Conditions: Diabetes Mellitus, Type 2
Keywords: type 2 diabetes obesity DXA MRI
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 78
Healthy volunteers: no

Brief summary:
This study assessed the safety, pharmacokinetics and efficacy of bimagrumab when administered in overweight and obese patients with type 2 diabetes

Detailed description:
A non-confirmatory, randomized, subject and investigator blinded, placebo controlled, parallel-arm study, investigating a 48-week treatment period with i.v. bimagrumab 10 mg/kg in overweight and obese subjects with type 2 diabetes.

Participants were randomized and assigned to one of the following 2 treatment arms in a ratio of 1:1:

Arm 1: Bimagrumab 10 mg/kg up to maximum 1200 mg, every 4 weeks (12 doses) until week 44.

Arm 2: Placebo, every 4 weeks (12 doses) until week 44.

The study consisted of a screening baseline period of 3 weeks, treatment period of 48 weeks and then a follow-up period of 8 weeks.

Treatment period visits were scheduled every 4 weeks until week 44. Administration of bimagrumab or placebo was done via an i.v. infusion over 30 minutes followed by flushing for 15 minutes. Subjects were asked to return to the Investigator site for dosing approximately every 4 weeks during the treatment period. During those visits, subjects were evaluated for safety, tolerability, PK and efficacy. The treatment period ended approximately 4 weeks after the last dose administration.

Arms:
arm 1: Bimagrumab (BYM338) 10 mg/kg up to maximum 1200 mg, every 4 weeks until week 44 (12 doses) arm 2: Placebo, every 4 weeks until week 44 (12 doses)

Interventions: intervention 1: BYM338 10 mg/kg intervention 2: Placebo
Intervention descriptions: intervention 1: intravenous infusion every four weeks intervention 2: intravenous infusion every four weeks

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
BYM338/Bimagrumab
Clinical Trial Protocol CBYM338X2211
A randomized, subject- and investigator-blinded, 
placebo-controlled study to assess the safety, 
pharmacokinetics and efficacy of intravenous bimagrumab 
in overweight and obese patients with type 2 diabetes
Document type:
Amended Protocol Version
EUDRACT number:
2016-004124-26
Version number:
v05 (Clean) Incorporating amendment 05
Clinical Trial Phase:
II
Release date:
17-Jan-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not be part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below.  Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO & PS)
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................12
Glossary of terms...............................................................................................................13
Protocol synopsis...............................................................................................................30
1
Introduction .......................................................................................................................34
1.1
Background............................................................................................................34
1.1.1
Relevant data summary.........................................................................35
1.2
Nonclinical data.....................................................................................................35
1.3
Clinical data...........................................................................................................36
1.3.1
Human safety and tolerability data .......................................................36
1.3.2
Human pharmacokinetic data................................................................36
1.3.3
Human pharmacodynamic data.............................................................37
1.4
Study purpose ........................................................................................................37
2
Study objectives and endpoints .........................................................................................37
2.1
Primary objective...................................................................................................37
2.2
Secondary objectives .............................................................................................37
2.3
Exploratory objectives...........................................................................................38
3
Investigational plan ...........................................................................................................39
3.1
Study design...........................................................................................................39
3.2
Rationale for study design .....................................................................................41
3.3
Rationale for dose/regimen, route of administration and duration of treatment....42
3.4
Rationale for choice of comparator .......................................................................43
3.5
Rationale for choice of background therapy..........................................................44
3.6
Purpose and timing of interim analyses/design adaptations..................................44
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3.7
Risks and benefits..................................................................................................44
3.7.1
Potential benefits...................................................................................44
3.7.2
Bimagrumab related risks .....................................................................45
3.7.3
Blood sample volumes..........................................................................48
3.7.4
Trial-related risks ..................................................................................48
4
Population..........................................................................................................................49
4.1
Inclusion criteria ....................................................................................................50
4.2
Exclusion criteria...................................................................................................50
5
Restrictions for Study Subjects .........................................................................................53
5.1
Contraception requirements...................................................................................53
5.2
Prohibited treatment...............................................................................................54
5.3
Dietary restrictions and smoking...........................................................................54
5.4
Other restrictions ...................................................................................................55
6
Treatment...........................................................................................................................55
6.1
Study treatment......................................................................................................55
6.1.1
Investigational treatment and control drugs..........................................55
6.1.2
Additional study treatment....................................................................56
6.2
Treatment arms......................................................................................................56
6.3
Permitted dose adjustments and interruptions of study treatment.........................56
6.4
Background therapy dose adjustments ..................................................................56
6.5
Treatment assignment and randomization.............................................................57
6.6
Treatment blinding.................................................................................................58
6.7
Treating the subject................................................................................................59
6.8
Emergency breaking of assigned treatment code ..................................................60
6.9
Treatment exposure and compliance .....................................................................60
6.10
Recommended treatment of adverse events ..........................................................61
6.11
Rescue medication.................................................................................................61
6.12
Concomitant treatment...........................................................................................61
6.13
Vitamin and mineral supplementation...................................................................62
7
Study completion and discontinuation ..............................................................................63
7.1
Study completion and post-study treatment ..........................................................63
7.2
Discontinuation of study treatment........................................................................63
7.3
Withdrawal of informed consent ...........................................................................64
7.4
Lost to follow-up ...................................................................................................64
7.5
Study Stopping rules..............................................................................................64
7.6
Early study termination by the sponsor .................................................................65
8
Procedures and assessments ..............................................................................................65


