Clinical trial NCT02468674
Conditions: Sarcopenia
Keywords: Sarcopenia, muscle wasting, elderly, strength, physical function, lean body mass, gait speed
Sponsor: Novartis Pharmaceuticals
Start date: 2015-07-22; Completion date: 2018-12-03
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This extension study was a 24-week off-drug follow-up of the core CBYM338E2202 (NCT ) study and the main objective was to determine the long-term durability of bimagrumab (BYM338) effect after a 6-month treatment period.

Detailed description:
Two populations were defined as below:

* Population I: Patients enrolled prior to the protocol amendment 1, who received bimagrumab 70 mg, 210 mg or 700 mg in the core study, were randomly assigned to two subgroups within each of three treatment arms to either receive bimagrumab at the same dose level or placebo. Patients receiving placebo in the core study continued receiving placebo in the extension study.
* Population II: Patients enrolled after protocol amendment 1, who received bimagrumab 700 mg or placebo in the core study, did not receive study medication in the extension study and were followed-up per schedule defined in this protocol amendment.

Arms: arm 1: Patients in Population I received 6 doses of bimagrumab 70 mg, 210 mg, 700 mg or placebo - one approximately every four weeks - over a 20-week period providing drug exposure for a total of 24 weeks. arm 2: Patients in Population II received either bimagrumab 700 mg or placebo in the core study and did not receive any investigational treatment in the extension study.
Interventions: intervention 1: bimagrumab intervention 2: Placebo
Intervention descriptions: intervention 1: bimagrumab low dose bimagrumab moderate dose bimagrumab high dose

Patients enrolled prior to the protocol amendment 1 (Population I ), who received bimagrumab in the core study, entered the extension study at Week 25 and were randomly assigned to two subgroups within each of three treatment arms to either receive bimagrumab at the same dose level or placebo. Study medication was administered as an intravenous infusion starting at Week 25 after treatment was initiated in the core study until week 45. intervention 2: Placebo

Patients enrolled prior to the protocol amendment 1 (Population I), who received placebo in core study, entered the extension study at Week 25 and received placebo as an intravenous infusion starting at Week 25 after treatment was initiated in the core study until week 45.

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine
BYM338/bimagrumab
Clinical Trial Protocol CBYM338E2202E1 / NCT02468674
A 24 week off drug extension, parallel group, study 
assessing durability of effect on skeletal muscle strength 
and function following a 6-month double-blind, placebo 
controlled study evaluating bimagrumab in older adults 
with sarcopenia (InvestiGAIT extension)
Document type:
Clinical Trial Protocol 
EUDRACT number:
2015-000471-27
Version number:
v01 (clean)
Development phase:
II
Release date:
26-Apr-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0, November, 2013


Novartis
Confidential
Page 2
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................10
Amendment 1 (26-Apr-2017)............................................................................................12
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.2
Purpose ..................................................................................................................15
2
Study objectives.................................................................................................................15
2.1
Primary objective(s)...............................................................................................15
2.2
Secondary objectives .............................................................................................15
15
3
Investigational plan ...........................................................................................................16
3.1
Study design...........................................................................................................16
3.2
Rationale of study design.......................................................................................18
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....19
3.4
Rationale for choice of comparator .......................................................................19
3.5
Purpose and timing of interim analyses/design adaptations..................................19
3.6
Risks and benefits..................................................................................................19
4
Population..........................................................................................................................21
4.1
Inclusion criteria ....................................................................................................21
4.2
Exclusion criteria...................................................................................................21
5
Treatment...........................................................................................................................21
5.1
Protocol requested treatment .................................................................................21
5.1.1
Investigational treatment.......................................................................21
5.1.2
Additional study treatment....................................................................22
5.2
Treatment arms ......................................................................................................22
5.3
Treatment assignment, randomization...................................................................22
5.4
Treatment blinding.................................................................................................23
5.5
Treating the patient................................................................................................23
5.5.1
Patient numbering .................................................................................23
5.5.2
Dispensing the investigational treatment ..............................................23
5.5.3
Handling of study treatment..................................................................24
5.5.4
Instructions for prescribing and taking study treatment........................24
5.5.5
Permitted dose adjustments and interruptions of study treatment..........25


Novartis
Confidential
Page 3
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
5.5.6
Recommended treatment of adverse events...........................................25
5.5.7
Rescue medication.................................................................................25
5.5.8
Concomitant treatment ..........................................................................25
5.5.9
Prohibited treatment ..............................................................................26
5.5.10
Discontinuation of study treatment or from study.................................26
5.5.11
Withdrawal of consent...........................................................................27
5.5.12
Lost to follow-up...................................................................................28
5.5.13
Emergency breaking of assigned treatment ...........................................28
5.5.14
Study completion and post-study treatment...........................................28
5.5.15
Early study termination .........................................................................29
6
Visit schedule and assessments .........................................................................................29
6.1
Patient demographics/other characteristics at study entry.....................................36
6.1.1
Subject demographics ...........................................................................36
6.1.2
Other characteristics at study entry .......................................................36
6.2
Treatment exposure and compliance .....................................................................36
6.3
Efficacy..................................................................................................................36
6.3.1
6 minute walk test..................................................................................37
6.3.2
Short physical performance battery.......................................................37
6.3.3
Gait speed..............................................................................................38
6.3.4
Total lean body mass and appendicular skeletal mass index (ASMI) 
assessed by DXA...................................................................................38
38
6.4
Safety.....................................................................................................................40
6.4.1
Physical examination.............................................................................40
6.4.2
Vital signs..............................................................................................41
6.4.3
Height and weight .................................................................................41
6.4.4
Laboratory evaluations ..........................................................................41
6.4.5
Electrocardiogram (ECG)......................................................................42
6.4.6
Echocardiography .................................................................................43
6.4.7
Pregnancy..............................................................................................43
43
43
43
6.7
Telephone contact..................................................................................................44
7
Safety monitoring ..............................................................................................................44
7.1
Adverse events.......................................................................................................44
7.2
Serious adverse event reporting.............................................................................46
7.3
Liver safety monitoring .........................................................................................47
7.4
Pregnancy reporting...............................................................................................48


Novartis
Confidential
Page 4
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
8
Data review and database management.............................................................................48
8.1
Site monitoring ......................................................................................................48
8.2
Data collection .......................................................................................................48
8.3
Database management and quality control ............................................................49
8.4
Data Monitoring Committee (DMC) .....................................................................50
8.5
Adjudication Committee........................................................................................50
9
Data analysis......................................................................................................................51
9.1
Analysis sets ..........................................................................................................51
9.2
Patient demographics and other baseline characteristics.......................................52
9.3
Treatments .............................................................................................................52
9.4
Analysis of the primary variable(s) .......................................................................52
9.4.1
Variable(s).............................................................................................52
9.4.2
Statistical model, hypothesis, and method of analysis..........................53
9.4.3
Handling of missing values/censoring/discontinuations.......................53
9.4.4
Supportive analyses...............................................................................53
9.5
Analysis of secondary variables ............................................................................53
9.5.1
Efficacy variables..................................................................................53
9.5.2
Safety variables .....................................................................................54
56
9.5.4
PK/PD ...................................................................................................56
9.6
Interim analyses .....................................................................................................56
9.7
Sample size calculation..........................................................................................56
10 Ethical considerations........................................................................................................57
10.1
Regulatory and ethical compliance........................................................................57
10.2
Informed consent procedures.................................................................................57
10.3
Responsibilities of the investigator and IRB/IEC ..................................................58
10.4
Publication of study protocol and results...............................................................58
11 Protocol adherence.............................................................................................................58
11.1
Protocol Amendments............................................................................................58
12 References .........................................................................................................................59
13 Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................61
14 Appendix 2: Sample Log...................................................................................................64
15 Appendix 3: Clinically notable laboratory values:............................................................66
67
 
71


Novartis
Confidential
Page 5
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
List of tables
26
Table 6-1
Assessment schedule for patients enrolled after the protocol 
amendment #1 .......................................................................................30
Table 6-2
Assessment schedule for patients enrolled prior to the protocol 
amendment #1 .......................................................................................32
Table 9-1
Standard deviation of SPPB..................................................................56
Table 9-2
Half-width of 95% confidence interval for SPPB.................................57
Table 13-1
Liver Event and Laboratory Trigger Definitions ..................................61
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers ...62
Table 15-1
Clinically notable lab values .................................................................66
List of figures
Figure 3-1
Study design for patients enrolled after the protocol amendment #1....16
Figure 3-2
Study design for patients enrolled prior to protocol amendment #1.....18
Figure 9-1
Comparisons between Treatment Arms for Population I......................53


Novartis
Confidential
Page 6
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
List of abbreviations
ActRII
Activin Type II receptor
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ASMI
Appendicular skeletal muscle index
AST
Aspartate aminotransferase
BDR
Bioanalytical Data Report
BUN
Blood urea nitrogen
b.i.d.
Twice a day
BMI
Body mass index 
BYM
Bimagrumab
CFR
US Code of Federal Regulations 
CK
Creatine kinase
CK-MB
Creatine kinase (heart muscle)
CK-MM
Creatine kinase (skeletal muscle)
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
CSR
Clinical Study Report
CV
Co-efficient of variation 
DMC
Data Monitoring Committee
DXA
Dual energy X-ray absorptiometry
eCCG
eCRF Completion Guidelines
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
EOS
End of study
EOT
End of treatment 
EU
European Union
EWGSOP
European Working Group on Sarcopenia in Older Persons
FAS
Full analysis set
FDA
US Food and Drug Administration 


Novartis
Confidential
Page 7
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
GCP
Good Clinical Practice
GS
Gait Speed
HgbA1C
Glycated hemoglobin
IB
Investigators Brochure
ICF
Inform Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notifications
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International units 
i.v.
Intravenous
LBM
Lean body mass
LFT
Liver function test (raised serum transaminases and/or bilirubin levels)
LLOQ
Lower Limit of Quantification
MedDRA
Medical dictionary for regulatory activities 
mSv
Milisieverts per hour (background radiation measurement)
OC/RDC
Oracle Clinical/Remote Data Capture
QA
Quality Assurance
QTcF
Fridericia QT correction formula 
PBO
Placebo
PD
Pharmacodynamics
PP
Per-protocol
RBC
Red cell count
SAE
Serious adverse event
SAF
Safety set
SD
Standard deviation


Novartis
Confidential
Page 8
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
 
sIBM
sporadic inclusion body myositis
SPPB
Short Physical Performance Battery 
µSv
Microsieverts per hour (ionizing radiation measurement)
WBC
White cell count
WHO
World Health Organization
γ-GT
γ-Glutamyltransferase
6MWT
6 Minute Walk Test


Novartis
Confidential
Page 9
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Glossary of terms
Assessment
A procedure used to generate data required by the study
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
A portion of the study which serves a specific purpose. Typical Epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination. 
Investigational treatment generally does not include protocol-specified 
concomitant background therapies  when these are standard 
treatments in that indication
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system
Protocol
A written account of all the procedures to be followed in a trial, which 
describes all the administrative, documentation, analytical and clinical 
processes used in the trial.
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Patient Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study


Novartis
Confidential
Page 10
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Protocol summary
Protocol number
CBYM338E2202E1
Title
A 24-week off drug extension parallel group study assessing the
durability of effect on skeletal muscle strength and function following a 6-
month double blind placebo controlled study evaluating bimagrumab in
older adults with sarcopenia
Brief title
A 24-week off drug extension study assessing the durability of effect of 
bimagrumab in older adults with sarcopenia previously participating in the 
6-month core study
Sponsor and Clinical 
Phase
Novartis 
Phase IIb
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of this extension study is to evaluate the durability of effect 
on skeletal muscle mass, strength and physical function upon 
discontinuation of treatment received in the core study 
Primary Objective(s) 

The primary objective is to assess the durability of effect of 
bimagrumab (BYM338) as measured by the short physical 
performance battery (SPPB) total score at week 49.
Secondary Objectives

To evaluate the safety and tolerability of bimagrumab following 
treatment withdrawal as assessed by measures such as vital signs, 
clinical laboratory variables, electrocardiogram (ECG), and adverse 
events (AE).

To evaluate the durability of effect of bimagrumab at week 49 as 
measured by:
o
6 minute walk test (6MWT)
o
mobility as measured in gait speed (GS) over 4 meters 
o
total lean body mass (LBM) and appendicular skeletal 
muscle index (ASMI) measured by dual energy X-ray 
absorptiometry (DXA)
Study design
This Phase IIb extension study is a 24 weeks off drug study following 24 
weeks of treatment in the core study (CBYM338E2202) in older patients 
with sarcopenia.
Population
The study population will be community-dwelling men and women ages 
70 years and older completing the full study treatment period (24 weeks) 
of the core study (CBYM338E2202) and willing to enter 
CBYM338E2202E1.
Inclusion criteria

Men and postmenopausal women aged 70 years or older that have 
participated in, and have completed the full study treatment period 
per protocol (24 weeks) in the preceding core study 
(CBYM338E2202)

Written informed consent must be obtained before any assessment 
of the extension study is performed (can be obtained at the End of 
Treatment (EOT) visit of the core study).
Exclusion criteria
Any condition which should have led to treatment discontinuation per 
protocol in the core study.


Novartis
Confidential
Page 11
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Investigational and 
reference therapy
none
Efficacy assessments

6MWT to assess functional improvement

SPPB to assess physical functional improvement

Usual GS to assess physical functional improvement

LBM and ASMI assessed by DXA to measure total and regional lean 
body mass.
Safety assessments

Physical examination

Vital signs

Weight

Laboratory evaluations

ECG
Data analysis
Summary statistics by treatment arm will be provided for the primary 
endpoint and continuous secondary endpoints. A 95% confidence interval 
for the difference between each continued bimagrumab dose arm vs. 
corresponding placebo switched from the same bimagrumab dose will be 
calculated at each visit. 
Key words
Durability of effect, safety of bimagrumab in patients with sarcopenia.


