifications e.g. for derived variables and derived datasets, to support the creation of CSR 
outputs. 
1.2 
Changes to SAP documentation  
Refer to corresponding guidance and Early Development Biostatistics (EDB) SAP Addendum 
template for detailed information on the requirements of documenting changes to SAP 
documentation. 
For the statistical methodology (SAP), any major changes occurring before database lock to 
the statistical methodology should be reflected in the SAP documentation via version control 
(new document version to be approved by the trial team as the original module. 
Major changes include, but are not limited to, changes in protocol that affect study design and 
statistical methodology.  
Minor changes to the SAP documentation can be captured e.g. by a study note to file / note in 
SAP Addendum or within the CSR itself.  Minor changes include, but are not limited to, change 
in statistical model.  Corrections of typographical errors or modification of spelling (from 
English to American, for example) do not need to be incorporated into the SAP documentation. 
Amendment 2 (October 2017) 
Amendment rationale 
The purpose of this amendment is to align with study design and endpoints as indicated in 
protocol V02 (September 2016) and protocol V03 (October 2017). 
Key changes in protocol V02:  
Two key changes in this amendment: 
a. The short physical performance battery (SPPB) replaced 6 minute walk test (6MWT) as 
primary outcome; 6MWT became secondary endpoint. This change was based on a 
combination of factors identified in medical literature and discussions with health 
authorities. 
b. The original plan was a four arm parallel design. This was modified to a two part design 
to reduce the exposure to experimental therapy until data are obtained to demonstrate 
sufficient risk benefit information. Part A was updated to a parallel two arm design with 
placebo and bimagrumab (BYM338) 700 mg; recruitment to intermediate bimagrumab 
doses of 70 mg and 210 mg were stopped. Based on Part A data, a decision will be taken 


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whether to continue to Part B, which will be a parallel four arm design with three active 
doses (70, 210, 700 mg) and placebo. 
Intensive safety monitoring was reduced based on published data from other BYM338 studies 
and a decision by the independent data monitoring committee (DMC) to a frequency aligned 
standard medical care. 
Key changes to protocol V03: 
The primary purpose of this amendment was to present a new safety observation and the 
resultant modification to the protocol. Also, sample size for Part A was readjusted to ensure 
sufficient information for decision making.
 
 
A new set of assessments has been added around 2 weeks post first 
study drug administration, and at the second and third dose to generate more data 
 
 
Table 1-1 
Key changes in assessment schedule in protocol amendments (V02-
V03) 
End Point 
Amendment 
Version 
Visits Added 
Visits Removed 
Other Details 
Echocardiography 
V02 
 
All 
Performed only at EOT 
for patients in V01 with 
baseline data 
FSH, LH, SHBG 
V02 
 
All 
 
 
V02 
 
All* 
 
 
  
 
V02 
 
All 
 
 
V02 
 
All 
 
 
V02 
 
All 
 
Coagulation 
parameters 
V02 
 
All 
 
Physical 
Examination 
V02 
 
102,103,105 
and 106 
 
Height 
 
 
EOS 
 
Body 
temperature, 
blood pressure,  
pulse rate 
V02 
 
101 
 
Electrocardiogram 
V02 
 
101, 102, 103, 
105, 106 and 
EOS 
 
Hematology 
V02 
104 
101, 103 , 105 
and 106 
 
Clinical Chemistry 
V02 
104 
101, 103 , 105 
and 106 
 


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End Point 
Amendment 
Version 
Visits Added 
Visits Removed 
Other Details 
Clinical Chemistry 
V03 
1015, 102, 
103 
 
 
Testosterone 
V02 
 
All except visit 1 
 
Urinalysis 
V02 
 
All except visit 1 
 
Cardiac panel 
V02 
 
101, 102, 103 
 
Vitamin D 
V02 
104 
103, 105 and 
EOS 
 
6MWT, 
 
V02 
 
102, 103 , 105 , 
106 and EOS 
 
SPPB 
V02 
 
102, 105 and 
EOS 
 
 
 
 
 
 
 
Diet assessment 
V02 
 
102, 103, 104, 
105,106** 
 
 
** Diet assessments may still be measured in case there is a significant change in weight  
 


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2 
Study objectives and design  
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective is to assess the effect of 24-weeks of bimagrumab treatment on patient 
physical function assessed by a change in the Short Physical Performance Battery (SPPB) 
total score from baseline to week 25 relative to placebo in older adults with sarcopenia. 
2.1.2 
Secondary objective(s) 
Secondary objectives are as follows: 
• To assess the effect of bimagrumab compared to placebo on the safety and tolerability 
of multiple doses of bimagrumab administered over 24 weeks as assessed by measures 
such as vital signs, clinical laboratory variables, electrocardiogram (ECG), 
echocardiogram (in a limited number of patients), and adverse events (AE) in older 
adults with sarcopenia. 
• To assess the effect of bimagrumab compared to placebo on improvement in physical 
performance as measured by change from baseline to week 25 in the 6 minute walk test 
(6MWT) distance in older adults with sarcopenia. 
• To assess the effect of bimagrumab compared to placebo on improvement in mobility 
as measured by change from baseline to week 25 in usual gait speed (GS; measured as 
a component of the SPPB) over 4 meters in older adults with sarcopenia. 
• To assess the effect of bimagrumab on total lean body mass and appendicular skeletal 
muscle index (ASMI) measured by DXA, as assessed by change from baseline to week 
25 compared to placebo in older adults with sarcopenia. 


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2.2 
Study design and treatment 
This Phase II-b study is a two-part randomized, double-blind, placebo-controlled, study design 
with approximately 339 older adults with sarcopenia assigned to one of four treatment groups: 
placebo, bimagrumab 70mg, bimagrumab 210mg, or bimagrumab 700mg. 
The study will consist of a 20-day screening period followed by a 28-day run-in period, and a 
24 week treatment period followed by a 4 week follow-up period. During the run-in period, all 
patients will be introduced to a 3 times per week exercise program, daily vitamin D and oral 
nutritional supplementation (ONS), and the performance-based endpoints. Towards the end of 
the run-in period, patients will be re-assessed for eligibility (utilizing the baseline eligibility 
criteria) and qualified patients will enter the treatment phase to receive six monthly doses of 


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assigned study drug. Patients randomized prior to implementation of protocol amendment v02 
will remain on their assigned treatment, but will be switched to the new assessment schedule at 
their next scheduled visit. It is estimated that approximately 18 patients will have been 
randomized into each of the four treatment groups at the initiation of this amendment (N= 
approx.72 through protocol amendment v01). 
2.2.1 
Part A 
Patients will be enrolled and randomized to receive either bimagrumab 700 mg or placebo (see 
Figure 2-1), until approximately 100 patients will have been enrolled in the bimagrumab 700 
mg arm and 60 patients in the placebo arm. At this point, recruitment into the study will be 
paused until Part A is completed and an interim analysis conducted. 
Figure 2-1 
Study design: Part A 
 
 
 
2.2.2 
Part B 
Part B will be performed based on Part A outcomes. 
New patients will be enrolled and randomized to receive either placebo, bimagrumab 70 mg or 
bimagrumab 210 mg (see Figure 2-2), until approximately 70 patients have been randomized 
into each arm. An additional 13 patients will be recruited into the 700 mg arm and additional 
26 patients into the placebo arm to allow effective randomization and bridging between Parts 
A and B. This will complete enrollment of approximately 339 patients into the study. Following 
the last patient visit in Part B, the study will end and the final analysis will take place to address 
the study objectives. 