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8.1
Assessment schedule .............................................................................................65
8.2
Informed consent procedures.................................................................................72
8.3
Subject screening...................................................................................................72
8.4
Subject demographics/other baseline characteristics.............................................73
8.4.1
Alcohol Test and Drug Screen..............................................................73
8.4.2
Hepatitis and HIV Screen......................................................................73
8.4.3
Testosterone and TSH...........................................................................73
8.5
Efficacy / Pharmacodynamics ...............................................................................73
8.5.1
Diabetes parameters ..............................................................................74
8.5.2
Imaging .................................................................................................74
8.5.3
Anthropometric measurements .............................................................75
8.6
Safety.....................................................................................................................76
8.6.1
Physical examination ............................................................................77
8.6.2
Vital signs..............................................................................................77
8.6.3
Pregnancy test .......................................................................................77
8.6.4
ECG evaluation.....................................................................................77
8.6.5
Hematology...........................................................................................78
8.6.6
Blood chemistry ....................................................................................78
8.6.7
Urinalysis ..............................................................................................78
8.7
Pharmacokinetics (PK) ..........................................................................................78
8.8
Other assessments..................................................................................................79
8.8.1
3 day food record ..................................................................................79
8.8.2
24 hour dietary recall assessment..........................................................79
8.8.3
Immunogenicity ....................................................................................79
8.9
Use of residual biological samples ........................................................................80
9
Safety monitoring..............................................................................................................81
9.1
Adverse events.......................................................................................................81
9.2
Serious adverse event reporting.............................................................................82
9.2.1
Definition of SAE .................................................................................82
9.2.2
SAE reporting........................................................................................83
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9.3
Liver safety monitoring .........................................................................................84
9.4
Lipase and amylase elevations...............................................................................86
9.5
Renal safety monitoring.........................................................................................86
9.6
Reporting medication errors including misuse/abuse............................................86
9.7
Pregnancy reporting...............................................................................................87
9.8
Early phase safety monitoring ...............................................................................87
10 Data review and database management.............................................................................88
10.1
Site monitoring ......................................................................................................88
10.2
Data collection.......................................................................................................88
10.3
Database management and quality control............................................................89
10.4
Data Monitoring Committee..................................................................................90
10.5
Adjudication Committee........................................................................................91
11 Data analysis......................................................................................................................91
11.1
Analysis sets ..........................................................................................................91
11.2
Subject demographics and other baseline characteristics......................................91
11.3
Treatments .............................................................................................................91
11.4
Analysis of the primary variable(s) .......................................................................91
11.4.1
Variable(s).............................................................................................91
11.4.2
Statistical model, hypothesis, and method of analysis..........................92
11.4.3
Handling of missing values/censoring/discontinuations.......................92
11.4.4
Sensitivity analyses ...............................................................................92
11.5
Analysis of secondary variable(s)..........................................................................93
11.5.2
Safety.....................................................................................................93
11.5.3
Pharmacokinetics ..................................................................................94
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................94
11.5.5
Other assessments .................................................................................94
11.6
Analysis of exploratory variables ..........................................................................94
11.7
Sample size calculation..........................................................................................95
11.8
Power for analysis of key secondary variables......................................................95
11.9
Interim analyses.....................................................................................................95
12 Ethical considerations........................................................................................................96
12.1
Regulatory and ethical compliance........................................................................96
12.2
Responsibilities of the investigator and IRB/IEC..................................................96
12.3
Publication of study protocol and results...............................................................97
13 Protocol adherence ............................................................................................................97
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13.1
Protocol Amendments ...........................................................................................97
14 References .........................................................................................................................98
15 Appendix 1: Liver Event Definitions and Follow-up Requirements...............................100
16 Appendix 2: Specific Renal Alert Criteria and Actions ..................................................102
List of tables
Table 3-1
Skin reactions considered possibly related to bimagrumab from 
unblinded data*.....................................................................................45
Table 3-2
Muscle symptoms considered possibly related to bimagrumab from 
unblinded data*.....................................................................................46
Table 6-1
Overview of study medication ..............................................................55
Table 6-2
Blinding levels ......................................................................................59
Table 8-1
Assessment schedule.............................................................................66
Table 8-2
Mixed Meal Tolerance Test ..................................................................71
Table 8-3
24-hour dietary recall ............................................................................71
Table 9-1
Safety monitoring guidance for amylase and lipase elevations ............86
Table 9-2
Summary of reporting requirements for medication errors...................87
Table 11-1
Operating characteristics for primary efficacy criterion based on 
DXA fat mass (placebo-corrected decrease statistically significant 
(1-sided p<0.1) and clinically relevant (estimated median 5 percent 
or more).................................................................................................96
Table 15-1
Liver Event Definitions.......................................................................100
Table 15-2
Actions required for Liver Events.......................................................100
Table 15-3
Exclusion of underlying liver disease .................................................101
Table 16-1
Specific Renal Alert Criteria and Actions...........................................102
Table 16-2
Follow-up of renal events....................................................................103
List of figures
Figure 3-1
Study design..........................................................................................41