Novartis
Confidential
Page 12
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Amendment 1 (26-Apr-2017)
Amendment rationale
The purpose of this amendment is to revise the extension study design to align it with changes 
recently implemented in the core study CBYM338E2202 while maintaining and further 
focusing the primary purpose of the extension study to evaluate the durability of effect of 24 
weeks of bimagrumab therapy upon treatment discontinuation.
The original study was designed to evaluate several questions i.e. how long the potential
effect of 24 weeks of bimagrumab treatment would be maintained following treatment 
discontinuation and if a 48 weeks continuous treatment would provide additional benefit over 
a 24 weeks treatment period. The randomized withdrawal feature of the design reduced the 
sample size of each treatment arm with the risk of not being able to address the questions. 
Novartis with this amendment is removing this withdrawal randomization feature and is 
refocusing the study on one main question: how long the potentially observed effects after 24 
weeks of treatment with bimagrumab will last once the treatment is discontinued? Therefore, 
all newly enrolled patients in this extension study will be followed off drug for a period of 24 
weeks. As a consequence, the size of each treatment arm will remain as per study entry and 
not reduced as the withdrawal randomization would otherwise do. Questions no longer 
addressed by this study may be addressed at later stage of the bimagrumab clinical 
development program if they are still relevant.
Patient visits over the 24 weeks are reduced from seven to three since there is no need for on-
site infusion every 4 weeks. This should substantially reduce patient burden and facilitate 
study acceptance. However in order to promote patients’ engagement and adherence to the 
study, there is a required exercise program 
and, monthly phone calls will 
be made to patients.
Patients active in the study upon implementation of this protocol amendment will remain on 
the original protocol visit schedule which reflects the randomized withdrawal design. This 
way all patients enrolled in this study prior to this protocol amendment will hav e a similar 
journey and even if the sample is small (estimated to approx. 45 patients) this sub-group of 
patients will provide valuable information on the effect of prolonged treatment for 49 weeks. 
At the time of this protocol amendment’s implementation it is anticipated that 10 to 15 
patients will be on going and will continue being dosed while newly enrolled patients will be 
followed off drug under a revised visit schedule.
The end of part A in the core study will trigger an interim analysis of the extension study data 
available at that time. Data from this extension study will be combined with the core study 
data and will enable decision making on the rest of the program. In addition, following this 
interim analysis, the global study team will be unblinded to the individual treatment codes 
from those patients included in this analysis. However, Novartis associates in the countries 
and site personnel will remain blinded to the treatment codes until the final study data base 
lock.
The rational for the changes implemented in the core study such as the change of primary 
endpoint, the reduction of the cardiac safety monitoring, 
 
 
are described in the core protocol amendment #2 (CBYM338E2202).
At the time of this amendment, approximately 45 patients have been enrolled in the study. 


Novartis
Confidential
Page 13
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The informed consent of the study will be amended. A copy of this amended protocol will be 
sent to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and Health 
Authorities. 
The main changes are the following:

Re-focus of the study on assessing the durability of effect of bimagrumab over a 24 week 
period off drug. As a result the withdrawal randomization design feature is removed and 
all newly enrolled patients are followed off drug, while patients previously enrolled will 
complete the study more or less as per the original visit schedule

Study is reduced to 24 weeks with site visits every 12 weeks instead of every 4 weeks and 
phone calls have been added in between visits to promote adherence and to record 
 
other associated feedback from study participants. 

Addition of a planned interim analysis

The need for unblinding of core treatment code for newly enrolled patients will follow the 
core study protocol procedure.

All IMP related sections are only applicable to those patients enrolled under the original 
protocol version

Inclusion/exclusion criteria were simplified as only patients willing and having fully 
completed the 24 weeks of core study treatment are eligible

As part of the alignment between the core and the extension studies, the following key 
changes are implemented in this extension study:

The SPPB replaced the 6MWT as primary endpoint, the 6MWT changed to a 
secondary endpoint

The 400 meter walk test was removed 

Echocardiography was eliminated and overall cardiac monitoring was reduced from a 
level of intense monitoring to one reflecting standard of care following the results of 
the dedicated profiling cardiac safety study

Additional safety monitoring guidance for patients with change in body weight since 
the core study baseline of +/- 5%

Removal of certain central laboratory assessments (i.e. urinalysis, coagulation 
measurement)

e-devices diaries 
 are replaced by paper diaries which are easier to 
use for this patient population
 

The frequency of the DXA assessment was reduced to a final one at the EOS only


Novartis
Confidential
Page 14
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
1
Introduction
1.1
Background 
CBYM338E2202E1 is a 24-week post-treatment follow-up study of the Phase IIb sarcopenia 
study CBYM338E2202. This core study is a multi-centered, parallel group dose ranging 
finding study to assess the effect of 6 monthly doses of bimagrumab on skeletal muscle mass, 
strength and function in older patients with sarcopenia.
Sarcopenia, the age-associated loss of skeletal muscle mass and physical function (Cruz-
Jentoft et al 2010; Fielding et al 2011), is a common geriatric syndrome with approximately 
2-13% of individuals over 65 years and up to 30% of adults over 80 years affected (Dam 2014, 
Volpato 2013). While there is no single set of diagnostic criteria for sarcopenia, multiple 
consensus statements all agree that reductions of muscle mass and gait speed (GS) are the key 
patient characteristics of sarcopenia with only subtle differences with respect to the 
recommended cutpoints for each of these measures. More recently, in the first data-driven 
analysis of older adult subjects, cutpoints were recommended for both of these measures as 
well as grip strength (Studenski 2014). The most well accepted sarcopenia criteria at this time 
are those from the European Working Group on Sarcopenia in Older Persons (EWGSOP) and 
the Asian Working Group for Sarcopenia, and subjects enrolled in the Phase IIb study in 
sarcopenia (E2202) must meet the universal thresholds for gait speed and geographic specific
thresholds for muscle mass for entry into the study (Cruz-Jentoft 2010).  
Sarcopenia is associated with a myriad of complications, including mobility limitations, an 
increased risk of falls, fractures and hospitalizations, as well as additional healthcare costs, 
and increased mortality (Cruz-Jentoft 2010, Janssen 2004, Visser 2011). In addition, 
sarcopenic patients frequently require assistance with basic and instrumental activities of daily 
living (e.g., bathing, shopping) and lose independence. The societal cost of sarcopenia was 
calculated at over 18 billion US dollars in 2000 (Janssen 2004).   
Currently, there is no pharmacological treatment for sarcopenia and recommended treatment 
for sarcopenia includes strength training and nutritional optimization (e.g., protein and 
Vitamin D).
As a potent inhibitor of the Activin Type II receptor (ActRII), bimagrumab blocks the effects 
of negative regulators of muscle growth including myostatin, activin A, and GDF11 working 
through this receptor. An accelerated loss of muscle mass, strength and physical function in 
the large and rapidly growing global aging population represents a substantial, unmet medical 
need and a novel opportunity for a pharmacotherapeutic that can promote skeletal muscle 
hypertrophy and improve patient function.
The efficacy and safety of bimagrumab in sarcopenia is currently being evaluated in the 
CBYM338E2202 core study. The core study protocol and the study design were substantially 
amended in September 2016, including changes to the primary and some of secondary 
endpoints.
To maintain consistency with the core study (CBYM338E2202), the Short Physical 
Performance Battery (SPPB) has become the primary endpoint for this extension trial and
several other pertinent functional measures (e.g., 6 minute walk test (6MWT), gait speed (GS), 
spontaneous physical activity) will be collected as 
 secondary 
 endpoints.


Novartis
Confidential
Page 15
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
1.2
Purpose 
The purpose of this extension study (CBYM338E2202E1) is to evaluate the durability of 
effect on skeletal muscle mass, strength and physical function following 24 weeks of 
treatment with bimagrumab, in older patients with sarcopenia upon discontinuation of 
treatment. 
The results of this extension study will support the design of a phase III study of bimagrumab 
treatment for sarcopenia.
2
Study objectives
2.1
Primary objective(s)

The primary objective is to assess the durability of effect of bimagrumab (BYM338) on 
physical function as measured by the SPPB total score at week 49. 
2.2
Secondary objectives

To evaluate the long term safety effect of bimagrumab following treatment withdrawal as 
assessed by measures such as vital signs, clinical laboratory variables, electrocardiogram 
(ECG), and adverse events (AE) 

To evaluate the durability of effect of BYM at week 49 as measured by:

6MWT

usual gait speed over 4 meters

total lean body mass (LBM) and appendicular skeletal muscle index (ASMI) 
measured by dual energy X-ray absorptiometry (DXA)


Novartis
Confidential
Page 16
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
3
Investigational plan
3.1
Study design
This Phase IIb extension study is a 24 weeks off drug follow-up observation trial to determine 
the durability of effect and the safety of bimagrumab in older patients with sarcopenia.
After completing 24 weeks of treatment in the core study (CBYM338E2202 End of Treatment 
(EOT) visit), newly consenting patients in the extension study CBYM338E2202E1 will 
continue with the same uniquely identified patient number that was assigned in the core study
and will be followed for an additional 24 weeks off drug (see Figure 3-1).  They will complete 
the end of study (EOS) at week 49. 
Patients enrolled prior to this amendment #1, will follow the original study design described 
below Figure 3-2 and will continue to be treated as per the regimen assigned at entry of the 
extension study. It is anticipated that approximately a total 45 patients will be followed under 
this design and 10 to 15 of them will still be in the study at the time of implementing this
amendment #1.
Figure 3-1
Study design for patients enrolled after the protocol amendment #1


Novartis
Confidential
Page 17
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Exercise program
All patients will be requested to continue their home exercise program (2-3 times each week) 
as it was prescribed and performed in the core study, CBYM338E2202. At the patient’s 
request, the study staff will be able to provide a new set of exercise instructions in order to 
encourage study participation and adherence.
The exercise program contains activities for muscle strength, endurance, balance and 
flexibility, as well as warm-up (i.e. walking) and cool-down periods to improve comfort, 
prepare the body for increased effort, and reduce the risk of training injuries. The exercise 
program is described in detail in the CBYM338E2202E1 Outcomes Manual.
 
 
 
Week 25/EOT – Joined Core and Extension visit
All EOT assessments of the core study will be performed 4 weeks after the last dose of study 
drug as outlined in core study CBYM338E2202.  Consenting, eligible patients will start in 
this extension study on the same day (i.e., EOT visit of CBYM338E2202). 
The ability and willingness of the patient to continue performing the home-based exercise 
program should be re-assessed by the investigator or a team member during this visit. 
For a complete list of assessments, please refer to Section 6 Table 6-1.
Subsequent Visits – Weeks 29-45
Between the extension study entry visit (week 25) and the EOS (week 49), newly enrolled
patients will only visit the site once for the week 37 visit. In between the visits, the patients 
will be contacted monthly by phone by the site personnel to enquire on the patient’s health
status and to check compliance with the 
 diaries.
For a complete and detailed list of assessments, please refer to Section 6 and Table 6-1.
End of study (EOS)/Week 49
This is the last planned visit in the study. It will take place at week 49 or earlier in case of 
premature study discontinuation.
Following the EOS visit, the patient will be followed by his/her treating physician according 
to the local standard of care and the patient’s situation.
For a complete and detailed list of assessments, please refer to Section 6 Table 6-1.


Novartis
Confidential
Page 18
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Figure 3-2
Study design for patients enrolled prior to protocol amendment #1
Management of patients enrolled prior to the protocol amendment #1
Patients enrolled prior to the study amendment #1 will continue to be dosed every 4 weeks 
until week 49 (EOT) and will then have a 4 weeks follow-up period until week 53 (EOS). 
These patients will also continue the exercise program described above.
Please refer to Section 6 and the specific Table 6-2 for a complete and detailed list of 
assessments for these patients.
3.2
Rationale of study design
The aim of developing bimagrumab therapy in elderly adults with sarcopenia is to enable 
them to increase their physical function to a certain level that they could afterwards maintain
without any support other than regular exercise and potentially vitamin D supplementation. 
This extension study is the natural follow-up of the patients treated for 24 weeks in the core 
study; it will evaluate the changes in physical function of this patient population over 24 week 
off-treatment period as well as assess the overall long-term safety of bimagrumab. 
The study population will be comprised of men and women aged 70 years or older with 
sarcopenia who participated in the core study CBYM338E2202. Only patients who complete 
the 24 weeks of treatment in the core study will be eligible for this study given the purpose to 
evaluate the durability of 24-week therapy. Of the 293 patients expected to enroll in the core 
Randomization: Patients randomized to either placebo or continuation of E2202 Bimagrumab dose
R
Treatment free
Follow-up Period 
BYM 70mg
R
BYM 700mg / PBO
BYM 70mg / PBO
PBO
BYM 700mg
R
329
#2
Exercise/Nutrition Program (all patients)
R
BYM 210mg
R
BYM 210mg / PBO
E2202
BYM 70 mg
E2202
BYM 210 mg
E2202
BYM 700 mg
E2202 PBO
Week  25
Dose #1
E2202
Week 21
EOT E2202= 
BL E2202E1
Randomized Withdrawal Period
37
#4
41
#5
45
#6
49
EOT
53
EOS
33
#3
PBO


Novartis
Confidential
Page 19
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
study, it is expected that approximately 200 patients will be eligible and will agree to 
participate in this extension study. 
Although patients enrolled under this amendment will not receive any investigational drug as 
part of this extension, they will have a standardized exercise program. The schedule of two to 
three exercise sessions per week will be maintained throughout the studies (core and 
extension) and will serve as a standard of care together with the vitamin D supplementation.
The code of the treatment received in the core study will remain blinded to sites and patients 
for the entire study duration including this extension study. This will avoid a potential 
reporting bias that patients and site staff may otherwise have when assessing physical function, 
mobility or reporting safety.
In line with the primary endpoint used in the core study, the extension will use the SPPB total 
score as the primary endpoint. The SPPB score and 4-meter gait speed have emerged as the 
predominant measures that characterize impaired lower extremity function in older adults in 
general and in those with sarcopenia and frailty (Studenski et al 2014). 
As the natural follow-up of the core study population, a number of efficacy (e.g. SPPB, 
) 
or safety (vital signs, laboratory measurements, cardiac adjudication) assessments are being 
carried over in the extension study in order to fully evaluate the patient journey over 
approximately a 1 year period. Given the absence of required monthly drug infusion, the
frequency of the visits is reduced in comparison to the core study in order to limit patients’ 
burden. However, in order to maintain patient’s compliance and avoid under-reporting of 
events such as 
 monthly phone calls to the patients will be performed.
As patients enrolled prior to the protocol amendment #1 will differ (e.g. placebo effect) from 
patients newly enrolled in the extension, it was decided to keep them on their 4-weekly dosing 
regimen as originally designed, to maximize the understanding of these regimen. They will 
therefore follow a different visit schedule.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
This extension study will assess the durability of the observed effect of bimagrumab upon 
treatment discontinuation. There is therefore no study drug administration as part of this study 
for patients enrolled following protocol amendment #1.
3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses/design adaptations
An interim analysis will be triggered by the analysis of the core study Part A at the 
completion of Part A. This interim analysis will analyze key efficacy data. The results from 
the interim analysis, together with core study Part A and any additional data on the rest of the 
program, will be used for the next step decision making.
3.6
Risks and benefits 
All patients in this study will participate in a structured, monitored, mildly intense exercise 
program designed to improve physical and emotional status in older adults with impaired 
physical function. In addition, results from the bimagrumab proof of concept study in 