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Figure 2-2 
 
 
Exercise program 
During screening, the ability of patients to perform the exercise program will be determined by 
a trained study staff member, to ensure patients have the ability to perform the required physical 
tasks. 
 
 
 
 
 
Drug treatment assignment 
In initial versions of the protocol (V00-V01) eligible patients (~72) were randomized in a 
1:1:1:1 ratio to receive i.v. doses of placebo or 70, 210, or 700 mg bimagrumab every 4 weeks 
until Week 21 for a total of 6 doses. 
In protocol V02-V03, Part A: At the conclusion of the baseline period (Visit 5), newly recruited 
eligible patients will be randomized in a 2:1 ratio to receive i.v. doses of bimagrumab 700mg 
or placebo every 4 weeks until Week 21 for a total of 6 doses. 
Part B: At the conclusion of the baseline period (Visit 5), eligible patients will be randomized 
in a 4:4:2:1 ratio to receive i.v. doses of bimagrumab 70mg, bimagrumab 210mg, bimagrumab 
700mg, or placebo every 4 weeks until Week 21 for a total of 6 doses. 
 


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3 
First interpretable results (FIR) 
3.1 
Interim FIR 
Interim first interpretable results (FIR) will be provided for this trial. 
The study FIR template can be found in CREDI in the study RAP folder  
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be marked as “Key” in the M9.1 Tracking sheet output 
list.  
Primary FIR will contain only overall summary; no subgroup analysis is needed. 
• Summary of patients disposition by treatment 
• Summary of patients under each analysis set by treatment 
• Summary of population demographics (age, sex, race – Caucasian, Black, Asian) by 
treatment  
• Summary of baseline characteristics (weight, height, BMI, ASMI, SPPB total score, gait 
speed, 6MWT, 
) by treatment. 
• Analysis of treatment-emergent adverse events (AE) 
o Summary of treatment emergent AEs by system organ class (SOC) and preferred 
term (PT) by treatment. 
o Overview of adverse events 
• Analysis of primary endpoint: Statistical analysis of SPPB change from baseline at week 
25 by treatment to evaluate the dual criteria as mentioned in section 10.1.3.1.  
• Supportive analysis of primary endpoint : Statistical analysis  of SPPB change from 
baseline using MMRM model as described in section 10.1.3.3 Arithmetic mean (SE) 
time profile: SPPB Total score, gait speed and 6MWT 
• In addition to the primary endpoint, analyses of the change over time (baseline to Week 
25) by treatment of the following endpoints will be included:  
o 6 minute walk test (6MWT) 
o Gait Speed (GS) 
o 
 
o Appendicular skeletal muscle index  
o 
 
 
Contents for extended FIR: 
• 
 
• 
 
• 
 


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• 
 
• 
  
 
 
4 
Interim analyses  
 
 
 
 
 
 
Primary analysis: To support the primary objective, the change in the Short Physical 
Performance Battery (SPPB) total score from baseline to week 25 will be compared between 
treatment groups. 
Timing of interim analysis: An interim analysis is planned to evaluate the efficacy and safety 
of multiple doses of bimagrumab in patients with sarcopenia.
 
 
 
 
 
 
 
 
 
Based on the planned use of Part A data for decision making, additional endpoints of safety 
(e.g., AEs, lab values, ECG), 
 background treatments (e.g., exercise, Vitamin D, diet), and 
efficacy (e.g., gait speed, 6MWT, 
, 
, LBM and ASMI by DXA, 
) may be included in the interim analysis. 
Outputs for interim analysis FIR document are discussed under section 3. 
5 
Subgroups 
Subgroup 1:  
Country Specific 
• Japan 
• Non-Japan 
Subgroup 2: 


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 Geographical: 
• Asian countries (Patients from study sites in Japan, Taiwan and South Korea). 
• Non-Asian countries (Patients from study sites not in Japan, Taiwan and South Korea). 
All of the summary reports for subgroup analysis will be summarized in three groups: Japan/ 
non-Japan, Asia/ non-Asia and overall. 
6 
Protocol deviations 
The major protocol deviations observed during study will be discussed with core clinical trial 
team (CTT) and will be summarized before IA lock. 
Table 6-1 
Protocol deviation codes and analysis sets 
Category    
   Deviation code 
Text description of deviation 
Data exclusion 
Subjects are excluded from all analysis in case of these PDs:  
Exclude subject completely 
from all analysis sets 
 
No additional PD here 
Subjects are excluded from full analysis set in case of these 
PDs:  
No additional PD here  
Exclude subject from full 
analysis set  
 
 
 
Subjects are excluded from per protocol analysis set in case of 
these PDs: 
Exclude subject from per 
protocol analysis set 
EXCL37 
 
 
COMD01 
 
   
  INCL04 
Subject is using therapies known to affect 
muscle mass, including androgens, androgen 
supplements.  
 
Subject took a prohibited medication while in  
the trial, however was not discontinued from 
the trial. 
"Time for 4 meters" should be greater or equal 
to 5 sec (which equates 0.8 m/sec) but less 
than 13.3 sec (which equates to 0.3 m/sec). 
Yes 
 
 
Yes 
 
 
Yes 
 
 
 
 
 
 
  No additional PD here 
After database lock and unblinding, the treatment allocation will be checked against the study 
drug actually received. 


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7 
Statistical methods: Analysis sets 
 
Assignment of patients to the different analysis sets 
 
will be performed prior to the unblinding of the treatment code and start of the final data 
analysis. 
The following analysis sets are defined for final analysis purposes: 
Randomized analysis set: All randomized patients, regardless of whether the patient received 
study drug. Subjects will be analyzed according to treatment assigned at randomization. 
Safety (SAF) analysis set: The SAF analysis set will consist of all patients who received at 
least one infusion of study drug. Patients will be analyzed according to the treatment actually 
received. If a patient received only part of the infusion (i.e. study drug infusion permanently 
discontinued), the patient will be regarded as having received study drug infusion and will be 
included in the SAF analysis set. 
Full analysis set (FAS):  
The full analysis set (FAS) comprises all subjects to whom study treatment has been assigned. 
Following the intent to treat principle, subjects will be analyzed according to treatment assigned 
at randomization. Patients who are randomized erroneously in IRT system and did not receive 
any treatment will be excluded. FAS is key analysis set to be used for most of the efficacy 
endpoints. 
Per Protocol (PP) analysis set: The 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 analysis set will be identified and finalized based on blinded review of 
the data, prior to the final database lock. Patients will be analyzed according to the treatment 
they were assigned to at randomization. The following are common examples of such 
deviations: 
• Subject entered the study even though they did not satisfy the entry criteria (INCL04) 
• Subject developed study/treatment withdrawal criteria during the study but was not 
withdrawn (EXCL37) 
• Subject took a prohibited concomitant medication (COMD01) 
• Subjects with SPPB baseline score (Baseline visit 2) should be less or equal to 9 
Per protocol set will be identified and finalized based on blinded review of data, prior data base 
lock. 
For definitions of major protocol deviations see Section 6 (Protocol deviations). 
 