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List of abbreviations
γGT
Gamma-glutamyl transferase
ADA
American Diabetes Association
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
bid
twice daily
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CK
creatinine kinase
CL
Clearance
CMR
cardiac magnetic resonance imaging
COPD
chronic obstructive pulmonary disease
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CT
computerized tomography
CV
coefficient of variation
D5W
Dextrose 5% solution
DMC
Data Monitoring Committee
DPP4
Dipeptidyl peptidase-4 inhibitor
DXA
Dual energy X-ray absorptiometry
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EoS
End of study
EoT
End of treatment
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FBM
fat body mass
FDA
Food and Drug Administration
FPG
Fasting plasma glucose
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
h
hour
HbA1c
glycated haemoglobin test
hCG
Human chorionic gonadotropin
HIV
human immunodeficiency virus
HOMA2-IR
Homeostatic model assessment 2 – insulin resistance
i.v.
intravenous
IA
Interim analysis
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine system
kg
kilogram(s)
LBM
lean body mass
LDH
lactate dehydrogenase
LFT
Liver function test
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MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MRI
Magnetic resonance imaging
MTT
Meal Tolerance Test
NCDS
Novartis Clinical Data Standards
NOAEL
no-observed-adverse-effect-level
PD
pharmacodynamic(s)
PG
pharmacogenetics(s)
PK
pharmacokinetic(s)
PoC
Proof of Concept
PRO
Patient reported outcome
QTcF
Fridericia QT correction formula
QUICKI
quantitative insulin-sensitivity check index
RNA
ribonucleic acid
s.c.
subcutaneous
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
sIBM
sporadic inclusion body myositis
S
Source data
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SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2D
Type 2 Diabetes 
TBL
total bilirubin
TMDD
target mediated drug disposition 
ULN
upper limit of normal
US
ultrasound
WHO
World Health Organization
WOC
Withdrawal of Consent
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Pharmacokinetic definitions and symbols
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Ctrough
The trough observed analyte concentration is the concentration that is just 
prior to the beginning of, or at the end, of a dosing interval
Tmax
The time to reach the maximum concentration after drug administration [time]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which 
is used as a comparator to the investigational drug being tested in the 
trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up), which applies across all arms of a study
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance”
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 other treatments 
administered as concomitant background therapy required or allowed 
by the protocol when used within approved indication/dosage
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 