Novartis
Confidential
Page 20
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
sarcopenic patients suggest that patients receiving active drug are likely to experience an 
increase in lean body mass and improvement in mobility performance. Given the half-life of 
bimagrumab, the effect is still expected to be present for an additional few weeks in the 
extension study after the last infusion.
Risks with bimagrumab
The risks of bimagrumab are not fully understood, but in healthy young, middle aged, and 
older adults and in patients with sporadic inclusion body myositis (sIBM) up through 78 years 
of age and in sarcopenic patients up to age 86, the drug was well tolerated and the AE profile 
was consistent across populations. Based on prior human studies there is a risk to participants 
of experiencing certain tolerability-related adverse events. The most common AEs include a 
transient skin condition (acne) and involuntary muscle contractions (i.e., twitches/spasms) as 
well as transient diarrhea.  Transient increases in AST and ALT have been observed, 
sometimes in association with CK elevation (suggesting a muscle source) and sometimes not. 
Other observed adverse events (AEs) include arthralgia, muscle strain erythema and rash. 
 
 
there have been no adverse cardiac findings in humans with current dose levels and regimens. 
Refer to the Investigator’s Brochure for a thorough evaluation of expected adverse events
observed in clinical studies to date as well as data from in vivo pharmacology, animal 
toxicology, animal and human pharmacokinetic (PK), immunogenicity studies. 
Blood draw risks
During the collection of blood samples, patients may experience pain and/or bruising at the 
insertion site of the needle/catheter. Although rare, localized clot formation, infections and 
nerve injury may occur. Lightheadedness and/or fainting may also occur during or shortly 
after the blood draw. Patients will be observed following all blood draws and discharged only 
when the Investigator observes stable health status. In addition, liquids by mouth in the form 
of water, fruit juice or a similar product will be provided following the blood draw to 
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  patient  from  DXA  will  be  about  25  µSv. 
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 (Njeh 1999). 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
During the study, the patients will be required to perform a prescribed set of exercises 2-3
times each week. The exercise program will involve warm-up (i.e., walking) and cool-down 
periods to improve comfort, prepare the body for increased effort, and reduce the risk of 
injury.


Novartis
Confidential
Page 21
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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. The risk of temporary muscle soreness will be reduced in these extension 
study participants as they will have already been participating in the exercise program for the 
full 8 month duration of the core study. In addition, the exercise programs will be tailored to 
each individual’s level of fitness and interest during the evaluation and mid-study visit with 
the site staff.
4
Population
The study population will be community-dwelling men and women ages 70 years and older 
completing 24 weeks of treatment of the core study (CBYM338E2202 EOT visit) and willing 
to enter CBYM338E2202E1; these patients will be eligible providing they meet all inclusion 
and exclusion criteria of the extension protocol. No additional exclusions should be applied
by the investigator. A relevant record (e.g., checklist) must be stored with the source
documentation at the study site. Failure to meet any entry criterion excludes a patient from
entering the post-treatment follow-up epoch.
It is expected that approximately 200 patients will participate in the extension study and that 
approximately 140 will complete it assuming a 30% drop out rate. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Men and postmenopausal women aged 70 years or older that have participated in, and 
have completed the full study treatment period per protocol (24 weeks/EOT visit) in 
the preceding core study (CBYM338E2202)
2. Written informed consent must be obtained before any assessment of the extension 
study is performed (can be obtained at the EOT visit of the core study).
4.2
Exclusion criteria
  This is an extension study and has the same exclusions as the core study. Because only 
participants who complete the core study are eligible for inclusion in this study, patients who 
no longer qualify or should be discontinued from the core study are excluded from 
participating in this study. Patients fulfilling the following criterion are not eligible for 
inclusion in this study:
1. Any condition which should have led to treatment discontinuation per protocol in the core 
study
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients, within and across study sites.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Patients newly enrolled after protocol amendment #1 will not receive any investigational 
treatment as part of this protocol. 


Novartis
Confidential
Page 22
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
For patients enrolled prior to protocol amendment #1 the investigational treatment is as follow:

Bimagrumab
 prepared by Novartis and supplied to the 
Investigator site as open labeled bulk medication.

Placebo will be a Dextrose 5% in water infusion supplied by the site
Study drug preparation will be detailed in a separate pharmacy manual.
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 throughout the study. If it is determined to be necessary from 
one of the planned diet assessments, patients will be instructed to consume a nutritional 
supplement to ensure adequate protein intake.
Even though patients enrolled based on protocol amendment #1 will not be exposed to 
bimagrumab or placebo, during this extension study, all enrolled patients in this study will receive 
specific study treatments as part of this protocol:

Vitamin D supplementation

Exercise program
The vitamin D3 (or D2 if D3 is not available) supplements will be locally sourced with a 
recommended dosage:
- daily administration of 800 IU to 4000 IU vitamin D3 (dose chosen by 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.
Exercise program is presented in more details in Section 3.1.
5.2
Treatment arms
Patients enrolled following protocol amendment #1 will not receive investigational treatment.
Patients enrolled prior to the protocol amendment #1 have been assigned to one of the 
following 2 treatment arms in a ratio of 1:1 to receive i.v. doses of the following and will 
continue with this treatment until their EOT:
1.  Patients on BYM338 70 mg in core study were randomized 1:1 to receive either BYM338 
70 mg or placebo (BYM 70/PBO) for 6 doses in the extension study
2.  Patients on BYM338 210 mg in core study were randomized 1:1 to receive either BYM338 
210 mg or placebo (BYM 210/PBO) for 6 doses in the extension study
3.  Patients on BYM338 700 mg in core study were randomized 1:1 to receive either BYM338 
700 mg or placebo (BYM 700/PBO) for 6 doses in the extension study
4.  Patients on BYM338 0 mg (placebo) in core study were randomized 1:1 to receive 
BYM338 0 mg (placebo) in both arms for 6 doses in the extension study
5.3
Treatment assignment, randomization
Not applicable.


Novartis
Confidential
Page 23
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
5.4
Treatment blinding
Patients as well as the site staff will remain blinded to core treatment allocation as well as the 
extension randomization code for patients enrolled prior to the extension protocol amendment 
#1 from the time of randomization in the core study CBYM338E2202 until the final database 
lock of the extension study CBYM338E2202E1. The Novartis core clinical study team will 
have access to the treatment codes after the interim analysis.  Other Novartis team members in 
the countries will remain blinded until the final study data base lock.
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 and the 
 bioanalyst. (2) Any 
potential visible difference in treatments will be concealed by the use of an opaque sleeve
(applicable only for patients enrolled prior to amendment#1. (3) Any potentially unblinding 
parameters (e.g. DXA results) will not be available to the patient, site or study team, 
Randomization data are strictly confidential and will be accessible only to authorized 
personnel until un-blinding as described above. The study bioanalyst will receive a copy of 
the randomization schedule to facilitate analysis of the samples. Both the un-blinded 
pharmacist and bioanalyst will keep treatment allocation information confidential. Un-
blinding will only occur in the case of patient emergencies (see Section 5.5.13) and as 
described above.
IMPORTANT for sites with patients enrolled prior to protocol amendment #1: Due to the 
difference in preparation methods between the active and placebo treatments, an un-blinded 
pharmacist who is independent of the study team will be required. This un-blinded pharmacist 
will receive the appropriate treatment allocation. Appropriate measures must be taken by the 
un-blinded pharmacist to ensure that the study team remains blinded throughout the course of 
dose administrations and the remainder of the study even in the follow-up epoch.
5.5
Treating the patient 
5.5.1
Patient numbering 
Patients in the extension study CBYM338E2202E1 will continue with the same uniquely
identified patient number that was assigned in the core study.
As in the core study, the patient 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.
Patients will be given the informed consent form (ICF) during one of the scheduled visits (e.g., 
Week 25 or at earlier visit) in study CBYM338E2202 to read and understand for their
participation in this extension study. Patients will NOT be signing the ICF before completing
the Week 25 (EOT) assessments of the core study.  
Patients who are eligible based on the inclusion/exclusion criteria will be asked to sign the 
ICF. If the patient fails for any reason, he/she should not enter the extension and should 
complete the EoS visit of the core study as per the core study protocol.
5.5.2
Dispensing the investigational treatment
Section only applicable to patients enrolled prior to the protocol amendment#1.


Novartis
Confidential
Page 24
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
The investigational drug, bimagrumab
 will be prepared by Novartis and 
supplied to the Investigator’s site as open labeled bulk medication.
Appropriate documentation of the patient 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 t he 
patient.
5.5.3
Handling of study treatment 
5.5.3.1
Handling of investigational treatment
For patients enrolled prior to protocol amendment#1 only
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.
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 un -blinded 
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 un-
blinded 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).
For ALL patients enrolled in the study
As in the core study, to avoid Vitamin D deficiency during the extension study, all patients 
will continue to receive vitamin D3 supplementation (or D2 if D3 is not possible) (800 IU-
4000 IU per day) from the start of the study to the EOS visit. The vitamin D supplements will
be locally sourced.
For more details refer to Section 5.1.2. 
5.5.4
Instructions for prescribing and taking study treatment
Section only applicable to patients enrolled prior to the protocol amendment#1.
 
 End of infusio n 


Novartis
Confidential
Page 25
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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).
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.
All dosages prescribed and dispensed to the patient during the study must be recorded on the
Dosage Administration Record electronic case report form (eCRF) page.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Section only applicable to patients enrolled prior to the protocol amendment#1.
Study drug dose adjustments are not permitted.
Study drug interruptions or dosing delays should be avoided wherever possible and should 
occur within the given window as detailed in the Section 6 and Table 6-2.
If a patient misses two doses the patient must be discontinued from investigational treatment 
(refer to Section 5.5.10)
5.5.6
Recommended treatment of adverse events
Acne may be treated with a face wash containing 4-10% benzoyl peroxide wash and over the 
counter topical treatments. On occasion, a prescription topical treatment (i.e., antibiotics) or 
oral antibiotic (i.e., minocycline 100 mg b.i.d.) may be recommended at the Investigator’s 
discretion. Early intervention is recommended when acne presents.
Muscle symptoms can be addressed with light self-massage of the involved area concentrating 
on improving circulation and relaxing muscle tissue. If excessive or prolonged soreness 
presents, then acetaminophen may be used as needed.
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.
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 prior and concomitant medications
or on the surgical and medical procedures eCRF pages.


Novartis
Confidential
Page 26
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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.
Use of the treatments displayed in the table below are NOT allowed throughout the extension 
study). The following treatments are not allowed because of their biological effect on muscle
anabolism or catabolism, which would potentially confound the assessment of efficacy.
5.5.10
Discontinuation of study treatment or from study
For patients enrolled prior to the protocol amendment#1.
Individual subject discontinuation
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the subject’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


Novartis
Confidential
Page 27
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1

Liver event definition met as per Appendix 1

Total of two (2) doses were missed in the entire study

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 as close 
to 28 days since the last dose received and complete the EOT visit and enter the Post-
treatment follow up.  The EOS visit should be scheduled 4 weeks after EOT. If they fail to 
return for these visits 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. Investigators or site 
personnel must contact the IRT to register the patient’s discontinuation from treatment.
For patients enrolled after the protocol amendment#1.
Patients have to be discontinued from the study if they receive any of the prohibited 
medication listed in Section 5.5.9. 
Patient can be discontinued if in the judgment of the investigator, taking into account the patient’s 
overall status prevents the patient from safely continuing in the study.
Patients should then return to the site to perform the EOS visit as soon as possible and not later 
than 4 weeks after the decision being taken.
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. No further
assessments must be 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.
NOTE: The investigator must also notify Novartis of the premature withdrawal.


Novartis
Confidential
Page 28
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
5.5.12
Lost 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 reasons will not be replaced.
5.5.13
Emergency breaking of assigned treatment
Emergency un-blinding 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. 
For patients enrolled prior to protocol amendment #1 
Emergency code breaks are performed using the IRT system. When the investigator contacts
the system to un-blind a patient, he/she must provide the requested patient identifying
information and confirm the necessity to un-blind 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 Global Trial Leader that the code has been broken.
The un-blinded 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 un-blinding is required at a
time when the investigator and backup are unavailable.
Study drug must be discontinued after emergency un-blinding. Study drug must also be 
discontinued for any patient whose treatment code has been inadvertently broken or for any 
non-emergencyreason (see Section 5.5.10).
For patients enrolled after protocol amendment #1, in case an emergency un-blinding of the 
core study treatment code is required, the investigator will have to follow the procedure 
described in the core study protocol CBYM338E2202.
5.5.14
Study completion and post-study treatment
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.
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.


Novartis
Confidential
Page 29
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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 schedule and assessments
For patients enrolled after the protocol amendment #1, the full assessment schedule is
presented in Table 6-1 below. Patients enrolled prior to the protocol amendment #1 will be 
followed according to the visit scheduled presented in Table 6-2.
In order to allow sufficient reflection time for the informed consent process, the extension 
study may be presented and discussed early enough in the core study in order to allow the ICF 
signature process to be done at the Week 25/core EOT visit. The ICF must not be signed 
before the core EOT visit to avoid complications in the safety reporting requirements.
Patients following Table 6-1 should be seen for all visits on the designated day within a
recommended ‘visit window’ of +/- 14 days. Day 1 must be the same day as the EOT visit of 
the core (i.e. the visit date is the date of the EOT visit of the core). 
Patients should arrive to the visit fasted when blood samples for laboratory assessments will 
be taken at that visit.
Assessments for a particular visit may be split over several days. These may not be 
consecutive days but should respect the visit window period.
Below are some recommendations for organizing and performing the study assessments at 
visits with blood sampling.