 
 
 
 


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7.1 
Recommended visit windows: 
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. If any visits are delayed or missed, the 
site personnel should ensure alignment of future visits according to the originally planned visit 
schedule: 
• Randomization / Day 1: + 2 days 
• Weeks 3: +/- 2 days 
• Weeks 5-13: +/- 4 days 
• Weeks 17-29: +/- 7 days 
 
7.2 
Patient disposition, background and demographic 
characteristics 
Relevant raw and derived data as described in this section will be presented in by-patient data 
listings. All by-patient data listings will be sorted by treatment group, region, center and patient 
if not indicated otherwise. 
Where relevant, “across all treatment groups” refers to the addition of a “Total” column within 
the planned presentation of the data. Similarly “overall” refers to overall levels of stratification 
of the relevant subgroup. 
7.2.1 
Patient disposition 
All randomized patients will be summarized using number (n) and percentage (%) overall and 
by subgroups (refer to Section 5) for each treatment group and across all treatment groups 
combined. Furthermore, for each study epoch (screening and treatment) the number of patients 
per treatment group and the overall number of patients who entered the epoch, completed, and 
discontinued within the epoch will be summarized in a similar manner, including the reasons 
for discontinuation. 
The number (n) and percentage (%) of randomized patients with protocol deviations will be 
summarized by category and deviation, overall and by subgroups (refer to Section 5), for each 
treatment group and across all treatment groups combined. Patients with protocol deviations 
will be listed. 
The number (n) and percentage (%) of randomized patients included in each analysis set will 
be summarized. Reasons for exclusions from analysis sets will be tabulated overall for all 
patients and by subgroups for each treatment group and across all treatment groups combined. 
Patient exclusion from analysis sets will be listed for all patients with reason(s) for exclusion, 
including both major protocol deviations and/or other exclusion criteria. 
7.2.2 
 Patient demographics and other baseline characteristics 
Descriptive statistics for demographics, baseline characteristics and disease history will be 
presented to describe the FAS. All summaries will be presented overall and subgroups (refer to 
Section 5) for each treatment group and across all treatment groups combined. Unless otherwise 
specified, percentages will be based on the number of patients in the FAS with data available. 


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7.2.2.1 
Demographics 
Demographic variables collected at screening include age in years (as recorded in the 
Demography eCRF), sex, race and ethnicity. 
 (see Section 5 [Subgroups]) 
7.2.2.2 
Patient baseline characteristics 
Unless otherwise stated, baseline is defined as the last available assessment performed prior to 
the start of the first infusion (except screening assessments) of study drug. All relevant 
pretreatment assessments, including baseline value will be summarized overall and subgroups 
(refer to section 5) using default descriptive statistics. Baseline characteristics will include 
physical descriptors of body size: height (cm), weight (kg), body mass index (BMI) (kg/m2)  
and ASMI; and functional measurements: 6MWT, SPPB total score, gait speed, 
 
.  
Disease history 
 
Medical history 
Relevant medical history/current medical conditions will be presented by number (n) and 
percentage (%) of all patients assigned to FAS according to the latest available Medical 
Dictionary for Regulatory Activities (MedDRA) primary system organ class (SOC) and 
preferred term (PT), regardless of whether the status is reported as ongoing or not ongoing. 
Unless otherwise specified, primary system organ classes will be sorted by descending order of 
total frequency and within each primary system organ class, the preferred terms will be sorted 
by descending order of total frequency as well. In the event of SOCs and/or PTs with equal total 
frequencies, the relevant SOCs and/or PTs will be sorted alphabetically. The number (n) and 
percentage (%) of patients having at least one medical history/current medical condition, and 
having at least one medical history/current medical condition in each primary SOC, and for 
each PT will be presented. Hence if a patient reported more than one medical history/current 
medical condition with the same PT, the medical history/current medical condition will be 
counted only once. If a patient reported more than one medical history/current medical 
condition within the same primary SOC, the patient will be counted only once at the system 
organ class level. 
Cardiovascular co-morbidities 
Occurrence (yes/no/unknown) of cardiovascular diseases as pre-specified in the Cardiovascular 
History eCRF will be presented by number (n) and percentage (%) of all patients assigned to 
FAS. The disease status (ongoing/not ongoing/not applicable) will be listed. 
 
 
 


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Nutritional status 
Nutritional status will be summarized by both descriptive measures for quantitative variables 
(calculated protein intake) and qualitatively for patient's daily protein intake categories (< 0.8 
grams 
protein/kg 
and 
≥ 
0.8 
grams 
protein/kg), 
nutritional 
status 
(sufficiently 
nourished/malnourished), and action taken if malnourished if available (dietary counseling with 
or without intervention/no dietary counseling). 
7.3 
Efficacy/ Pharmacodynamic assessments 
Total LBM, ASMI 
Dual energy X-ray absorptiometry (DXA) will be used to assess changes in total lean body mass 
(LBM) and appendicular skeletal muscle index (ASMI). DXA instruments use an x-ray source 
that generates and is split into two energies to measure bone mineral mass and non-bone/non-
fat mass generalized as fat-free mass (LBM). LBM of the arms and legs when collectively 
presented and normalized for the person’s height is identified as appendicular skeletal muscle 
index (ASMI) and soft tissue from which fat mass (total body fat) and fat-free mass are 
estimated. 
Baseline data (all relevant pre-treatment assessments, including Baseline value) of total LBM, 
ASMI will be summarized using descriptive statistics. 
SPPB 
The short physical performance battery (SPPB) contains three physical functional activities for 
the lower extremities divided into three functional components: balance test, usual gait speed 
and chair stand test. A score (0-4) will be calculated for each of the three components. In 
addition a total SPPB score will also be calculated. In each case the lowest possible value is 
zero (0). 
Higher values correspond to better functional condition.  
Balance test: Total standing balance score is calculated as the sum of the scores of side-by-side 
stand, semi-tandem stand and tandem stand. 
• Side-by-side stand: held for 10 sec = 1 point, not held for 10 sec or not attempted = 0 
points. 
• Semi-tandem stand: held for 10 sec = 1 point, not held for 10 sec or not attempted = 0 
points. 
• Tandem stand: held for 10 sec = 2 points, held for 3 to 9.99 sec = 1 point, held for less 
than 3 sec or not attempted = 0 points. 