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assessments are planned
Randomization 
number
A 
unique 
identifier 
assigned 
to 
each 
randomized 
subject, 
corresponding to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part 
of the required study procedures; includes investigational drug, active 
drug run-ins or background therapy.
Study treatment
Any drug administered to the study participants as part of the required 
study procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc
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
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data


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Protocol synopsis
Protocol number
CBYM338X2211
Title
A randomized, subject- and investigator-blinded, placebo-controlled study 
to assess the safety, pharmacokinetics and efficacy of intravenous 
bimagrumab in overweight and obese patients with type 2 diabetes
Brief title
Safety, pharmacokinetics and efficacy study of bimagrumab in overweight 
and obese patients with type 2 diabetes
Sponsor and Clinical 
Trial Phase
Novartis
Phase II
Intervention type
Drug, Diet, and Moderate exercise 
Study type
Interventional 
Purpose and 
rationale
The main purpose of this study is to evaluate the efficacy of bimagrumab 
to decrease total body fat and improve glycemic control by improving 
insulin sensitivity in overweight and obese subjects with type 2 diabetes. 
This study will enable decision making for the development of bimagrumab 
in overweight and obesity and/or metabolic indications.
Primary Objective(s)
To evaluate the treatment effect of bimagrumab on total body fat mass.
Secondary 
Objectives
To evaluate the treatment effect of bimagrumab on total body fat mass 
after 6 months of treatment.
To evaluate the treatment effect of bimagrumab on glycemic control and 
parameters of insulin sensitivity.
To evaluate the safety and tolerability of bimagrumab in overweight and  
obese subjects with type 2 diabetes.
To evaluate the pharmacokinetics of repeat doses of bimagrumab in 
overweight and obese subjects with type 2 diabetes.
To evaluate the immunogenic response to repeat dosing of bimagrumab in 
overweight and obese subjects with type 2 diabetes.
To evaluate the treatment effect of bimagrumab on anthropometric body 
measurements and on lean body mass.
Exploratory 
Objectives
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Study design
This is a randomized, subject and investigator blinded, placebo-controlled, 
parallel arms study, investigating a 48-week treatment period with 
intravenous bimagrumab in overweight and obese subjects with type 2 
diabetes. Approximately 68 subjects are planned to be enrolled and 
randomized. 
Eligible subjects
will be randomized in a 1:1 ratio to bimagrumab or placebo.
Population
Approximately 68 overweight and obese subjects (BMI: 28-40 kg/m2
inclusive) with type 2 diabetes
Males and females between the ages of 18-75 years inclusive
Key Inclusion criteria

Male and female, age 18 to 75 years (inclusive), in stable health
condition as determined by past medical history, physical examination,
vital signs, electrocardiogram, and laboratory tests at screening.

Type 2 diabetes, with an HbA1c between 6.5% and 10% (inclusive) at
screening

On any one of the following anti-diabetes regimens with stable
treatment for approximately 3 months prior to randomization:
1) metformin monotherapy; 2) DPP4 inhibitor agent monotherapy;
3) combination therapy of metformin and DPP4 inhibitor agent;
4) no anti-diabetes therapy.

Body mass index (BMI) of 28.0 to 40.0 kg/m2 (inclusive) at screening.

Body weight between 65 and 140 kg (inclusive) at screening, and with
a stable body weight (±5 kg) by history (patient report) and stable
physical activity within 3 months prior to screening.
Key Exclusion 
criteria

Pregnant or nursing (lactating) women, where pregnancy is defined as
the state of a female after conception and until the termination of
gestation confirmed by a positive hCG laboratory test.

Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using highly effective
methods of contraception during dosing and for 6 months after
stopping of investigational drug.