Assessments should be performed sequentially in the morning as follows: ECG collection, 
vital signs, blood sampling.

After blood sampling, patients should be offered breakfast.
For patients enrolled prior to the protocol amendment #1, the visits window to be applied is 
+/- 3 days. When scheduling the assessments of a visit, the same principle as stated above 
should apply. In addition, study treatment administration should be the last procedure.
Patients who discontinue t h e  study should NOT be considered withdrawn from the study 
UNLESS they withdraw their consent (see Section 5.5.11). They should return and complete 
the EOS visit. If they fail to return for these visits for unknown reasons, every effort should
be made to contact them as specified in Section 5.5.12.
Patients enrolled prior to the protocol amendment #1, who prematurely discontinue study 
treatment, should return as close to 28 days following the last dose received and complete the 
EOT visit. Their EOS visit should be scheduled 4 weeks after their EOT.
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.


Novartis
Confidential
Page 30
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Table 6-1
Assessment schedule for patients enrolled after the protocol amendment #1
Epoch
Screening 
epoch
Post-treatment follow-up epoch
Timepoint
1
1
2
3
4
5
6
7
Site Visit
1(EOT)
1 (EOT)
2
3 (EOS)5
Phone contact
X
X
X
X
Month
7
7
8
9
10
11
12
13
Week
25
25
29
33
37
41
45
49
Day
1
1
29
57
85
113
141
169
Obtain Informed consent
x
Inclusion/Exclusion criteria
x
Relevant medical history
x2
Demography
x
Physical examination
*
s
s
Body weight
*1
x
x
Body height
*1
Blood pressure/pulse rate 
(sitting)
*1
x
x
Electrocardiogram
*1
x
x
Laboratory samples 
(hematology, biochemistry, 
vitamin D)
*
x
x
Vitamin D3 supplementation
Equivalent to daily administration of 800 IU to 4000 IU
Supervised exercise
*1
x
Home based exercise
2-3 times per week
6 minute walk test
*1
x
x
Short physical performance 
*1
x
x


Novartis
Confidential
Page 31
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Epoch
Screening 
epoch
Post-treatment follow-up epoch
battery
Exercise diary
Daily by the patient to report level of home based exercise
DXA
*
x
Diet assessment/ nutritional 
status
*1
x
x
AE3/SAE4
x2
Any time as per AE/SAE reporting requirement
Concomitant therapies
x2
Any time as per Concomitant therapies reporting requirement
Comments
Any time as per investigator judgement
Epoch disposition
x
x
S : mark procedure documented in the patient’s source file only and not in the CRF
* Assessment performed at EOT visit of the core study. 3rd party data will be automatically transferred.
1 Site must re-enter the data from EOT of core study onto the corresponding eCRF page of the extension study
2 Ongoing events/conditions (i.e. SAEs/AEs, concomitant medications, cardiovascular and other relevant medical history) at EOT of the core study must be recorded on the appropriate eCRF of 
the extension study
3 From the time of signing informed consent until EOS
4 From the time of signing informed consent until 30 days after a patient stopped study participation
5 Patients who discontinue study should return for EOS visit within the next 4 weeks unless they withdraw their consent


Novartis
Confidential
Page 32
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Table 6-2
Assessment schedule for patients enrolled prior to the protocol amendment #1
Epoch 
Screening 
Epoch
Treatment Epoch
Post-treatment 
Follow-up Epoch
Visit
1
1
2
3
4
5
6
7 (EOT)4
8(EOS)4
Month
7
7
8
9
10
11
12
13
14
Week
25
25
29
33
37
41
45
49
53
Day
1
1
29
57
85
113
141
169
197
Hours
Pre-dose
Pre-
dose/
*EOT 
of core
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Obtain informed consent
x
Inclusion / Exclusion 
criteria 
x
Relevant med. hist. / 
Current med. 
cond./Cardiovascular
medical his.
X7
Concomitant Meds / 
Therapies
X7
Any time as per concomitant therapies reporting requirement
Demography
X8
Physical examination9
*8
s
s
s
s
s
Body weight
*8
x
x
x
x 
x
Body height
*8
x 
Blood pressure / Pulse 
rate (sitting)
*8
x
x
x
x 4
x
Electrocardiogram
(ECG)
*8
x
x
x
x 
x


Novartis
Confidential
Page 33
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Epoch 
Screening 
Epoch
Treatment Epoch
Post-treatment 
Follow-up Epoch
Visit
1
1
2
3
4
5
6
7 (EOT)4
8(EOS)4
Month
7
7
8
9
10
11
12
13
14
Week
25
25
29
33
37
41
45
49
53
Day
1
1
29
57
85
113
141
169
197
Hours
Pre-dose
Pre-
dose/
*EOT 
of core
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Echocardiography
*
x10
Hematology
*
x
x
x 
Clinical Chemistry
*
x
x
x 
Cardiac Panel
*
Vitamin D quantification
*
x
x 
Vitamin D3 
supplementation
Equivalent to daily administration of 800 IU to 4000 IU
Supervised exercise
*8
x
x
x 4
Home-based exercise
2-3 times per week
6 minute walk test 
*8
x
x
x 
Short physical 
performance battery
*8
x
x
x
Exercise diary
Daily by the patient to report level of home based exercise
Lean Body Mass and 
Appendicular skeletal 
mass index by DXA
*
x
x 4
Randomization
x


Novartis
Confidential
Page 34
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Epoch 
Screening 
Epoch
Treatment Epoch
Post-treatment 
Follow-up Epoch
Visit
1
1
2
3
4
5
6
7 (EOT)4
8(EOS)4
Month
7
7
8
9
10
11
12
13
14
Week
25
25
29
33
37
41
45
49
53
Day
1
1
29
57
85
113
141
169
197
Hours
Pre-dose
Pre-
dose/
*EOT 
of core
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Pre-
dose
0
Drug administration
x
x
x
x
x
x
Diet assessment / 
nutritional status
x
x
x
x 4
AEs2, 7
As required per AE reporting requirement
SAEs 3, 7
As required per SAE reporting requirement
Comments
Any time as per investigator judgement
Epoch disposition6
x
x 4
x 4
* Assessment performed at EOT visit of the core study. 3rd party data will be automatically transferred.  
S : mark evaluation documented in the patient source file only and not in the CRF
2 For randomized patients, from the time of signing informed consent until EOS
3 For all patients, from the time of signing informed consent until 30 days after a patient stopped study participation


Novartis
Confidential
Page 35
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
4 Patients who discontinue study treatment should return for EOT visit 28 days after last dose received and continue into the Post-Treatment Epoch with EOS visit 4 weeks after EOT unless they 
withdraw their consent
5 Screening epoch to obtain informed consent, demography and confirm I/E criteria for extension study is captured at visit 1 prior to dosing.
6 Disposition captured at completion of each epoch:  Screening; Treatment; and Post-Treatment Follow-up
7 Ongoing SAEs/AEs at EOT of core must be recorded as AEs/SAEs on the appropriate eCRF of the extension study.  Ongoing concomitant medications and ongoing cardiovascular/relevant 
medical history/current medical conditions must be recorded on the appropriate eCRF pages of the extension study.
8 Site must re-enter the data from EOT of core onto the corresponding eCRF page of the extension study.
9 Physical examinations are performed at scheduled visits.  Details of the exams are recorded in the source documents. Medical history of the core study which is ongoing at EOT of core is
included in the Relevant and Medical History eCRF of the extension study. Significant findings observed after informed consent signature of the extension study which meet the definition of an 
Adverse Event must be appropriately recorded on the Adverse Event eCRF of the extension study
10. Echocardiography at EOT will only be performed for patients with new abnormal finding on the echocardiography reading of the core Week 25/EOT visit.
.


Novartis
Confidential
Page 36
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
6.1
Patient demographics/other characteristics at study entry
6.1.1
Subject demographics
Subject demographic data to be collected on all patients include: date and /or year of birth,
sex, race, predominant ethnicity. The demographic data of the extension study will be the
same as the demographic data of the core study. Instructions for completing the extension 
study eCRF will be provided in the eCRF completion guidelines (eCCGs).
6.1.2
Other characteristics at study entry
At the core study week 25 EOT visit before a patient enters the extension study, the
investigator must review the following baseline data of the core study (CBYM338E2202):
Cardiovascular History eCRF, Medical History eCRF. Any cardiovascular or medical history
that is still ongoing at week 25 EOT of the core study must be recorded on the Cardiovascular
History eCRF or Medical History eCRF of the extension study.  
Similarly, any concomitant medications ongoing at week 25 EOT of the core study must be 
recorded on the Prior and Concomitant Medications eCRF of the extension study. 
In addition, any ongoing AEs at week 25 EOT of the core study must be recorded as AEs in 
the extension study eCRF.
Instructions for completing the extension study eCRF will be provided in the eCCGs.
6.2
Treatment exposure and compliance 
Throughout the study, patients will be required to participate in an exercise program with 
defined minimum requirements (see Section 3.1). Patients will record their training sessions 
on an exercise diary to track program adherence. The content of the paper diary will be 
recorded in the Exercise diary eCRF. 
In addition patients will have vitamin D supplementation (see Section 5.1.2) recorded in the 
prior and concomitant eCRF.
For patients enrolled prior to the protocol amendment #1 only:
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.
 
6.3
Efficacy
Physical function efficacy assessments will be done at all sites by trained site
personnel to ensure standard results. Training of the assessment protocols will be provided to
each study site team by Novartis.
Efficacy measurements in the study will include:


Novartis
Confidential
Page 37
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1

6MWT to assess physical function

SPPB to assess physical function

Usual Gait Speed to assess physical function

Total LBM and ASMI assessed by DXA to measure lean body mass and skeletal muscle 
mass of the arms and legs, respectively.
6.3.1
6 minute walk test
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. 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.
Patients will be instructed by the test administrator using a script and established testing 
protocol. The testing should be conducted on an individual basis (patient and testers) with no 
additional audience or support other than that of the trained personnel conducting the test. If a 
walking aid is required, patients will be asked to use the least assistive walking aid that in
their opinion will enable them to complete the 6MWT test safely. Patients should be 
encouraged to use the same walking aid when performing all tests throughout the study. 
A change in walking aid to perform the test is permitted if required for safety reasons (e.g.,
deterioration of balance). The testing should occur at approximately the same time of the day 
throughout the study to prevent any possible diurnal variations. The same test administrator
should perform all repeat tests on a patient whenever possible to reduce technician-related
differences in test performance.
Complete details of course set-up, test administration, equipment and recording into the eCRF 
are described in the CBYM338E2202E1 Outcomes Manual.
6.3.2
Short physical performance battery
The SPPB has been shown to be highly predictive of subsequent disability, hospitalization,
institutionalization, and mortality in community- dwelling elders in epidemiological studies
and outpatient clinics (Guralnik et al 2000; Studenski at al 2003). The disability remains
even after adjustment for level and severity of comorbidity and self-report functional status.
Collectively, SPPB might be considered to be a nonspecific but highly sensitive indicator of
global health status reflecting several underlying physiological impairments.
The SPPB evaluates lower extremity function 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. Complete details of test administration, equipment and recording into the 
eCRF are described in the CBYM338E2202E1 Outcomes Manual.


Novartis
Confidential
Page 38
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
6.3.3
Gait speed
Gait speed in this study will be assessed as part of the SPPB, over a 4 meter distance of a 
6 meter course. 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 from one store to 
another).
Usual gait speed represents one of the most suitable 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 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 CBYM338E2202E1 Outcomes Manual.
6.3.4
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 LBM and
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%.
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 byexperienced staff.
Details of the test administration are provided in the CBYM338E2202E1 Imaging Manual.


Novartis
Confidential
Page 39
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1


Novartis
Confidential
Page 40
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
6.4
Safety 
6.4.1
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. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and/or pelvic exams may be performed.
Skin-related issues will be assessed by the investigator or assigned clinician at each physical 
exam time point. Particular attention should be devoted to the assessment of acne due to the
previously noted increased incidence of acne in people treated with bimagrumab.
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 on the eCRF. Medical history of the core study which is 
ongoing at EOT of core is included in the Relevant and Medical History eCRF of the extension 
study. Significant findings observed after informed consent signature of the extension study which 


Novartis
Confidential
Page 41
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
meet the definition of an Adverse Event must be appropriately recorded on the Adverse Event 
eCRF of the extension study.
6.4.2
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 three consecutive assessments are made, with the subject seated quietly for 
approximately five minutes preceding each repeat assessment. 
All readings should be 
recorded on the eCRF.
Vital signs will be collected at scheduled visits indicated in Table 6-1 and Table 6-2 as 
appropriate. Whenever possible, at each visit, vital signs should be collected using the same 
arm.
6.4.3
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 at scheduled visits indicated in Table 6-1 and
Table 6-2 as appropriate.
If a weight decrease of 5% or more compared to the core baseline is seen, a comprehensive 
diet assessment should be conducted as per Section 5.1.2.
Body mass index (BMI) will be calculated using the following formula:
• B M I = Body weight (kg) / [Height (m)]2
6.4.4
Laboratory evaluations
In the case where a laboratory result is outside the reference range for the laboratory
parameter 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.
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 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 be contacted.


Novartis
Confidential
Page 42
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
6.4.4.1
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.
6.4.4.2
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, creatinine, γ-GT, glucose 
(fasting), HgbA1c, phosphate, lipase, amylase, potassium, total protein, AST, ALT, sodium, 
magnesium, triglycerides, urea/BUN, uric acid, and vitamin D.
6.4.4.3
Cardiac Biomarker Panel
The following tests will be measured centrally: creatine kinase (CK), CK-MB and CK-MM, 
and troponin I and T only as part of the EOT/Week 25 joined visit with the core study as per 
Table 6-2.
6.4.5
Electrocardiogram (ECG)
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
A standard local 12 lead ECG will be performed supine at scheduled visits indicated in 
Tables 6-1 and 6-2 as appropriate.
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

patient initials

patient 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). 
The eCRF will contain:

date and time of ECG

heart rate


Novartis
Confidential
Page 43
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1

PR interval

QT interval uncorrected

QTcF

QRS duration
Original ECG tracings, appropriately signed, will be archived at study site.
6.4.6
Echocardiography
Section only applicable to patients enrolled prior to the protocol amendment#1.
Two dimensional echocardiography measurements will be assessed during the study as per the 
Table 6-2. The images will be transmitted to a central reading vendor for independent review.
Sites will receive appropriate training for data transfer as well as an Echocardiography
manual that will include detailed instructions and data transfer procedures.
6.4.7
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.