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Gait Speed: Gait speed 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 
patient will perform two recorded trials of walking across the defined course. The fastest time 
in seconds (to the nearest 0.01 sec) a patient takes to complete the assessment will be scored 
and recorded in the Gait Speed section of the SPPB eCRF. If only one walk was performed, this 
time will be used. Any walking aid(s) used during the SPPB gait speed test performance will 
be captured in the eCRF. The scoring system is as follows: 
• Time < 4.82 sec = 4 points. 
• Time ≥ 4.82 to ≤ 6.20 sec = 3 points. 
• Time ≥ 6.21 to ≤ 8.70 sec = 2 points. 
• Time > 8.70 sec = 1 point. 
• Patient is unable to do the walk = 0 points. 
Chair stand test: At first the chair stand test will be done one time (singular chair stand test). If 
the patient used arms to stand or the test could not be completed then the test procedure will be 
stopped and the score for the test is 0 points. If the patient stood up without using arms the aim 
of the second part of the test is to stand up five times (repeated chair stand test). The scoring 
system is as follows: 
• Time to complete 5 stands ≤ 11.19 sec = 4 points. 
• Time to complete 5 stands ≥ 11.20 to ≤ 13.69 sec = 3 points. 
• Time to complete 5 stands ≥ 13.70 to ≤ 16.69 sec = 2 points. 
• Time to complete 5 stands ≥ 16.70 to ≤ 60 sec = 1 point. 
• Patient is unable to complete 5 chair stands or has completed stands in > 60 sec = 0 points. 
The total SPPB score will be calculated as the sum of the total standing balance score, gait speed 
test score and chair stand test score.  
Handling of missing data: If a test is not done (i.e. test not done is ticked in the eCRF) there 
will be no imputation of data. Since the standing balance tests become progressively more 
difficult with each test, if the result for the tandem stand or semi-tandem stand is missing the 
result will be imputed by 0 points, provided that the previous test(s) had been performed. In all 
other cases there will be no imputation. 
Baseline data (all relevant pre-treatment assessments, including Baseline value) of the total 
SPPB score with the corresponding scores of the three individual component tests: balance test, 
gait speed, and chair stand test will be tabulated in a frequency table. Categories for each of the 
individual component tests will be: 
• 0 points. 
• 1 point. 
• 2 points. 
• 3 points. 
• 4 points. 
Categories for the total SPPB score will be: 


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• 0 to 5 points. 
• 6 to 9 points. 
• 10 to 12 points. 
In addition to the scores, the actual time of the timed function tests will be summarized for the 
individual components using descriptive statistics: 
• Balance test: Side-by-side stand, semi-tandem stand and tandem stand, number of seconds 
held. 
• If the patient attempted the test and is indicated as “Held for 10 seconds” then a value 
of 10 seconds will be used. 
• If the patient attempted the test and is not indicated as “Held for 10 seconds” then the 
reported number of seconds will be used. 
• Gait speed test: Times of the first and second gait speeds.  
• If the patient attempted the test successfully, time for 4 meters as reported in seconds. 
• Chair stand test: 
• If the patient attempted the test successfully, the time to complete five stands as 
reported in seconds will be used. 
If a patient did not attempt a test or failed, the patient will have a missing time for that test. 
Six Minute Walk Test (6MWT) 
The 6 minute walk test (6MWT) is a simple, economical and reproducible test that measures 
how many meters a person can walk in 6 minutes. Total distance walked will be summarized 
by descriptive statistics. All subjects will be included in the descriptive statistics with the actual 
distance walked. In circumstances where the test is interrupted for reasons other than patient 
fatigue the test may be repeated once, preferably on the same day (with a minimum 20 minute 
rest period). Total distance walked will be summarized by descriptive statistics. Walking aids 
used for the test will be summarized by category: 
• Ankle foot orthotic 
• Knee-ankle foot orthotic/long leg brace 
• Cane with 1 point of floor contact 
• Cane with >1 point of floor contact 
• Crutch 
• Hemi-walker 
• Walker without wheels 
• Wheeled walker 
• Rollator 
The number (n) and percentage (%) of patients who prematurely discontinued the test will be 
presented. Walking aids used for the test will be summarized by both descriptive measures for 
quantitative variables (number of aids used) and qualitatively for different devices used. 
 


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7.5 
Other Assessments 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. Further detail of this investigation is available in protocol. 
 
 
 
 
 


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8 
Treatments (study drug, other concomitant therapies, 
compliance) 
Relevant raw and derived data as described in this section will also be presented in by-patient 
data listings. All by-patient data listings will be sorted by treatment group, region, center and 
patient if not indicated otherwise. 
Where relevant, “across all treatment groups” refers to the addition of a “Total” column within 
the planned presentation of the data. Similarly “overall” refers to overall levels of stratification 
of the relevant subgroup. 
8.1 
Study drug administration 
Compliance is expected to be good since study drug will be administered by the investigator or 
study personnel, unless the patient misses clinic visits. Compliance will be calculated for each 
patient as follows: 
• Compliance (%) = (Number of study drug infusions received/Number of treatment epoch 
visits) * 100 
Here the number of treatment epoch visits is counted as the number of planned treatment visits 
until study treatment discontinuation or study treatment completion (i.e. last study drug 
infusion). 
If a patient received only part of an infusion (i.e. infusion start time is recorded but study drug 
infusion permanently discontinued is indicated as “Yes” in the Dose Administration Record – 
Infusion eCRF), the patient will be regarded as having received study drug infusion at that visit 
for the purpose of compliance calculation. 
 
 
 
 
 
8.2 
Prior and concomitant medications 
The number (n) and percentage (%) of patients taking prior and concomitant medications will 
be summarized in separate tables by Anatomical Therapeutic Chemical (ATC) classification 
and PT, by treatment group and across all treatment groups combined. 
Medications will be presented by anatomical main group (the 1st level of the ATC codes), sorted 
by descending frequency of the total number of patients with at least one medication in each 
ATC Level 1 category. Within each ATC Level 1, the PTs will be sorted by descending 
frequency of the total number of patients with at least one medication in each PT. In the event 
of ATC categories and/or PTs with equal total frequencies, the relevant ATC categories and/or 
PTs will be sorted alphabetically. Tables will present the overall number (n) and percentage 
(%) of patients receiving at least one medication and receiving at least one medication of a 
particular ATC code. 
Prior medications are defined as medications started and stopped prior to the start of the first 
infusion of study drug. Concomitant medications are defined as any medication which started 


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or stopped on or after the start of the first infusion of study drug up to the last infusion of study 
drug + 56 days or are ongoing. 
Prior or concomitant medication will be identified based on recorded or imputed start and end 
dates of medication taken. If it cannot be established that the use of a prior medication has ended 
prior to the start of the first infusion of study drug due to a missing end date, then it will be 
considered concomitant. Algorithms for date imputations will be provided in RAP Module 8 
(Programming Specifications). 
 