Diabetes other than type 2 such as type 1 diabetes, surgically
induced-diabetes; "brittle" type 2 diabetes as per investigator
judgment, history of severe hypoglycemic episodes in the year
preceding screening, or hypoglycemic unawareness.
Study treatment

Bimagrumab (BYM338)

Placebo
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Efficacy/PD 
assessments

DXA scan for whole body, trunk, appendicular fat and lean mass

HbA1c, HOMA2-IR, QUICKI and Matsuda Index for glycemic response

Anthropometric measurement of fat by weight, body mass index (BMI),
waist circumference; hip circumference; waist to hip ratio
Key safety 
assessments

Adverse events

Physical exam

Vital signs

Laboratory evaluations

ECG

Urinalysis
Other assessments

PK samples

IG (immunogenicity)

Dietary intake – including but not limited to total calories, protein, fat,
carbohydrate.
Data analysis
The primary aim of the study is to assess the effect of bimagrumab on 
body fat mass at Week 48 of the treatment period compared to baseline.
The study design enables evaluation of efficacy based on the following 
dual criteria: 1) statistical significance (superior treatment effect, 1-sided 
10% level) in fat mass; and 2) clinical relevance of the change in fat mass 
(median treatment effect of at least 5%). Weight loss of 5% has been 
shown to translate into clinical benefit in an overweight and obese 
population with T2D. Fat mass loss of a similar magnitude to 5% weight 
loss is expected to translate into similar clinical benefits, (such as on 
glycemic control) in a similar population.
The randomization will be stratified by BMI category (>=28.0 kg/m2 and 
<=33.0 kg/m2, or >33.1 kg/m2 to <=40.0 kg/m2) in order to achieve an 
approximate balance of BMI distribution across the two treatment groups. 
The cutoff value of 33 kg/m2 represents the expected median BMI in the 
population based on internal data; therefore, the two randomization strata 
are expected to be of similar size. However, equal size strata will not be 
enforced. A minimum of 10 subjects will be targeted for enrollment in the 
smaller stratum to ensure acceptable precision of the treatment effect in 
both strata (see Section 11.7).
A longitudinal model describing fat mass over time will be used, using all 
of the data collected from both randomization strata and adjusting for 
baseline fat mass, treatment arm, baseline BMI. Variables indicating time
and time by treatment interaction will be included. An unstructured within-
subject covariance will be used. The change in fat mass at Week 24 will 
be estimated from that model. In addition, the proportion of subjects
reaching at least 5% fat loss at Week 24 will be presented by treatment 
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group.
Key words
Bimagrumab, type 2 diabetes, obesity, myostatin, MRI, DXA


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1
Introduction
1.1
Background
More than just a consequence of poor lifestyle choices, obesity is now viewed as a disease 
that is complex, multifactorial, chronic and resistant to many forms of treatment 
(Mechanick et al 2016). Obesity is a risk factor for increased overall mortality and is 
estimated to have caused 3.4 million deaths worldwide in 2010 (Lim et al 2012). 
Many co-morbidities are associated with obesity, such as type 2 diabetes, hypertension, 
dyslipidemia and coronary heart disease (Apovian et al 2015). A body weight reduction of 
5-10% has been associated with significant and clinically meaningful improvements in insulin
sensitivity, glycemic control, hypertension and dyslipidemia (Goldstein 1992; Vidal 2002;
Van Gaal et al 2005).
There are no approved obesity interventions that preserve or build lean mass while promoting 
fat mass loss.
The activin type 2 receptors (ActRIIA and ActRIIB, collectively abbreviated as ActRII) 
modulate signals for ligands belonging to the transforming growth factor beta (TGF-β) 
superfamily such as myostatin, GDF-11, and activin.  Myostatin, activin A, and GDF-11 are 
negative regulators of skeletal muscle growth, acting via the ActRII receptor signaling 
pathway to inhibit muscle protein synthesis and myocyte differentiation and proliferation. 
Blockade of these ligands' action through blockade of ActRII is known to increase skeletal 
muscle mass, which in turn is hypothesized to improve peripheral insulin sensitivity, 
since skeletal muscle is one of the major glucose utilizing tissues in the body. Inhibition of 
ActRII with an antibody has been shown to reduce white adipose tissue in mice on a normal 
or high-fat diet, while increasing skeletal muscle mass, potentially by inducing a functional 
increase in brown fat (Fournier et al 2012).
Bimagrumab (BYM338), a recombinant human, monoclonal antibody, binds competitively to 
ActRII with greater affinity than its natural ligands. Bimagrumab is in development for 
muscle wasting indications and has resulted in a significant increase in skeletal muscle mass 
in healthy volunteers, in patients with sporadic inclusion body myositis (sIBM), and in 
patients with sarcopenia. Bimagrumab single dose resulted in a profound impact on body 
composition with a maximal reduction in fat mass of ~ 8% and an increase in lean mass of 
~ 3% (DXA), in overweight and obese pre-diabetic patients. The net effect on total body 
weight was neutral. Insulin sensitivity was improved by ~ 18% as measured with a two-step 
hyperinsulinemic euglycemic clamp. This effect was associated with an absolute reduction in 
HbA1c of 0.2%, an effect size which has been associated with prevention of progression to 
diabetes in a similar population (DeFronzo et al 2011, Knowler et al 2002). 
The current study is designed in overweight and obese individuals with type 2 diabetes to 
evaluate the effect of bimagrumab on body composition and to enable evaluation of the 
metabolic impact of these changes on metabolic parameters. The intent is to evaluate whether 
loss of fat mass along with increased lean mass will favorably improve glycemic control. 
In addition, the impact of adiponectin, levels of which might increase in response to the 
enhanced muscle growth resulting from ActRIIB blockade (Suzuki et al 2008), on liver fat 