Novartis
Confidential
Page 44
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
6.7
Telephone contact
Sites will contact patients by telephone on a monthly basis as per Table 6-1. At least 3 
attempts on different days should be documented before considering the contact as missed.
During these telephone contacts, site staff should query the patient in a structured manner on 
adherence to the exercise program, occurrence of 
 any potential adverse event. 
 
 
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 1.


Novartis
Confidential
Page 45
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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 duration (e.g. start and end date)
7. whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)
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.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.


Novartis
Confidential
Page 46
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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 as appropriate; 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 (IN). 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 such as but not limited to events of spontaneous muscle contraction
with associated pain, diarrhea, or cardiac events that may require adjudication (see Section
8.5).
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 Global Trial Leader. 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. The telephone and fax numbers
of the contact persons in the local Drug Safety and Epidemiology department, specific
to the site 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.


Novartis
Confidential
Page 47
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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.
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 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.
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 13-1-Appendix 1 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 13-1-Appendix 1 should be followed up by the 
investigator or designated personal at the trial site, as summarized below and detailed in
Table 13-1-Appendix 1.

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.


Novartis
Confidential
Page 48
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
7.4
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.
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.


Novartis
Confidential
Page 49
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
All data captured for this study will have an external originating source (either written or 
electronic); the eCRF is not considered as source.
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 that 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 a 
blinded expert reader will perform the quantitative analysis. The analysis results are 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.
Randomization codes assigned to patients enrolled before Amendment #1 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 un-blinded and made available for data analysis. Any
changes to the database after that time can only be made after written agreement by 
Novartis Development management.


Novartis
Confidential
Page 50
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
8.4
Data Monitoring Committee (DMC)
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 will be to independently review and evaluate the unblinded safety
data generated during the study as defined in this protocol. The DMC will also ensure 
that study participants are not exposed to unnecessary or unreasonable risks and that the study 
is conducted with high scientific and ethical standards. Finally, the DMC must make 
recommendations to the Sponsor on the actions to be taken on the study, which may include 
the following:

Discontinuation of the study.

Suggested modifications to the study protocol and/or the informed consent document.

Continuation of the study according to the protocol and the relevant amendments. The
DMC is accountable to the Sponsor for appropriate monitoring of the study data.
Although the DMC may make recommendations to the Sponsor about changes in the conduct 
of the study, final decisions will be made by Novartis. In the case of early termination, 
consultation with Health Authorities may be required.
Members of the DMC will not share any un-blinded information with anyone outside of the
DMC. Particularly, the Sponsor will remain fully blinded to any results until the interim 
analysis as described in S e c t i o n  5 . 4 unless the DMC recommends changes in the
conduct of the study (for example, early termination due to negative safety findings).
An independent statistical reporting team not involved in the conduct of the studies will 
prepare the information for the DMC according to the specifications from the DMC
statistician. The main tasks may include:

Generation of unblinded outputs for the DMC, including tables, figures, and listings, as
required.

Preparation of any other reports requested by the DMC during the closed session.

Review of the unblinded reports before sending to the DMC.
The frequency of the DMC meetings will be determined by the members and ratified in the 
DMC Charter.
8.5
Adjudication Committee
An independent adjudication committee will be used for specific cardiac safety events (i.e. 
cardiomyopathy, heart failure, ischemic heart disease and cardiac rhythm disturbances).


Novartis
Confidential
Page 51
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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 report at the 
end of the study.
The clinical database will be searched by the clinical team for targeted cardiac adverse
events mentioned above. When an adverse event is identified for adjudication, the clinical
site will be notified and will be requested to document the adverse event in detail and
submit any applicable supplemental data which may be available, including copies of source 
documents. Source documents include, but are not limited to, relevant clinical notes, ECGs,
operative and pathology reports, hospital discharge summaries. In addition, an interview with the
subject maybe needed in person or via telephone.
The outcome of the adjudication or the expert review will be captured in the clinical data base.
9
Data analysis 
9.1
Analysis sets 
Full analysis set (FAS): The FAS comprises all subjects enrolled in the study..
Safety set (SAF): The safety set comprises all subjects who received at least one dose of study 
drug from the core or extension study and enrolled in the extension study. 
Per-protocol set (PP): The Per-protocol set comprises all subjects in the FAS who do not have 
major protocol deviations that could confound the interpretation of analyses conducted on the 
FAS. The following are common examples of such protocol deviations: 
•
Subject entered the study even though they did not satisfy the entry criteria
•
Subject developed study/treatment withdrawal criteria during the study but was not 
withdrawn
•
Subject received the wrong treatment or incorrect dose
•
Subject took a prohibited concomitant medication
The PP set will be identified and finalized based on blinded review of the data, prior to the 
database lock.
To facilitate different analysis on patients enrolled before and after the protocol amendment, 
two populations are defined as in below: 

Population I is defined to include patients enrolled prior to protocol amendment 1, who 
will be continuing the treatment as originally assigned and follow the original schedule 
until end of the study. 

Population II is defined to include patients enrolled after protocol amendment 1, who will 
be followed up per schedule defined in this protocol amendment. 


Novartis
Confidential
Page 52
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
9.2
Patient demographics and other baseline characteristics
Descriptive statistics for demographics and baseline characteristics will be presented to 
describe the FAS. For Population I, all summaries will be presented by treatment group in the 
extension study and overall. For Population II, all summaries will be presented by treatment 
assigned in the Core study and overall.
Demographic variables taken at screening, including age, sex, child bearing potential of 
female subjects, height, weight, body mass index of baseline, race and ethnicity, will be 
summarized. 
Baseline characteristics may include and are not limited to: nutritional status,  exercise, 
tobacco/alcohol use, quadriceps strength, total and appendicular LBM, SPPB and 6MWT.
Descriptive statistics (mean, median, standard deviation, minimum and maximum, Q1 and Q3) 
will be presented for continuous variables for each treatment group and overall in the FAS. 
The number and percentage of subjects in each category will be presented for categorical 
variables for each treatment group and overall. 
9.3
Treatments
For Population I, for each subject, cumulative exposure to study treatment will be calculated 
as the number of days of drug exposure = last infusion date – first infusion date + 56 days. 
The first infusion date refers to the first dose date following the last dose in the core study. 
The duration of exposure to study drug will be summarized by treatment group as a 
continuous variable. 
For Population I, prior and concomitant medications will be summarized by treatment group 
in separate tables.  Medications will be presented in alphabetical order, by ATC codes and 
grouped by anatomical main group (the 1st level of the ATC codes). Tables will also show the 
overall number and percentage of subjects receiving at least one drug of a particular ATC 
code and at least one drug in a particular anatomical main group. 
Prior medications are defined as drugs taken and stopped prior to first dose of study treatment.  
Any medication given at least once between the day of first dose of study treatment and the 
date of the last study visit will be a concomitant medication, including those which were 
started pre-baseline and continued into the treatment epoch. Prior or concomitant medication 
will be identified based on recorded or imputed start and end dates of medication taking. If it 
cannot be established that the use of a prior medication has ended prior to the first dose of 
study treatment due to a missing end date, then it will be considered concomitant.  
For Population II, no exposure will be presented, but concomitant medications will be 
presented. 
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
The primary endpoint is SPPB at Week 49. 


Novartis
Confidential
Page 53
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
9.4.2
Statistical model, hypothesis, and method of analysis
Figure 9-1
Comparisons between Treatment Arms for Population I
No formal hypothesis testing will be performed in the study. All efficacy analyses will be 
based on FAS.
Summary statistics, i.e., mean, median, 25th percentile, 75th percentile, standard deviation, 
minimum and maximum, the number of non-missing observations, and 95% confidence 
interval will be provided for the primary endpoint by treatment arm for each population. 
For Population I, a 95% confidence interval for the difference in the primary endpoint
between each continued bimagrumab dose arm vs. corresponding placebo switched from the 
same bimagrumab dose will be calculated, as shown as primary comparisons in Figure 9-1.
For Population II, the summary will be presented by treatment assigned in the core study.
9.4.3
Handling of missing values/censoring/discontinuations
Summary statistics will be provided for observed data (no imputation). 
9.4.4
Supportive analyses 
The same analysis will be performed on PP set.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
Secondary variables include: 

6MWD at Week 49

Gait speed at Week 49

Total and appendicular lean body mass and ASMI as measured by DXA


Novartis
Confidential
Page 54
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Lean body mass will be logarithmically transformed for analysis. 
For each continuous secondary variable, summary statistics (mean, median, 25th percentile, 
75th percentile, standard deviation, minimum and maximum, the number of non-missing 
observations, and 95% confidence interval) will be provided by treatment arm at each visit for 
each population. 
For Population I 95% confidence interval will be provided for the difference between each 
continued bimagrumab dose arm vs. corresponding placebo (switched from the same 
bimagrumab dose arm) at each visit. 95% confidence interval will be provided for the 
difference between each continued bimagrumab dose arm and the placebo arm continued 
from the core study at each visit, as shown as the secondary comparisons in Figure 9-1.
 
9.5.2
Safety variables
All safety evaluations will be performed on the safety set (SAF) and analyzed for Population I
and Population II separately. For Population I, all safety will be summarized by treatment 
group assigned in this extension study.  Safety will be compared between the 3 continued 
bimagrumab dose arms against the placebo arm continued from the core study. For Population 
II, safety analysis will be presented by the treatment assigned in the Core study.
Adverse events
Treatment emergent adverse events (events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term) will be summarized. Only primary paths within MedDRA will be considered 
for adverse event reporting.
Summary by treatment group in this study will be provided for Populations I and II separately. 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having any AE, having an AE in each primary system organ class and having each 
individual AE (preferred term). Summaries will also be presented for AEs by severity and for 
study treatment related AEs. If a subject reported more than one adverse event with the same 
preferred term, the adverse event with the greatest severity will be presented. If a subject 
reported more than one adverse event within the same primary system organ class, the subject 
will be counted only once with the greatest severity at the system organ class level, where 
applicable. 
Separate summaries will be provided for death, serious adverse event, other significant 
adverse events leading to discontinuation of study treatment and adverse events leading to 
dose adjustment (including study treatment discontinuation).
Safety topics of interest such as cardiovascular events defined in the Safety Profiling Plan will 
be listed and analyzed separately. 


Novartis
Confidential
Page 55
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
Vital signs
Summary statistics in vital signs for each visit will be presented by vital sign and treatment 
group for Populations I and II separately. 
All information collected will be listed by subject and abnormal values will be flagged.
Laboratory data
The summary of laboratory evaluations will be presented for the following groups of 
laboratory tests (see respective sections for details) for Populations I and II separately: 

Hematology 

Clinical chemistry 
Descriptive summary statistics for each study visit will be presented. These descriptive 
summaries will be presented by test group, laboratory test and treatment group. 
Subjects with abnormal laboratory values will be listed and selected parameters will be 
flagged during study conduct according to pre-defined clinically relevant values. 
Newly occurring or worsening liver enzyme abnormalities will be summarized. 
ECG 
Summary statistics for Populations I and II separately will be presented for ECG variables by 
visit and treatment group.
The following quantitative variables will be summarized: ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, and corrected QT interval (QTcF). 
QTcF will summarized by computing the number and percentage of subjects with:

QTc > 500 msec 

QTc > 480 msec

QTc > 450 msec

PR > 250 msec
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
subject listing of all quantitative ECG parameters. 
Echocardiography 
For Population I summary statistics will be presented by visit and treatment group for the 
following measurements: 

Left ventricular wall (anterior and posterior) and septal thickness

Left ventricular mass and mass index

End-diastolic volume

End-systolic volume

Left ventricular ejection fraction

Left ventricular diastolic and systolic diameter


Novartis
Confidential
Page 56
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1

Left atrial size and volume

Right ventricular wall thickness and function

Interrogation of all valves for function, stenosis, regurgitation and morphology
9.5.4
PK/PD 
Not Applicable
9.6
Interim analyses 
An interim analysis will be triggered by the analysis of the core study Part A. Data from 
primary and key secondary efficacy parameters will be summarized. This interim analysis will 
provide a preliminary evaluation of endpoints over approximately 12 months; and together 
with core study Part A data will support next step decision making.
9.7
Sample size calculation
All the subjects from the core (CBYM338E2202), if eligible, can enter this extension study 
after they complete informed consent. 
The standard deviation of SPPB can be found in the references in Table 9-1, which are also 
referred by the core study protocol. 
Table 9-1
Standard deviation of SPPB
Reference
Study description
SD
Perera et al (2006)
N=492 community dwelling adults
2.7 (Baseline)
Kwon et al. (2009)
N=424 older sedentary adults
1.42 (Baseline)
Papanicolaou et al (2013)
N=120 sarcopenic elderly women
1.48 (Baseline)
2.19 (After 6 months 
treatment)


Novartis
Confidential
Page 57
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
1.93 (After 6 months 
placebo)
With 40 to 50 patients per each bimagrumab dose arm,, assuming a standard deviation of 
SPPB of 1.5, 2.0, 2.5, and 3.0, the half-width of 95% confidence interval for SPPB is 
presented below in Table 9-2.
Table 9-2
Half-width of 95% confidence interval for SPPB
SD=1.5
SD=2.0
SD=2.5
SD=3.0
50 patients per arm: 
0.42
0.55
0.69
0.83
40 patients per arm: 
0.46
0.62
0.77
0.93
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed 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.


Novartis
Confidential
Page 58
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
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 patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, 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 prior 
to implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety monitoring should be followed.