10 
Statistical methods for Pharmacodynamic (PD) parameters 
Relevant raw and derived data as described in this section will be presented in by-patient data 
listings. All by-patient data listings will be sorted by treatment group, region, center and patient 
if not indicated otherwise. 
Where relevant, “overall” refers to overall levels of stratification of the relevant subgroup. 
Table 10-1 Analysis set to be used for different endpoints  
Endpoint 
                                  Type of Analysis 
Summary (Table / Graph) 
Statistical Analysis 
SPPB (Primary) 
FAS 
PPS/FAS 
Gait Speed  
FAS 
PPS/FAS 
6MWT 
FAS 
FAS 
LBM 
FAS 
FAS 
ASMI 
FAS 
FAS 
 
 
 
 
 
 


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Endpoint 
                                  Type of Analysis 
Summary (Table / Graph) 
Statistical Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Safety endpoints 
Safety analysis set 
Safety analysis set 
 
 
 
Listings* 
 
 
All subjects 
All Subjects 
*Unless specified otherwise 
Summary of continuous endpoints: 
All continuous endpoints (SPPB total score, 6MWT, Gait Speed, LBM, ASMI, 
 
 
 will be summarized using 
descriptive statistics, overall and subgroups (refer to section 5) per treatment and visit for 
change from baseline.  
Measurements for all available visits will be taken into consideration. 
10.1 
Analysis of the primary variable(s) 
The primary objective of this study is to assess the effect of 24 weeks of bimagrumab treatment 
on patient physical function assessed by a change in Short Physical Performance Battery 
(SPPB) total score from baseline to week 25 relative to placebo in older patients with 
sarcopenia.  
10.1.1 
Variable 
The primary endpoint is SPPB change from baseline to week 25. The baseline value should be 
the one obtained at Visit 5 whenever possible. If Visit 5 data is not available, the SPPB data 
from Visit 3 should be used. If the individual participant does not have SPPB data from either 
Visits 3 or 5, then the person should be excluded from the analysis.    


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10.1.2 
Descriptive statistics 
SPPB total score as well as score in different domains will be summarized using table and 
graphics as explained in section 10 ‘summary of continuous endpoints’. Additionally a shift 
table will be prepared to reflect the patient count under each absolute SPPB total score category 
from baseline to week 25. 
10.1.3 
Statistical model, hypothesis and method of analysis 
This study is planned to be conducted in two parts. 
10.1.3.1 Analysis for Part A 
Part A is focused on proof of concept of BYM338 on SPPB change from baseline score in older 
adults with sarcopenia. In this part maximum dose of BYM338 (700mg) will be compared with 
placebo to establish the following criteria: 
 
 
Analysis plan: Change from baseline SPPB total score at 25 week will be analyzed using an 
analysis of variance model (ANCOVA) with treatment and subgroup1 (Japan / non-Japan) as 
fixed effects and baseline SPPB total score as covariate. A 95% two sided confidence interval 
(CI) of treatment vs placebo will be estimated for treatment vs placebo contrast. To establish 
‘statistical significance’, the lower CI is required to be positive. 
 
 
Analysis plan: Change from baseline SPPB total score at 25 week will be analyzed using an 
analysis of variance model (ANCOVA) with treatment and subgroup 1 (Japan/ non-Japan) as 
fixed effects and baseline SPPB total score as covariate. In order to establish ‘clinical 
significance’, the point estimate of treatment vs placebo is required to be more than 1 unit. 
 
Primary analysis will be performed on PPS (per protocol set). 


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10.1.3.3 Supportive analysis 
As a supportive analysis, a mixed repeated measures analysis of variance (MMRM) will be 
done on absolute change from baseline with a covariate for treatment (placebo or bimagrumab 
dose group), visit, baseline, visit*baseline, visit*treatment and subgroup1 (Japan/ non-Japan) 
(Japan, non-Japan). If Japanese subjects are enrolled, then Japan will be considered a separate 
region and give rise to a separate fixed covariate in the analysis. A saturated covariance structure 
for observations within the same subject will be used. Treatment to placebo comparison (70 mg 
vs. placebo, 210 mg vs. placebo, and 700 mg vs. placebo) at the 6 month time point will be 
estimated along with 95% two sided confidence interval and one sided p-value for treatment 
superiority over placebo will be reported. No adjustment for multiplicity will be done. If 
convergence problems are noted due to a sparse number of Japanese subjects, then the analysis 
may be redone while omitting this covariate. For MMRM analysis following visits will be 
considered: baseline, V103, V104, V106, V107. 
Additionally for Part A, in order to investigate the overall occurrence of 1 unit increase in 
different treatment arms; responders will be modelled using treatment and subgroup1 (japan/ 
non-Japan) as covariates to compare the relative responder rate. A patient will be identified as 
responder if SPPB change from baseline score at week 25 ≥1. 


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10.1.4 
Sensitivity analysis 
In case the PP analysis is different from the FAS set, the primary analyses will be repeated for 
the full analysis set (FAS) as confirmation of the primary analysis results. 
10.1.5 
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 SPPB are independent of unobserved measurements (missing 
at random [MAR]). Therefore the missing values will not be imputed for primary analysis. 
10.2 
Analysis of secondary 
 variables 
10.2.1 
Secondary variables 
Secondary endpoints are: 
• Gait speed measured as a component of the SPPB over 4 meters change from baseline: 
      Gait speed will be reported in two ways. 
a. Average gait speed. 
b. Fastest gait speed which is accounted for under SPPB scoring. 
The change in gait speed from baseline at V103, V104, V106, and V107 will be analyzed 
using a MMRM model with treatment, visit, baseline, visit*baseline, visit*treatment and 
subgroup1 (Japan/ non-Japan) as covariates. Treatment to placebo comparison (70 mg vs. 
placebo, 210 mg vs. placebo, and 700 mg vs. placebo) at the each visit will be estimated 
along with 95% two sided confidence interval and one sided p-value for treatment 
superiority over placebo will be reported. No adjustment for multiplicity will be done. 
A MCP-MOD (only V107, for Part B) analysis will be performed with same candidate 
families as used for the primary end point will be used (linear, convex, concave families). 
The underlying assumptions of the repeated mixed model (homogeneity of slopes and 
normality) may be assessed by QQ plots of the studentized residuals. In case of departure 
from normality, the log of the ratio to baseline will be analyzed instead the change from 
baseline   
 
• 6 minute walk test (6MWT) change from baseline. 
The change in 6 minute walk test from baseline at V104 and V107 will be analyzed in a 
similar manner to the gait speed with an MCP-MOD (only V107 at Part B) analysis as 
well as MMRM model. 
 