Novartis
Confidential
Page 59
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
12
References
Available upon request.
Barthuly AM, Bohannon RW, Gorack W (2012) Gait speed is a responsive measure of 
physical performance for patients undergoing short-term rehabilitation. Gait Posture; 36(1):61-
4.
Cesari M, Kritchevsky SB, Penninx BW, et al (2005) Prognostic value of usual gait speed in 
well-functioning older people--results from the Health, Aging and Body Composition Study. J
Am Geriatr Soc; 53:1675-80.
Chandler JM, Duncan PW, Kochersberger G, et al (1998) Is lower extremity strength gain 
associated with improvement in physical performance and disability in frail, community-
dwelling elders? Arch Phys Med Rehabil; 79(1):24-30.
Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al (2010) Sarcopenia: European consensus on 
definition and diagnosis Report of the European Working Group on Sarcopenia in Older 
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.
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.
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.
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.
Njeh CF, Fuerst T, Hans D, et al (1999) Radiation exposure in bone mineral density 
assessment. App. Radiation and Isotopes; 50: 215-236.
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 


Novartis
Confidential
Page 60
Clinical Trial Protocol v01 clean
Protocol No. CBYM338E2202E1
(SARM), MK-0773 in female participants with sarcopenia. J Nutr Health Aging. 2013; 
17(6):533-43
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.
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.
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.
Visser M, Schaap LA. Consequences of sarcopenia, Clin Geriatr Med. 2011Aug;27(3):387-99
Volpato Bianchi L, Cherubini A, Landi F, Maggio M, Savino E, Bandinelli S, Ceda GP, 
Guralnik JM, Zuliani G, Ferrucci L. Prevalence and clinical correlates of sarcopenia in 
community-dwelling older people: application of the EWGSOP definition and diagnostic 
algorithm. 
J 
Gerontol 
A 
Biol 
Sci 
Med 
Sci. 
2014 
Apr;69(4):438-46


Novartis
Confidential
Page 61
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1
13
Appendix 1: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 13-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS
3 x ULN < ALT / AST 5 x ULN
1.5 x ULN < TBL 2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and TBL > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia
Any adverse event potentially indicative of a liver toxicity * 


Novartis
Confidential
Page 62
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s 
Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of 
known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of 
known Gilbert 

Repeat LFT within 48 hours

If elevation persists, discontinue 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 


Novartis
Confidential
Page 63
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1
Criteria
Actions required
Follow-up monitoring
syndrome)
the study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × 
ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE 
potentially 
indicative of a 
liver toxicity*

Consider study drug interruption or 
discontinuation 

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver 
damage-related conditions; the non-infectious hepatitis; the benign, malignant and unspecified 
liver neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) 
stable values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at 
elevated level after a maximum of 6 months, (4) liver transplantation, and (5) death.


Novartis
Confidential
Page 64
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1
14
Appendix 2: Sample Log
Sample Log (all matrices):  Time schedule for collection of blood for safety, 
 
and pharmacodynamic (PD) assessments as per Table 6-1 and 6-2 as 
appropriate.  
Sample volumes are the maximum size at any given visit.
For patients newly enrolled following protocol amendment#1
For patients enrolled prior to protocol amendment #1. All samples are to be collected 
pre-dose.  
Study Epoch
Visit #
Day
Safety1
size (ml)
SCR
1
1
Post 
Treatment 
Follow-up 
1
1
30*
2
85
30
3
169
30
1 Includes when applicable: clinical chemistry (incl. vitamin D), hematology, 
* Sample collected at EOT visit of the core study E2202
Study 
Epoch
Visit #
Day
Safety1
size (ml)
SCR
1
1
Treatment
1
1
2
29
30
3
57
4
85
30
5
113
6
141
7
169
30
Post 
Treatment 
Follow-up
8
197
30


Novartis
Confidential
Page 65
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1
1 Includes when applicable: clinical chemistry (incl. vitamin D), hematology, 


Novartis
Confidential
Page 66
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1
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


Novartis
Confidential
Page 67
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1


Novartis
Confidential
Page 68
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1


Novartis
Confidential
Page 69
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1


Novartis
Confidential
Page 70
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1


Novartis
Confidential
Page 71
Clinical Trial Protocol v01 clean 
Protocol No. CBYM338E2202E1

SAP_001.pdf: 
Clinical Development
BYM338/bimagrumab
Study CBYM338E2202E1 / NCT02468674
A 24 week off drug extension, parallel group, study 
assessing durability of effect on skeletal muscle strength 
and function following a 6-month double-blind, placebo 
controlled study evaluating bimagrumab in older adults 
with sarcopenia (InvestiGAIT extension)
RAP Module 3: Detailed Statistical Methodology
Author(s):
, Trial Statisticians 
Document type:
RAP Module 3: Detailed Statistical Methodology
Document status:
Final/Amendment 1
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Release date:           14-August-2018
Number of pages:     36


Novartis
Confidential
Page 2
RAP Module 3
CBYM338E2202E1
Table of contents
Table of contents .................................................................................................................2
1
Introduction to the RAP document......................................................................................4
1.1
Scope........................................................................................................................4
1.2
Changes to SAP document ......................................................................................4
2
Study design and objectives ................................................................................................5
2.1
Study objectives.......................................................................................................5
2.2
Study design.............................................................................................................6
3
Statistical and analytical plans.............................................................................................8
3.1
Statistical methods: Analysis sets............................................................................8
3.2
Patient disposition, background and demographic characteristics ..........................9
3.2.1
Patient disposition...................................................................................9
3.2.2
Patient demographics and other baseline characteristics ......................10
3.3
Treatments (study drug, other concomitant therapies, compliance)......................14
3.3.1
Study drug administration.....................................................................14
3.3.2
Prior and concomitant medications.......................................................15
3.4
Analysis of the primary variable(s) .......................................................................15
3.4.1
Descriptive statistics..............................................................................15
3.4.2
Statistical model, hypothesis and method of analysis...........................16
3.4.3
Handling of missing values/censoring/discontinuations.......................16
3.4.4
Supportive analysis ...............................................................................16
3.5
Analysis of secondary 
..................................................16
3.5.1
Variables ...............................................................................................16
3.5.2
Descriptive statistics..............................................................................17
3.5.3
Statistical model, hypothesis and method of analysis...........................18
3.5.4
Supportive analysis ...............................................................................20
3.6
Statistical methods for safety and tolerability data................................................20
26
3.8
Interim analyses.....................................................................................................26
3.8.1
Interim Analysis FIR.............................................................................27
3.9
Sample size calculation..........................................................................................27
4
Statistical methods planned in the protocol and determination of sample size.................28
5
Clinical Study Report - Appendix 16.1.9 Documentation of statistical methods ..........28
5.1
Introduction............................................................................................................28
5.2
Precision and summary statistics...........................................................................28
5.3
Study Day 1 and other study days .........................................................................29
5.4
Definition of Baseline and post-baseline measurements.......................................30


Novartis
Confidential
Page 3
RAP Module 3
CBYM338E2202E1
5.5
Analysis visits........................................................................................................30
5.5.1
Visit naming..........................................................................................30
5.6
Handling of missing values/censoring/discontinuations .......................................31
5.7
Imputation of missing and incomplete dates .........................................................31
5.8
Statistical methodology and assumptions..............................................................31
5.8.1
Two sample t-test ..................................................................................31
5.8.2
ANCOVA..............................................................................................31
5.8.3
Negative binomial analysis ...................................................................32
32
32
6
Appendix ...........................................................................................................................34
6.1
Protocol deviations ................................................................................................34
7
References .........................................................................................................................36


Novartis
Confidential
Page 4
RAP Module 3
CBYM338E2202E1
1
Introduction to the RAP document
1.1
Scope
The SAP document contains detailed information to aid the production of Statistics & 
Programming input for trial “CBYM338E2202E1”. 
1.2
Changes to SAP document
Any major changes occurring before database lock to the statistical methodology should be 
reflected in the SAP documentation via version control.
Major changes include, but are not limited to, changes in protocol that affect study design and 
statistical methodology. For study BYM338E2202E1, the major changes made to SAP 
document are reflected in Amendment 1 version and details are below: 
Amendment 1 (June 2018)
This amendment was developed to reflect the changes in Protocol Amendment 1. The purpose 
of the amendment was to revise the extension study design to align it with the changes recently 
implemented in the core study CBYM338E2202 while maintaining and further focusing the 
primary purpose of the extension study to evaluate the durability of effect 24 weeks of 
bimagrumab therapy upon discontinuation.
Changes to the RAP 
Statistical and analytical plan: Changed the primary objective of the study.
Statistical methods: Analysis sets: Changed to reflect the analysis sets of the protocol and 
that we have two Populations.
Patient disposition, background and demographic characteristics: Changed to reflect that 
we have two Populations. Updated the analysis sets summary table to also be done 
Treatments (study drug, other concomitant therapies, compliance): Changed to reflect 
that we have two Populations. Updated the duration of exposure summary tables to also be 
done 
 
Statistical methods for Pharmacodynamic (PD) parameters: Changed to reflect that we 
have two Populations. The primary objective/endpoint of the study was changed to reflect 
existing protocol, the secondary endpoints to reflect the current protocol and removed 
imputation by LOCF and to include CI at selected summary statistics. Change the definition 
of Sarcopenic to remove SPPB total score<=9.
. Added an 
ANCOVA analysis and a supportive analysis section for selected secondary endpoints.
Statistical methods for safety and tolerability data : Changed to reflect that we have two 
Populations and to remove patient diary as per the new protocol. Added summary tables for 
notable vital signs,  newly occuring notable values in clinical laboratory evaluations, and 
notable echocardiography values along with the definition of notable echocardiography 
values. Calarified the notable criteria for liver 
 enzyme abnormalities. Changed 
the adverse events section 
 add clarity on the handling of AE’s 
continuing from the core study and how AESI will be analyzed.
Interim analyses : Changed to reflect that an IA is required.


Novartis
Confidential
Page 5
RAP Module 3
CBYM338E2202E1
Sample size calculation : Changed to reflect the change in the primary endpoint.
Clinical Study Report – Appendix 16.1.9 Documentation of statistical methods : Changed 
to reflect the changes in the analysis.
2
Study design and objectives
2.1
Study objectives
Objective
Endpoint
Analysis
Primary
The primary objective is to assess the durability of 
effect of bimagrumab (BYM338) on physical function 
as measured by the SPPB total score at Week 49. 
Total SPPB at Week 49
Section 3.5
Secondary

To evaluate the long term safety effect of 
bimagrumab following treatment withdrawal as 
assessed by measures such as vital signs, 
clinical laboratory variables, electrocardiogram 
(ECG), and adverse events (AE)

To evaluate the durability of effect of BYM 
at week 49 as measured by: 

6MWT 

Usual gait speed over 4 meters (Gait speed) 

Total lean body mass (total LBM) and 
appendicular skeletal muscle index (ASMI) 
measured 
by 
dual 
energy 
X-ray 
absorptiometry (DXA)

Safety variables
6MWT at Week 49
Gait speed at Week 49
Total LBM and ASMI at 
Week 49
Section 3.7
Section 3.6


Novartis
Confidential
Page 6
RAP Module 3
CBYM338E2202E1
2.2
Study design
This Phase IIb extension study is a 24 weeks off drug follow-up observation trial to determine 
the durability of effect and the safety of bimagrumab in older patients with sarcopenia. 
After completing 24 weeks of treatment in the core study (CBYM338E2202), newly consenting 
patients in the extension study CBYM338E2202E1 will continue with the same uniquely 
identified patient number and be followed for an additional 24 weeks off drug. They will 
complete the EOS at week 49. 


Novartis
Confidential
Page 7
RAP Module 3
CBYM338E2202E1
Figure 2-1
Study design for patients enrolled after the protocol amendment #1
Patients enrolled prior to protocol amendment #1 will follow the original study design and will 
continue to be treated as per the regimen assigned at the entry of the extension study. 


Novartis
Confidential
Page 8
RAP Module 3
CBYM338E2202E1
Figure 2-2
Study design for patients enrolled prior to protocol amendment #1
3
Statistical and analytical plans
The planned analysis is described in Section 9 of the protocol (Appendix 16.1.1). 
The primary objective of this study is to assess the durability of effect of bimagrumab 
(BYM338) in older adults with sarcopenia as measured by week 49 SPPB.
Unless otherwise stated, summary tables/figures/listings will be on all subjects included in the 
population under consideration. Data will be summarized with respect to demographic and 
baseline disease characteristics, efficacy, and safety assessments.
3.1
Statistical methods: Analysis sets
The following analysis sets are defined:
Full analysis set (FAS): The FAS comprises of all subjects enrolled in the study.


Novartis
Confidential
Page 9
RAP Module 3
CBYM338E2202E1
Safety set (SAF): The safety set comprises of all subjects who received at least one dose of 
study drug from the core or extension study and enrolled in the extension study. Subjects will 
be analyzed according to the treatment actually taken.
Per-protocol set (PP): The Per-protocol set comprises all subjects in the FAS who do not have 
major deviations that could confound the interpretation of analyses conducted on the FAS. The 
following are common examples of such protocol deviations:
•
Subject entered the study even though they did not satisfy the entry criteria
•
Subject developed study/treatment withdrawal criteria during the study but was not 
withdrawn
•
Subject received the wrong treatment or incorrect dose
•
Subject took a prohibited concomitant medication
The PP set will be identified and finalized based on blinded review of the data, prior to the final 
database lock.
 
 
To facilitate different analysis on patients enrolled before and after the protocol amendment #1, 
two populations are defined as below:

Population I is defined to include patients enrolled prior to protocol amendment 1, who 
will be continuing the treatment as originally assigned and follow the original schedule 
until end of the study.

Population II is defined to include patients enrolled after protocol amendment 1, who 
will be followed up per schedule defined in this protocol amendment.
3.2
Patient disposition, background and demographic 
characteristics
The analysis in this section will be based on FAS. For Population I, all summaries will be 
presented by treatment group in the extension study and overall. For Population II, all 
summaries will be presented by treatment assigned in the Core study and overall.
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 Population, treatment group, 
 center 
and patient if not indicated otherwise.
Where relevant, “overall” refers to the addition of a “Total” treatment column within the 
planned presentation of the data. 
3.2.1
Patient disposition
All patients will be summarized using number (n) and percentage (%), overall 
 center, by each treatment group and overall, for 


Novartis
Confidential
Page 10
RAP Module 3
CBYM338E2202E1
Populations I and II separately. Furthermore, for each study epoch (screening, treatment and 
follow-up as applicable to the populations) 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.
At the final analysis, the number (n) and percentage (%) of patients with protocol deviations 
will be summarized by category and deviation, for each treatment group and overall, 
 
. Patients with protocol deviations will be listed.
The number (n) and percentage (%) of patients included in each analysis set will be summarized
by treatment group and overall,
 for Populations I and II
separately. At the final analysis, the reasons for exclusions from analysis sets will be tabulated 
overall for all patients
 for each treatment 
group and overall. 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.
3.2.2
Patient demographics and other baseline characteristics
Descriptive statistics for demographics and baseline characteristics at Week 25 will be 
presented to describe the FAS. All summaries will be presented by treatment group and overall 
 for Populations I and II separately.
Descriptive statistics (n, mean, median, standard deviation, minimum and maximum (not for 
IA), Q1 and Q3) will be presented for continuous variables for each treatment group and overall 
in the FAS. The number and percentage of subjects in each category will be presented for 
categorical variables for each treatment group and overall. Unless otherwise specified, 
percentages will be based on the number of patients in the FAS with data available.
3.2.2.1
Demographics
Demographic variables taken at screening, including age, sex, child bearing potential of female 
subjects, height (cm), weight (kg), body mass index (BMI) (kg/m2), race and ethnicity will be 
summarized.
3.2.2.2
Other patient characteristics
Patient characteristics at Week 25 will be summarized. Patient characteristics will include: 
nutritional status, protein intake, total and appendicular lean body mass (LBM and ASMI), 6 
minute walk test (6MWT), Gait Speed, Short Physical Performance Battery (SPPB) total score, 
. 
3.2.2.2.1 Nutritional status/protein intake
For both populations, nutritional status at Week 25 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 


Novartis
Confidential
Page 11
RAP Module 3
CBYM338E2202E1
status (sufficiently nourished/malnourished), and action taken if malnourished if available 
(dietary counseling with or without intervention/no dietary counseling).
3.2.2.2.2 Efficacy assessments
Total LBM, ASMI
Week 25 data (all relevant pre-treatment assessments, including baseline value, relative to Week 
25) of total LBM, ASMI will be summarized using descriptive statistics for both population I 
and population II, separately.
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. 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 as defined 
in the CRF page. 
Summaries at Week 25 will be provided for both population I and population II, separately. 
SPPB
The short physical performance battery (SPPB) evaluates lower extremities in three functional 
components: Standing balance, gait speed and chair stand. A score will be calculated for each 
of the three components. In addition a total SPPB score will also be calculated. 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 = 2 points, held for less 
than 3 sec or not attempted = 0 points.
Gait speed will be assessed as part of the SPPB, over a 4 meter distance of a 6 or 4 meter course. 
Gait speed assesses a person’s usual walking speed. The patient will perform two recorded trials 
of walking across the defined course. The fastest time in seconds (to the nearest 0.01 sec will 
be recorded. 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.


Novartis
Confidential
Page 12
RAP Module 3
CBYM338E2202E1
•
Patient is unable to do the walk = 0 points.
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.
Week 25 data (all relevant pre-treatment assessments, including baseline value, relative to Week 
25) of the total SPPB score with the corresponding scores of the three individual component 
tests: Standing balance, gait speed, and chair stand 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:
•
0 to 6 points.
•
7 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 (see Section 5.22.1 [Precision and summary 
statistics]). For balance tests, if the patient attempted the test and is indicated as “Held for 10 
seconds” then a value of 10 seconds will be used.
If a patient did not attempt a test or failed, the patient will have a missing time for that test.
3.2.2.2.3 Diaries
 


Novartis
Confidential
Page 13
RAP Module 3
CBYM338E2202E1
Exercise adherence diary
Site staff should query the patient on adherence to the exercise program, 
 
 recorded in the exercise diary during the monthly telephone call. Exercise adherence 
diary at Week 25 will be summarized for both population I and population II, separately. 


Novartis
Confidential
Page 14
RAP Module 3
CBYM338E2202E1
3.3
Treatments (study drug, other concomitant therapies, 
compliance)
The analysis in this section will be based on SAF set. 
For Population I, all summaries will be presented by treatment group in the extension study and 
overall. For Population II, all summaries will be presented by treatment assigned in the Core 
study and overall.
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 Population, treatment group, 
 
center and patient if not indicated otherwise.
Where relevant, “overall” refers to the addition of a “Total” treatment column within the 
planned presentation of the data. 
3.3.1
Study drug administration
For Population 1, the analysis of study treatment data will be based on the safety analysis set. 
For each subject, cumulative exposure to study treatment will be calculated as the number of 
days of drug exposure=last infusion date - first infusion date + 56 days. The first infusion date 
refers to the first dose date following the last dose in the core study. The duration of exposure 


Novartis
Confidential
Page 15
RAP Module 3
CBYM338E2202E1
to study drug will be summarized by treatment group,
as a 
continuous variable. The volume administered will also be summarized by visit and by 
treatment group as a continuous variable.
For Population 2, no exposure data will be presented.
3.3.2
Prior and concomitant medications
Prior medications, concomitant medications ongoing at the entry of the extension study and 
concomitant medications initiated in the extension study will be summarized by treatment group 
in separate tables. Medications will be presented in alphabetical order, by ATC codes and 
grouped by anatomical main group (the 1st level of the ATC codes). Within 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 also show the 
overall number (n) and percentage (%) of subjects receiving at least one drug of a particular 
ATC code and at least one drug in a particular anatomical main group. 
Summary by treatment group in this study will be provided for Populations I and II separately.
Prior medications are defined as drugs taken and stopped prior to first dose of study treatment
for population I, or prior to the first visit (Week 25) in the extension study for population II. 
Any medication given at least once between the day of first dose of study treatment and the date 
of the last study visit for population I, or between the first visit (Week 25) in the extension study 
and the end of the study visit for population II, will be a concomitant medication, including 
those which were ongoing at the entry of the extension study and continued into the study. Prior 
or concomitant medication will be identified based on recorded or imputed start and end dates 
of medication taking. If it cannot be established that the use of a prior medication has ended 
prior to the first dose of study treatment 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).
3.4
Analysis of the primary variable(s)
The primary analysis population for efficacy will be the Full Analysis Set.
The primary objective of this study is to assess the durability of effect of bimagrumab 
(BYM338) in older adults with sarcopenia as measured by the SPPB total score.
The primary endpoint is SPPB at week 49.
3.4.1
Descriptive statistics
Descriptive statistics (i.e. N, mean, SD, median, 25th percentile, 75th percentile, minimum, 
maximum (not included for Interim Analysis), the number of non-missing observations, and 
95% confidence intervals), per treatment, for each population separately, will be provided for 
the primary endpoint. 
Longitudinal plots (Mean +/- SE), by treatment of observed values vs time profile will be 
produced, for each population separately. 


Novartis
Confidential
Page 16
RAP Module 3
CBYM338E2202E1
3.4.2
Statistical model, hypothesis and method of analysis
For Population I, a 95% confidence interval for the difference in the primary endpoint between 
each continued BYM338 dose arm vs. corresponding placebo switched from the same BYM 
dose will be calculated at Week 49. The CI of the difference will be calculated using a t-test 
comparing the values at Week 49 between BYM338 dose arms vs. corresponding placebo. 
Summary statistics will also be presented by treatment arm. 
For Population II, the summary statistics will be presented by treatment assigned in the core 
study.
3.4.3
Handling of missing values/censoring/discontinuations
Summary statistics will be provided for observed data (no imputation in general, except special 
cases of the balance test described in section 1.3.2.2.2).
3.4.4
Supportive analysis
The same analysis will be performed on the PP analysis set 
 in two ways:
Proportions of patients being sarcopenic at Week 25 and Week 49 will be summarized by 
treatment, for population I and II separately. The criteria of being sarcopenic are from core 
study protocol inclusion criteria: 

Gait speed < 0.8 m/sec

ASMI <= 7.26 kg/m2 for men and <= 5.5 kg/m2 for women, or for Asian countries <= 
7.0 kg/m2 for men and <= 5.4 kg/m2 for women
3.5
Analysis of secondary 
The analyses described in this section will be based on FAS. 
3.5.1
Variables
Secondary efficacy variables include:

6MWT at Week 49

Gait speed at Week 49

Total LBM and ASMI as measured by DXA at Week 49 
 


Novartis
Confidential
Page 17
RAP Module 3
CBYM338E2202E1
3.5.2
Descriptive statistics
Descriptive statistics (i.e. N, mean, SD, median, 25th percentile, 75th percentile, minimum and 
maximum (min/max not included for Interim Analysis), the number of non-missing 
observations, and 95% confidence interval), per treatment group and visit, will be provided for 
each continuous variable and each population separately. 
Longitudinal plots (Mean +/- SE), by treatment of observed values vs time profile will be 
produced for each continuous variable and each population separately. 
 
For Population II, 
 
Lean body mass (LBM and ASMI) will be logarithmically 


Novartis
Confidential
Page 18
RAP Module 3
CBYM338E2202E1
transformed before the analysis. The results of the analysis will be back-transformed from the 
log-scale before reporting.
3.5.3
Statistical model, hypothesis and method of analysis
3.5.3.1
6MWT, Gait speed, SPPB total score, total LBM and ASMI
For population I, the 95% confidence interval will be provided for the difference between each 
continued BYM dose arm and corresponding placebo (switched from the same BYM dose arm) 
at each visit. 95% confidence interval will also be provided for the difference between each 
continued BYM dose arm and the placebo arm continued from the core study at each visit. 
The confidence interval at Week 49 for SPPB total score between each continued BYM dose 
arm and corresponding placebo (switched from the same BYM dose arm) for population I is 
provided as the primary analysis. For population II, the summary statistics at Week 49 are 
provided as the primary analysis. 
For population II, SPPB total score, 6MWT, Gait speed, total LBM and ASMI at Week 49 will 
be explored at final analysis using an analysis of variance model (ANCOVA) with treatment 
assigned in the core study 
 as fixed effects and Week 25 SPPB total score as covariate. 


Novartis
Confidential
Page 19
RAP Module 3
CBYM338E2202E1
3.5.3.8
Exercise adherence
Below analysis applies to both population I and population II. 
During the study, patients will be instructed to complete an Exercise Adherence e-diary. The 
diary will capture physical activity per defined categories in the diary. 
 
 
 
 
 
 
 
 
For each exercise category, summary statistics for the total time spent will be provided by 
treatment group (for population I, and treatment assigned in the core study for population II) 
and visit. 
3.5.3.9
Other assessments
400 Meter Walk Test
400 meter walk test was removed upon protocol amendment 1. If any data captured prior to 
protocol amendment 1 are available in the database, those will be listed only, by treatment arm 
at the final analysis. 


Novartis
Confidential
Page 20
RAP Module 3
CBYM338E2202E1
3.5.4
Supportive analysis
The same analysis defined above for the Gait speed, 6MWD, 
, and total 
LBM will also be performed 
:
3.6
Statistical methods for safety and tolerability data
Analyses in this section will be based on SAF. 
For Population I, all summaries will be presented by treatment group in the extension study and 
overall. For Population II, all summaries will be presented by treatment assigned in the Core 
study and overall.
 
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, 
 center and 
patient if not indicated otherwise.
Descriptive statistics (mean, median, standard deviation, minimum and maximum) for safety
variables will be presented for the SAF analysis set.
Where relevant, “overall” refers to the addition of a “Total” treatment column within the 
planned presentation of the data. 
3.6.1.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, echocardiography, 
, nutrition status and protein 
intake, as well as subject demographics, baseline characteristics, and treatment information.
3.6.1.2
Descriptive analyses
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 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 (including mean, SD, median, minimum and maximum) will be provided 
by treatment and visit/time, for each population separately.
For population I, notable vital signs values will be considered “newly occurring” if they had 
not been present at Week 25 but present during the treatment epoch. If assessments cannot be 
made at Week 25 due to missing value(s), post-Week 25 values meeting the notable criterion 
will be considered as newly occurring. Similar definition applies for population II, post-
treatment follow-up epoch. Notable vital signs are considered to be the following:


Novartis
Confidential
Page 21
RAP Module 3
CBYM338E2202E1

Systolic blood pressure: 
o
>150mmHG or increase from Week 25 of >=20 mmHg
o
<90mmHG or decrease from Week 25 of >=20 mmHg

Diastolic blood pressure: 
o
>90mmHG or increase from Week 25 of >=15 mmHg
o
<50mmHG or decrease from Week 25 of >=15 mmHg

Pulse rate: 
o
>100bpm or increase from Week 25 of >=15 bpm
o
<60bpm or decrease from Week 25 of >=15 bmp
Summaries of newly occurring notable values will be summarized by population and by epoch. 
All vital signs data will be listed by population, treatment, subject, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged.
ECG evaluations
Summary statistics (including mean, SD, median, minimum and maximum) will be presented 
for ECG variables by visit and treatment group, for each population separately.
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
A listing of all newly occurring or worsening abnormalities by epoch will be provided for both 
populations, as well as a by-subject listing of all quantitative ECG parameters.
Clinical laboratory evaluations
All laboratory data will be listed by Population, treatment, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics (including mean, SD, 
median, minimum and maximum) will be provided by treatment and visit/time for Hematology, 
Clinical chemistry and Coagulation testing, for each population separately. For urinalysis, 
frequency tables will be presented.