• DXA parameters: total lean body mass and appendicular skeletal muscle index (ASMI) 
change from baseline  
The ratio to Baseline in total LBM and appendicular skeletal muscle index (ASMI) will 
be analyzed with MMRM model. Data will be transformed using natural logarithm 
before analysis. Log transformed ratio to baseline DXA parameters (LBM / ASMI) will 
be analyzed using an MMRM model with log baseline, treatment, subgroup1 (Japan/ 


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non-Japan), visit, visit*baseline, visit*treatment. A saturated covariance structure will 
be used for observations coming from same subject. All results for treatment vs placebo 
contrast will be back transformed to the original scale to present adjusted geometric 
mean ratio with two sided 95% CI and one sided p-value for treatment superiority over 
placebo will be reported. 
Visits to be considered for this analysis: Baseline, V104, V107. 
Scatter plot matrix will be produced to explore the association between mean change in total 
LBM and aLBM and other efficacy variables (gait speed, total SPPB and 6MWT) by treatment, 
subgroup1 (Japan/ non-Japan) and visit. 
MMRM results will be reported at IA. 


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10.2.3 
Additional analysis 
HA questions 
Sarcopenia Assessment: 
All randomized patients will be evaluated by treatment groups based on their baseline and week 
25 performances under each of the following categories to assess sarcopenia status based on 
different assessment criteria: 
1. Assessment of lean mass using ASMI (for protocol): 
• Non-Asian countries: ≤ 7.26 kg/m2 for men and ≤ 5.5 kg/m2 for women to be assessed 
during screening. 
• Asian countries: ≤ 7.0 kg/m2 for men and ≤ 5.4 kg/m2 for women to be assessed 
during screening 
2. Alternative method for measuring lean mass (for FNIH): 
• ALM/BMI (appendicular lean mass from DXA / [weight in kg/ ht in m2]) qualifying 
cut off points  <0.789 for men and <0.512 for women (Studenski et. al. 2014) 
3. 
 
 
 
 
 
 
 
4. GS <0.8m/sec 
5. Protocol-defined sarcopenia: Meets criteria #1 and #4 
6. FNIH-defined sarcopenia: Meets criteria #2 and #4 
7. EWGSOP-defined severe sarcopenia: Meets criteria #1, #3 and #4 


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A single table representing n and percentages of subjects meeting each individual criterion 
at baseline and week 25 will be reported by treatment groups. 
Analysis of AEs of special interest: 
Number and percentage of AEs under each of the following categories will be summarized by 
treatment groups: 
 
 
 
Treatment adherence: 
Per protocol 6 doses are planned for each patient. 
Treatment adherence of patients will be represented by summarizing patients by number of 
doses using the definition explained in section 8.1.  
11 
Safety analysis  
Relevant raw and derived data as described in this section will also be presented in by-patient 
data listings. All by-patient data listings will be sorted by treatment group, region, center and 
patient if not indicated otherwise. 
Descriptive statistics for safety variables will be presented for the safety analysis set. 
Where relevant, “overall” refers to overall levels of stratification of the relevant subgroups.  
11.1 
Cardiac toxicity – cardiomyopathy analysis 
The odds ratio (to placebo) of experiencing at least one cardiac toxicity event (based on events 
identified by the investigator in the cardiomyopathy eCRF) will be calculated together with 2-
sided 95% confidence intervals for each of the bimagrumab treatment groups versus placebo 
treatment group. A p-value comparing each bimagrumab regimen (70 mg, 210 mg and 700 mg) 
versus pooled placebo will be calculated using Fisher’s exact test. The odds ratio, 95% 
confidence interval for the odds ratio will be presented for each independent comparison. The 


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results of these analyses will be presented in tabular form. Kaplan-Meier estimate for time to 
the first confirmed event with 95% confidence intervals will be presented for each treatment 
group. Differences between placebo and each of the bimagrumab treatment groups will be 
quantified by log-rank test. If a patient does not have a cardiac toxicity event the data will be 
censored to the study discontinuation/premature discontinuation date (see section 13.6.2for 
more details). 
The same analysis may be also performed by subgroups in case of enough events of interest are 
observed in both groups or if the rates seem to be different in both groups. Alternatively, Cox 
regression analysis may be performed including subgroups as a covariate in case of imbalance 
between patients is observed  
Cardiac toxicity events (based on events as identified by the investigator and evaluated by the 
adjudication committee) will be listed in by-patient data listings. All by-patient data listings 
will be sorted by treatment group, region, center and patient if not indicated otherwise. 
11.2 
Adverse events 
Adverse events data analysis will be based on the safety analysis set. Adverse events will be 
deemed treatment-emergent if the date of onset or worsening of the AE is on or after the date 
of first infusion of study drug until the end of the study (as per protocol end of study defined as 
approximately 56 days after last infusion of study drug). Percentages will be calculated relative 
to the number of patients in the safety analysis set. Only treatment-emergent AEs (TEAEs) will 
be summarized but all AEs reported will be listed in by-patient data listings. All by-patient data 
listings will be sorted by treatment group, region, center and patient if not indicated otherwise. 
Separate summaries would be created for: 
• TEAEs regardless of study drug relationship. 
• TEAEs with suspected study drug relationship. 
• Other significant TEAEs leading to dose adjustment or discontinuation of study drug. 
Missing or incomplete TEAE onset dates will be imputed; algorithms for date imputations will 
be provided in RAP Module 8 (Programming Specifications). No imputation will be applied to 
TEAE end dates. Hence, if the end date is missing, the duration of the TEAE will be 
“continuing”. 
The most current MedDRA dictionary version will be used for coding and will be described in 
a footnote. 
Where relevant, “overall” refers to overall levels of stratification of the relevant subgroup. 
TEAEs by primary system organ class and preferred term 
The number (n) and percentage (%) of patients with TEAEs will be summarized by primary 
SOC, PT by overall and subgroups and treatment group. Unless otherwise specified, primary 
system organ classes will be sorted by descending order of total frequency and within each 
primary system organ class, the preferred terms will be sorted by descending order of total 
frequency as well. In the event of SOCs and/or PTs with equal total frequencies, the relevant 
SOCs and/or PTs will be sorted alphabetically. The number (n) and percentage (%) of patients 
having at least one TEAE, and having at least one TEAE in each primary system organ class, 
and for each PT will be presented. Hence if a patient reported more than one TEAE with the 