Novartis
Confidential
Page 22
RAP Module 3
CBYM338E2202E1
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 
 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 
o
Hy’s law

Shift tables of LFTs/
 enzymes presenting a cross-tabulation of Week 25 and 
worst post Week 25 values

Change from Week 25 summary tables of LFTs/
 enzymes by visit.
Adverse events
Summaries will be provided for:
•
Adverse events by SOC and PT


Novartis
Confidential
Page 23
RAP Module 3
CBYM338E2202E1
•
Adverse events by severity
•
Treatment emergent adverse events (Population I only)
•
Post-treatment adverse events (Population II only)
•
Death
Adverse events of special interest (AESI)
Summary by treatment group in this study will be provided for Populations I and II separately.
All by-patient data listings will be sorted by Population, treatment group, center and patient if 
not indicated otherwise.
Adverse events continuing from the core study but not worsening in severity during the 
extension, will also be entered in the extension study database. These adverse events, will be 
presented in the listings but not in the tables. Adverse events continuing from the core study, 
but worsening in severity during the extension, will be entered as new events in the database 
and will be included in both tables and figures.
In addition to summary tables, safety topics of interest such as: cardiovascular events
spontaneous muscle contractions; diarrhea and diarrhea-like events defined in the Safety 
Profiling Plan (SPP) will be listed separately.
Adverse events by SOC and PT
The number (n) and percentage (%) of patients with adverse events will be summarized by 
primary SOC, PT 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. A subject with multiple adverse events within a SOC or PT is only 
counted once towards the total of this SOC or PT.
Separate summaries will be provided by SOC and PT for:
•
Adverse events
•
Treatment emergent adverse events (Population I only)
•
Post-treatment adverse events (Population II only)
•
Serious adverse events
•
Treatment emergent serious adverse events (Population I only)
•
Post-treatment serious adverse events (Population II only)
•
Other significant adverse events leading to discontinuation of study treatment 
•
And adverse events leading to dose interruption (including study treatment 
discontinuation) (Population I).
Adverse events by severity
The number (n) and percentage (%) of patients with adverse events will be summarized by 
severity, primary system organ class, PT and treatment group. If a patient reported more than 


Novartis
Confidential
Page 24
RAP Module 3
CBYM338E2202E1
one adverse event with the same PT, the adverse event with the greatest (maximum) severity 
will be presented. If a patient reports more than one adverse event within the same primary 
system organ class, only one adverse event will be counted for that patient at the highest severity 
level in the total row for each primary system organ class. If adverse event “severity” is missing, 
this variable will be listed as missing and treated as missing in summaries.
Separate summaries will be provided for: 
•
Adverse events
•
Treatment emergent adverse events (Population I only)
•
Post-treatment adverse events (Population II only)
Treatment emergent adverse events
Adverse events will be deemed treatment-emergent if events started after the first dose of study 
treatment or events present prior to the first dose of study treatment but increased in severity,
until 56 days after the last dose of study treatment. For Population II, the dose received at Core 
Week 21 visit is the scheduled last dose. For patient entering the extension study, their last visit 
in the core study is Week 25, which is the first visit in the extension study. Therefore, treatment 
emergent adverse events after Week 25 (Core EOT) are collected in the extension study. Such
treatment emergent adverse events cannot be identified completely based on extension study 
database alone, therefore cannot be summarized with accuracy. .
Treatment emergent adverse events will be summarized for population I. Only primary paths 
within MedDRA (SOC) will be considered for adverse event reporting.
Post-treatment adverse events
Adverse events with date of onset or worsening after the date of last infusion of study drug + 
56 days are considered as post-treatment adverse events. 
Based on the extension study database alone, the post-treatment adverse events will not be 
identified accurately according to above definition. Also, to take into consideration that adverse 
events starting between Week 25 and Week 29 could potentially fall into the definition of 
treatment emergent adverse events, adverse events of population II will be summarized by time 
interval, with adverse events starting date in the interval of: 

Week 25 to Week 25 + 35 days

Week 25 + 36 days onward
The summary will be done for Population II only. 
Deaths
All the deaths in the clinical database will be listed.
Deaths may be summarized by primary reason for death (specification) and will be presented 
by primary system organ class, PT and treatment group, for each population separately. 
Contributing reason for deaths will be listed only.


Novartis
Confidential
Page 25
RAP Module 3
CBYM338E2202E1
Adverse events of special interest (AESI)
The number (n) and percentage (%) of patients with adverse events of special interest will be
summarized by risk level PT (levels 1-7) and treatment group. For each risk level PT, exposure-
adjusted incidence rate (IR), will be calculated as the number of patients experiencing at least 
one AE in each category relative to the total patient years of the “at risk”*100. The total patients 
years of the “at risk” is defined, as the the sum of time in years to first occurence of a particuliar 
AE or time in years to EOS visit for subject who did not encounter a particuliar AE. For 
Population I, for each treatment group, total exposure will be calculated as the sum of exposure 
(days) of all patients per treatment group, divided by 365.25 (years).   The calculation formula,
for the number of days of drug exposure can be found in Section 3.3.1.
Other safety evaluations
Echocardiography
Summary statistics will be presented by visit and treatment group for the following 
measurements:
•
Left ventricular wall (posterior) and septal thickness
•
Left ventricular mass and mass index
•
End-diastolic volume
•
End systolic volume
•
Left ventricular ejection fraction
•
Left ventricular diastolic diameter
•
Left atrial size and volume
•
Right ventricular wall thickness and function
•
Interrogation of all valves for function, stenosis, regurgitation and morphology.
Summary statistics for echocardiography measurements at each scheduled visit as relevant, will 
be presented for each treatment group (see Section 2.1 [Precision and summary statistics]), for
each population separately.
Notable echocardiography values are considered to be the following:

LV posterior wall thickness:
o
change from baseline >50% (increase)
o
wall thickness at the end >15 mm 

Septal thickness:
o
change from baseline >50% (increase)
o
wall thickness at the end >15 mm 

Left ventricular ejection fraction:
o
relative decrease of >15% from baseline
o
absolute value of LVEF <45 
For notable echocardiography values, baseline is defined as Week 25.


Novartis
Confidential
Page 26
RAP Module 3
CBYM338E2202E1
Summaries of newly occurring notable values will be summarized by population and by epoch, 
and notable values will be flagged. 
All echocardiography results will be listed by Population, treatment, subject and visit/time. 
Nutrition status/protein intake
Nutrition status/protein intake during the study will be similarly as described in 3.2.2.2.1.
3.6.1.3
Graphical presentation of results
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
3.8
Interim analyses
An interim analysis will be triggered by the analysis of the core study Part A. Data from primary 
and key secondary efficacy parameters will be summarized. The interim analysis will provide 
a preliminary evaluation of endpoints over approximately 12 months; and together with core 
study Part A data will support next step decision making. Analyses based on PP set will not be 
included for IA. 
The interim analysis will cover following analyses: 

Patient disposition

Analysis sets

Demographics and patient characteristics at Week 25 (nutritional status, protein intake,
6MWT, SPPB total score, Gait Speed, 
, and ASMI)

Treatments (Study drug for population I, prior and concomitant medication for both 
populations)


Novartis
Confidential
Page 27
RAP Module 3
CBYM338E2202E1

Primary analysis: SPPB at Week 49, summaries of population I and II separately

Secondary analyses: 6MWT, Gait speed, LBM and ASMI, summaries for population I 
and II separately

Safety analyses: 
o
Nutrition status/protein intake
o
Population I: TEAE, ECG, Vital sign, and notable Lab
o
Population II: notable Lab. 

Supportive analysis: 
o
Proportion of sarcopenic patients at Week 25 vs Week 49. 
 
 Such analysis 
will be detailed in a separate document when it becomes necessary and/or be generated for the 
final analysis. 
3.8.1
Interim Analysis FIR
Among the outputs planned to be released for the IA, key statistical outputs listed below will 
be released in priority: 

Summary of patients disposition by treatment

Summary of patients under each analysis set by treatment

Summary of demographic characteristics by treatment

Summary of patient characteristics at Week 25 (6MWT, SPPB total score, Gait Speed, 
, and ASMI) by treatment.

Analysis of primary endpoint: SPPB at Week 49 for both populations. 

In addition to primary endpoint, statistical summary from Week 25 to Week 49 
performance along with figures of time course and/or change from Week 25 will be 
provided for following endpoints (secondary endpoints) for both populations:
o
6 minute walk test (6MWT)
o
SPPB total score
o
Gait Speed (GS)
3.9
Sample size calculation
All the subjects from the core (E2202), if eligible, can enter this extension study after they 
complete informed consent. The study is not powered for hypothesis testing.


Novartis
Confidential
Page 28
RAP Module 3
CBYM338E2202E1
With 40 to 50 patients per each bimagrumab dose arm, assuming a standard deviation of SPPB 
of 1.5, 2.0, 2.5, and 3.0, the half-width of 95% confidence interval for SPPB is presented below 
in Error! Reference source not found..
Table 3-1: Half-width of 95% confidence interval of SPPB
SD=1.5
SD=2.0
SD=2.5
SD=3.0
50 patients per arm
0.42
0.55
0.69
0.83
40 patients per arm
0.46
0.62
0.77
0.93
4
Statistical methods planned in the protocol and 
determination of sample size
Data will be analyzed by Clinbay according to the data analysis section 9 of the study protocol 
which is available in Appendix 16.1.1 of the CSR.  Important information is given in the 
following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
5
Clinical Study Report - Appendix 16.1.9 Documentation of 
statistical methods
5.1
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.
5.2
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
For the Interim Analysis, to avoid patient level unblinding, minimum and maximum will not be 
included in the summary statistics for all except Safety summaries. 
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.
Where Confidence Intervals will be presented alongside the summary statistics, these will 
originate from a one-sample t-test. 


Novartis
Confidential
Page 29
RAP Module 3
CBYM338E2202E1
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:
•
< 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 be 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.
 
 
 
5.3
Study Day 1 and other study days
The date of first infusion of study drug at the extension study for population I, and the date of 
the first follow-up visit for population II 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/follow-up visit date at extension study) +1, which could be Day 1, Day 2, Day 3, etc.


Novartis
Confidential
Page 30
RAP Module 3
CBYM338E2202E1
For event dates before Day 1, study day for an event date is calculated as: (event date – first 
infusion/follow-up visit date at extension study), 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.
5.4
Definition of Baseline and post-baseline measurements
Baseline is defined as the core study baseline, for both populations. In the planned analyses, 
Week 25 has been referred to majority of the time, and it is referring to a relative baseline to 
the extension study, which is defined as the Visit 1 pre-dose assessments of the extension study 
(Week 25, EOT visit of the core study) for population I and  for population II defined as the 
Visit 1 assessments of the extension study (Week 25, EOT visit of the core). This visit will be 
labeled as Week 25 in the reports. 
5.5
Analysis visits 
5.5.1
Visit naming
Table 1
Visit schedule for both populations
Visit 
No.
Visit
Target Visit Day
Start  day of
visit window
Mid-point
End day 
of visit window
1
Week 25
1
-
1
15
2
Week 29
29
16
29
43
3
Week 33
57
44
57
71
4
Week 37
85
72
85
99
5
Week 41
113
100
113
127
6
Week 45
141
128
141
155
7
Week 49 (EOT)*
169
156
169
183
8
Week 53 (EOS)*
197
184
197
End of study
*For population II, Week 49 (EOS) and no Week 53.
Multiple assessments within visits
For visit multiple records may exist in one particular visit for a particular assessment (e.g. 
laboratory assessments). The following rules (unless otherwise specified) will be applied to 
obtain one value per patient per assessment per visit which will be used in the assessment by-
visit summaries.

the closest to the actual target visit day is chosen for both continuous variables and 
categorical variables based on continuous variables  (if two assessments have the same 
distance, then the earlier one by assessment date or visit date will be chosen); 

For qualitative variables (i.e., laboratory abnormalities or most extreme values analysis), 
the worst/most extreme (high & low) record will be used.  


Novartis
Confidential
Page 31
RAP Module 3
CBYM338E2202E1
5.6
Handling of missing values/censoring/discontinuations
In general, unless otherwise indicated, no data imputation will be done for the missing values.
5.7
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.
5.8
Statistical methodology and assumptions
5.8.1
Two sample t-test
For Population I, the two-sample t-test will be used in order to obtain 95% confidence intervals 
for the difference between: 

each continued BYM338 dose arm vs. corresponding placebo, and

Each continued BYM338 dose arm vs. continued placebo arm, 
for the following endpoints: 

Week 25 to 49 on the 6MWT

Week 25 to 49 on the SPPB

Week 25 to 49 on the Gait speed

Week 25 to 49 in log transformed values on LBM and ASMI
The t-test will assume Equal variances when the null hypothesis of variance equality cannot be 
rejected, and Unequal variances when the variance equality hypothesis is rejected.
5.8.2
ANCOVA
For Population II, ANCOVA model is used to explore the durability of BYM338 on the 
following endpoints:

Week 49 on the SPPB

Week 49 on the 6MWT

Week 49 on the Gait speed

Week 49 in log transformed values on LBM and ASMI
The endpoint value at extension baseline as a covariate, treatment arm (as assigned in the core 
study for population II)
will be included as fixed effects. The 95% 
confidence intervals for the difference between arms receiving BYM338 and Placebo during 
the core study will be estimated.


Novartis
Confidential
Page 32
RAP Module 3
CBYM338E2202E1
 
 


Novartis
Confidential
Page 33
RAP Module 3
CBYM338E2202E1


Novartis
Confidential
Page 34
RAP Module 3
CBYM338E2202E1
6
Appendix
6.1
Protocol deviations
Exceptions to the following inclusion/exclusion are considered as major protocol deviations. 
The list with corresponding actions to remove subjects from certain analysis set will be defined 
prior to unblinding. 


Novartis
Confidential
Page 35
RAP Module 3
CBYM338E2202E1
Inclusion/Exclusion
Exclusion Criteria Text
Criteria Number 
Inclusion
Inclusion 1
Men and postmenopausal women aged 70 years or older that have 
participated in, and have completed the full study treatment period per 
protocol (24 weeks/EOT visit) in the preceding core study 
(CBYM338E2202);
Inclusion 2
Written informed consent must be obtained before any assessment of the 
extension study is performed (can be obtained at the EOT visit of the 
core study).
Exclusion 1 
Use of prohibited treatments as per recommendations in Protocol Table 
5-1;
Exclusion 2 
History of severe hypersensitivity reaction in the core study;
Exclusion 3
History of breaking the blind (inadvertently or for emergency reasons) in 
the core study;
Exclusion 4 
History of adverse event(s) in the core study that in the judgement of the
investigator, taking into account the subject’s overall status, prevent the 
subject from entering the extension study);
Exclusion 5
Clinically significant abnormal liver function tests that would have 
resulted in discontinuation of study drug while participating in the core 
study as per protocol (as outlined in Protocol Appendix 1) such as SGOT 
(AST), SGPT (ALT), alkaline phosphatase, or serum bilirubin (except 
Gilbert’s Disease);
Exclusion 6 
Patient has any medical condition or laboratory finding (e.g., an 
unexplained or clinically significant lab result), which, in the opinion of 
the investigator taking into consideration the subject’s overall status, 
prevents the subject from continuing participation in the study, may 
interfere with participation in the study, might confound the results of 
the study, or pose an additional safety risk to the subject in administering 
bimagrumab;
Exclusion 7 
Concurrent enrollment in a clinical trial involving an investigational drug 
or off-label use of a drug, or any other type of medical research judged 
to be scientifically or medically incompatible with this study (not 
including enrollment in BUM338E2202 core study).
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients, within and across study sites.


Novartis
Confidential
Page 36
RAP Module 3
CBYM338E2202E1
7
References
References are available upon request.