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same PT, the TEAE will be counted only once. If a patient reported more than one TEAE within 
the same primary system organ class, the patient will be counted only once at the system organ 
class level. 
TEAEs by study drug relationship 
The number (n) and percentage (%) of patients with TEAEs will be summarized by relationship, 
primary system organ class, PT by overall and subgroups and treatment group. If a patient 
reported more than one TEAE with the same PT, the AE with the strongest relationship (related) 
will be presented. If a patient reports more than one TEAE within the same primary system 
organ class, only one TEAE will be counted for that patient at the strongest relationship (related) 
in the total row for each primary system organ class. If TEAE “relationship” is missing, this 
variable will be listed as missing and treated as missing in summaries. 
TEAEs by severity 
The number (n) and percentage (%) of patients with TEAEs will be summarized by severity, 
primary system organ class, PT by overall and subgroups and treatment group. If a patient 
reported more than one TEAE with the same PT, the TEAE with the greatest (maximum) 
severity will be presented. If a patient reports more than one TEAE within the same primary 
system organ class, only one TEAE will be counted for that patient at the highest severity level 
in the total row for each primary system organ class. If TEAE “severity” is missing, this variable 
will be listed as missing and treated as missing in summaries. 
Overview of serious adverse events 
An overview of treatment-emergent AE/SAEs will be generated for 
• TEAEs 
• TESAEs 
• TESAEs leading to death. 
• TESAEs with suspected relationship to study drug. 
• TESAEs leading to discontinuation or dose adjustment of the study drug 
The number of patients with at least one TESAE in each category (patients with multiple 
TESAEs in each category are counted only once in each category) will be presented by 
treatment group, overall and by subgroups. 
11.3 
Deaths 
All the deaths in the clinical database will be listed. 
Deaths will be summarized by primary reason for death (specification) and will be presented 
by primary system organ class, PT and treatment group. Contributing reason for deaths will be 
listed only. 
SAEs for screen failure subjects 
Serious adverse events of screen failure subjects will be reported in a separate by-patient listing 
with key available information, (e.g., subject number, age/sex/race, preferred term, system 
organ class and action taken). 


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11.4 
Laboratory data 
All laboratory data will be listed by treatment, region, center, patient, and visit/time and if 
normal ranges are available abnormalities will be flagged. If ranges are available abnormalities 
and clinically notable values will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment by overall and subgroups and visit/time for Hematology, Clinical chemistry and 
Coagulation testing, for each population separately. For urinalysis, frequency tables will be 
presented. 
Summaries of newly occurring notable values will be similar to those of vital signs.  
Notable values are values which are considered as: 
• Low: Value below the lower limit of the normal range (LLN). 
• High: Value above the upper limit of the normal range (ULN). 
Liver enzyme abnormalities 
Newly occurring or worsening liver enzyme abnormalities will be summarized, for each 
population separately, using: 
• Number of subjects with newly occurring notable liver or pancreatic enzyme 
abnormalities will be summarized similarly to those of vital signs. Notable criteria for 
the table: 
o ALT or AST > 3 x ULN 
o ALT or AST > 5 x ULN 
o ALT or AST > 8 x ULN 
o TBL > 1.5 x ULN 
o TBL > 3 x ULN 
o ALP > 2 x ULN 
o ALP > 5 x ULN 
o ALT or AST > 5 x ULN & TBL > 2 x ULN 
o ALP > 5 x ULN & TBL >2 x ULN Hy’s law 


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Hormone panels (follicle stimulating hormone (FSH), luteinizing hormone (LH), Sex hormone-
binding globulin (SHBG) and testosterone, thyroid stimulating hormone (TSH). free thyroxine 
if available) will be summarized by gender separately. 
Notable laboratory values will be considered “newly occurring” if they had not been present at 
Baseline. If assessments cannot be made at Baseline due to missing value(s), post-baseline 
values meeting the notable criterion will be considered as newly occurring. 
Boxplots to visualize trends in longitudinal safety data will be created. 
11.5 
Vital signs 
Vital signs include height (cm), weight (kg), BMI (kg/m2), temperature (oC), pulse (beats/min), 
mean systolic blood pressure (SBP) (mmHg) and mean diastolic blood pressure (DBP) 
(mmHg). Height will be measured only once at Screening, hence BMI will be calculated for 
each visit using the Screening value of height and with the actual body weight value measured 
at the scheduled visit. Mean sitting and mean standing SPB/DBP will be calculated from the 
three assessments taken per visit and will be used for tabulation (as recorded in the Vital Signs 
eCRF). 
Summary statistics for vital sign variables at each scheduled visit and for the change from 
Baseline in vital signs at each scheduled post-baseline visit and End of Treatment/End of Study 
as relevant, will be presented using descriptive statistics. Change from Baseline will be derived 
only for patients with both Baseline and post-baseline measurements. 
Notable vital signs values will be considered “newly occurring” if they had not been present at 
Baseline. If assessments cannot be made at Baseline due to missing value(s), post-baseline 
values meeting the notable criterion will be considered as newly occurring. 
• Systolic blood pressure:  
• >150mmHG or increase at Week 25 of >=20 mmHg 
• <90mmHG or decrease at Week 25 of >=20 mmHg 
• Diastolic blood pressure:  
• >90mmHG or increase at Week 25 of >=15 mmHg 
• <50mmHG or decrease at Week 25 of >=15 mmHg 
• Pulse rate:  
• >100bpm or increase at Week 25 of >=15 bpm 
• <60bpm or decrease at Week 25 of >=15 bmp 
• Body weight:  
• +5% from Week 1 to 25 in kg 
• -5% from Week 1 to 25 in kg 
Notable newly occurring vital sign abnormalities will be summarized by count and percentages 
by treatment group, overall and by subgroups. 
All vital signs data will be listed by treatment, region, center, patient, and visit and if ranges are 
available abnormalities will be flagged. 
Boxplots to visualize trends in longitudinal safety data will be created. 


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11.6 
ECG 
All ECGs must be recorded after 10 minutes rest in the supine position. The Fridericia QT 
correction formula (QTcF) will be used for clinical decisions.  
Summary statistics will be presented for ECG parameters by visit and the change from Baseline 
will be presented at each scheduled post-baseline visit and End of Treatment/End of Study as 
relevant, for each treatment group. Change from Baseline will be derived only for patients with 
both Baseline and post-baseline measurements. 
The following quantitative variables will be summarized: ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, and corrected QT interval (QTc). Both Bazett (QTcB) and 
Fridericia (QTcF) corrections will be presented for QTc. 
QTc will also be summarized by computing the number and percentage of subjects with: 
• QTc > 500 msec 
• QTc > 480 msec 
• QTc > 450 msec 
• PR > 250 msec 
• QTc change from Week 25 > 30 msec 
• QTc change from Week 25 > 60 msec 
Data of patients with newly occurring or worsening ECG abnormalities at any scheduled or 
unscheduled visit after Baseline will be listed. 
All ECG data will be listed by treatment, region, center, patient and visit, abnormalities will be 
flagged. 
Boxplots to visualize trends in longitudinal safety data will be created. 
11.7 
Echocardiography 
The following echocardiography measurements will be collected: 
• Left ventricular end-diastolic volume (mL) 
• Left ventricular end-systolic volume (mL) 
• Left ventricular ejection fraction (%) 
• Interventricular septum thickness (mm) 
• Left ventricular end-diastolic diameter (mm) 
• Left ventricular end-systolic diameter (mm) 
• Left ventricular posterior wall thickness (mm) 
• Left ventricular anterior wall thickness (mm) 
• Left ventricular mass (g) 
• Left ventricular mass index (g/m2) 
• Relative wall thickness (ratio) 
• Fractional shortening (%) 
• Left atrial area (cm2) 


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• Left atrial volume (mL) 
• Right ventricular wall thickness (mm) 
• Right ventricular diameter in mid cavity (mm) 
Summary statistics for echocardiography measurements and for the change from Baseline at 
each scheduled post-baseline visit and End of Treatment/End of Study as relevant, will be 
presented for each treatment group. 
Change from Baseline will be derived only for patients with both Baseline and post-baseline 
measurements. 
All echocardiographic data will be listed by treatment group, region, center, patient and visit. 
11.8 
Other safety variables 
Other safety variables will be summarized descriptively by visit and treatment group and will 
be listed by treatment group, patient, and visit. Other safety variables include: 
• 
 


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13 
Clinical Study Report - Appendix 16.1.9 Documentation of 
statistical methods 
13.1 
Introduction 
This appendix details the statistical methods in addition to the report text. All analyses will be 
performed by using SAS® Version 9.3 or higher. 
13.2 
Precision and summary statistics 
If not otherwise specified, default summary statistics for quantitative variables for all analyses 
 will include: 
• The number of patients in each category (n). 
• Mean 
• Standard deviation (SD) 
• Minimum 
• Median 
• Maximum 
Summary statistics for all qualitative variables will be presented in contingency tables and will 
include number (n) and percentage (%) of patients. Percentages will be presented to one decimal 
place. The number of missing assessments will be displayed as part of a “missing” category, 
where appropriate. 
Data will be aligned within tables by the decimal point. 
All values will be rounded using the SAS® function ROUND. If the original data has N decimal 
places (as derived from the raw data) (i.e. decimal precision [N]), then the summary statistics 
will contain the following decimal places (with a maximum of 3 decimals): 
• The minimum, maximum: N. 
• The mean and median: N + 1. 
• The SD and standard error (SE): N + 2. 
For application of inferential statistics, the least squares (LS) means and corresponding 
confidence intervals (CIs) will be reported with one extra decimal relative to the individual raw 
data. The odds ratios and corresponding CIs will be reported with two decimal places where 
relevant. 
The p-values will be reported as follows: 


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• < 0.0001 will be presented as “<0.0001” (i.e. 0.00009 will be presented as
“<0.0001”). 
•  ≥ 0.0001 will be rounded to four decimal places. 
Note: Rounding will applied after the “<0.0001” rule. 
All significant p-values (i.e. < 0.05) will be flagged by means of an “*” for ease of review. 
13.3 
Study Day 1 and other study days 
The date of first infusion of study drug is defined as Study Day 1. All other study days will be 
labeled relative to Day 1. 
For event dates on or after Day 1, study day for an event date is calculated as: (event date – first 
infusion date) +1, which could be Day 1, Day 2, Day 3, etc. 
For event dates before Day 1, study day for an event date is calculated as: (event date – first 
infusion date), which could be Day -1, Day -2, etc., referring to 1 day, 2 days, etc., before Day 
1, respectively. 
Subsequently, Day 0 is not defined. 
13.4 
 Definition of Baseline and post-baseline measurements 
Baseline is defined as the last available assessment prior to the start of the first infusion of study 
drug, including pre-dose assessments from Day 1. However this should not include any 
screening assessment. If all the pre dose values except screening are not available in data base 
then baseline should be considered as missing. 
Assessments performed after the start of the first infusion are considered post-baseline 
assessments. 


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Change from Baseline is calculated where Baseline and post-baseline values are both available: 
• Change from Baseline = (post-baseline value – Baseline value). 
• Percentage Change from Baseline at each post-baseline visit: 
• Percentage Change from Baseline = [(post-baseline value – Baseline value)/Baseline 
value] * 100 
• Ratio from Baseline = (post-baseline value /Baseline value) (used in log transformed 
model) 
13.5 
Protocol-defined visits 
 
Visit Number 
Visit Name  
Days 
1 
Screening 
-50 to 30  
2 
Run-In Visit 1  
-29 to -23 
3 
Run-In Visit 2 
-22 to -16  
4 
Run-In Baseline 1 
-15 to -10  
5 
Run-In Baseline 2 
-5 to -1  
101 
W1D1 
1 + 2 days 
1015 
W3D1 
15 +/-2 days 
102 
W5D29 
29 +/- 4 days 
103 
W9D57 
57 +/- 4 days 
140 
W13D85 
85 +/- 4 days 
105 
W17D113 
113 +/- 7 days 
106 
W21D141 
141 +/- 7 days 
107 
W25D169 (End of treatment) 
169 +/- 7 days 
199 
EOS 
197 +/- 7 days 
 
13.6 
Analysis visits 
13.6.1 
Visit naming 
 
Visit Number 
Visit Name 
Target visit day 
Start day of 
visit window 
Midpoint 
End day of 
Visit 
window 
1 
Screening 
-50 to 30  
 
Not remapped 
 
2 
Run-In Visit 1  
-29 to -23 
 
Not remapped 
 
3 
Run-In Visit 2 
-22 to -16  
 
Not remapped 
 
4 
Run-In Baseline 1 
-15 to -10  
 
Not remapped 
 
5 
Run-In Baseline 2 
-5 to -1  
 
Not remapped 
 
101 
W1D1 
1  
 
Not remapped 
 


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1015 
W3D1 
15 
 
15 
22 
102 
W5D29 
29  
2  
29 
43 
103 
W9D57 
57 
44  
57 
71  
140 
W13D85 
85  
72  
85 
99  
105 
W17D113 
113  
100  
113 
127  
106 
W21D141 
141 
128  
141 
155  
107 
W25D169 (End of 
treatment) 
169 
156  
Not remapped  Not 
remapped  
199 
EOS 
197 
  
Not remapped   
By-visit presentations will be presented according to the nominal visit number, no visit 
windowing will be applied.  
13.6.2 
 Early discontinuation visit remapping 
Patients who prematurely withdraw from the study for any reason, will be scheduled for an End 
of Treatment visit approximately 28 days following their last study drug infusion, at which time 
all of the assessments listed for that visit will be performed. 
After the End of Treatment visit is completed, patients should return after an additional 4 weeks 
(28 days) for an End of Study visit.  
13.7 
Handling of missing values/censoring/discontinuations 
In general, unless otherwise indicated, no data imputation will be done for the missing values. 
13.8 
Imputation of missing and incomplete dates 
Adverse event and concomitant medication dates will be imputed per the Novartis standard 
tables, listings and figures (TLFs) conventions as detailed in the RAP Module 8 (Programming 
Specifications). All missing or incomplete dates shall however be listed in by patient data 
listings as recorded in the eCRF. 


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14 
References 
References are available upon request.