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and abdominal fat contents (through an hepatic insulin-sensitizing effect, enhanced fat 
oxidation and reduced lipid synthesis) will be studied.
1.1.1
Relevant data summary
1.2
Nonclinical data
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1.3
Clinical data
1.3.1
Human safety and tolerability data
1.3.2
Human pharmacokinetic data
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1.3.3
Human pharmacodynamic data
1.4
Study purpose
The purpose of this study is to enable decision making for the development of bimagrumab in 
overweight/obesity and metabolic indications.
2
Study objectives and endpoints
2.1
Primary objective
Primary objective
Endpoints related to primary objective

To evaluate the treatment effect of
bimagrumab on total body fat mass

Body fat mass by DXA at Week 48
2.2
Secondary objectives
Secondary objectives
Endpoints related to secondary objectives
To evaluate the treatment effect of
bimagrumab on total body fat mass
after 6 months of treatment

Body fat mass by DXA at Week 24
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Secondary objectives
Endpoints related to secondary objectives

To evaluate the treatment effect of
bimagrumab on glycemic control and
parameters of insulin sensitivity.

HbA1c, fasting glucose and insulin,
HOMA2-IR, QUICKI, Matsuda index based
on MTT at Week 24 and Week 48.

To evaluate the safety and tolerability
of bimagrumab in overweight and
obese subjects with type 2 diabetes.

Adverse events, Vital Signs, ECG,
Laboratory Values, Immunogenicity.

To evaluate the pharmacokinetics of
repeat doses of bimagrumab in
overweight and obese subjects with
type 2 diabetes.

PK samples – pre (Ctrough) and post dose
during treatment and follow-up periods.
Tmax and Cmax (Day 1, Day 168 and Day
308) will be derived.

To evaluate the immunogenic response
to repeat dosing of bimagrumab in
overweight and obese subjects with
type 2 diabetes.

Anti bimagrumab antibodies pre-dose,
during treatment and at the end of study.

To evaluate the treatment effect of
bimagrumab on anthropometric body
measurements and on lean body mass.

Body weight, BMI, waist circumference,
waist-to-hip ratio, lean body mass (LBM)
by DXA at Week 24 and at Week 48.
2.3
Exploratory objectives
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3
Investigational plan
3.1
Study design
This is a non-confirmatory, randomized, subject and investigator blinded, placebo-controlled, 
parallel arm study, investigating a 48-week treatment period with i.v. bimagrumab 10 mg/kg 
in overweight and obese subjects with type 2 diabetes. Approximately 68 subjects are planned 
to be enrolled and randomized
Screening (Days -21 to -8)
Potential subjects will undergo an onsite screening visit to determine their eligibility for the 
study (see enrollment criteria Section 4). Subjects who qualify for enrollment following 
screening will be scheduled for baseline assessments.
The investigator must recommend a lifestyle intervention (U.S. Department of Health and 
Human Services Food and Drug Administration Center for Drug Evaluation and Research 
2008) that includes dietary counseling for weight loss with a daily caloric deficit of 
approximately 500 kcal, with a diet that follows the American Diabetes Association (ADA) 
guidance for optimal glycemic control, and with protein intake of at least 1.2 g/kg/day to 
support muscle anabolism.  
Subjects must be encouraged to follow a diet containing approximately 45-50% of calories as 
carbohydrate, 20-25% protein, and 30% fat. Subjects will receive counseling for physical 
activity and will be encouraged to follow the ADA walking program guidelines (please refer 
to the SOM). These interventions will be initiated at screening after eligibility is confirmed.
Baseline (Days -7 to -1)
Prior to dosing (Day 1), subjects who are eligible for enrollment following screening will 
return to the clinic to undergo baseline assessments as defined in Section 8.1
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(Assessment schedule). To facilitate study conduct, subjects may opt to be domiciled on 
Day -1 to complete baseline assessments prior to dosing on Day 1. Subjects will receive a
mobility tracker device to monitor their physical activity.
Randomization and Dosing (Day 1)
Eligible subjects, based on screening and baseline assessments, will be randomized in a 1:1 
ratio to receive either bimagrumab or placebo. Randomization will be stratified according to 
baseline BMI into 2 strata:

BMI between 28.0 kg/m2 and 33.0kg/m2 (inclusive) and

BMI above 33.1 kg/m2 and up to 40.0 kg/m2 (inclusive).
Administration of bimagrumab or placebo will be done via an intravenous infusion over 
30 minutes, followed by approximately 15 minutes for flushing and then an observation 
period that will include safety and tolerability and PK sampling. Following all assessments, 
subjects may be discharged from the Investigator site when the Investigator judges them to be 
medically stable, in good general health and not needing further observation.
Treatment period (Days 1 - 336)
Subjects should continue on anti-diabetes background therapy as per eligibility criteria 
(see Section 4.1) throughout the study. If, however, during the course of the study, a subject 
experiences an improvement or a deterioration of his/her glycemic control, modification of 
his/her background therapy can be made as defined in Section 6.4 (Background therapy dose 
adjustments).
Administration of bimagrumab or placebo will be done via an intravenous infusion over 30 minutes 
followed by 10 to 20 minute observation period once every 4 weeks for a total of twelve doses. 
Bimagrumab will be dosed based on body weight at 10 mg/kg, with a dose cap of 1200 mg for 
body weight equal to and above 120 kg. Placebo will be provided by the site as 5% Dextrose 
solution (D5W) (see Pharmacy Manual for more details).
Subjects will receive regular monitoring and advice on diet and physical activity as part of 
their monthly site visits (please refer to Section 8.1 (Assessment schedule)) throughout the 
study, and will be contacted by telephone, or scheduled for an in-person assessment, once 
between each monthly site visit to provide a 24-hour dietary recall. Additional methods for 
promoting weight loss may be incorporated into or used in place of standard clinical care; 
these methods may include the use of electronic tools for reporting dietary intake, weight or 
physical activity, and for receiving feedback on weight trends and lifestyle changes.
Subjects will be asked to return to the Investigator site for dosing approximately every 
4 weeks during the treatment period. During these visits, subjects will be evaluated for safety, 
tolerability, PK and efficacy. The specific assessments for each of these visits are detailed in 
Section 8.1 (Assessment schedule).
The treatment period will end approximately 4 weeks after the last dose administration.


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Follow Up (Days 364 -392)
After completion of the treatment period, subjects will have a follow-up period of 8 weeks 
with regular monitoring for safety and efficacy beginning at Week 48 and continuing until the 
end of study visit (EOS) which will take place 12 weeks after the last study drug 
administration. The specific assessments for the follow up and end of study visits are detailed 
in Section 8.1 (Assessment schedule).
Figure 3-1
Study design
3.2
Rationale for study design
The rationale for key elements of the study design include:

Randomization: To decrease the chance of an imbalance in subject characteristics
(e.g., age, BMI) between treatment groups.

Stratification: BMI was selected as a stratification parameter as it is an important
predictor of response for parameters of body composition/body weight and HbA1c
(internal data). The expected median value for BMI in this subject population is 33 kg/m2 
(internal data), therefore 2 strata above and below/inclusive of the median will ensure a
balanced representation of subjects between placebo and active drug in each strata, i.e.
strata of approximately similar size between the 2 arms.

Subject- and investigator-blinding: To mitigate the risk of bias in treatment allocation,
reporting and causality assessment of adverse events. Furthermore, this design decreases
the potential confounding effect of intentional or unintentional behavioral changes made
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
Placebo arm: Inclusion of a placebo group will allow the analysis of whether or not
bimagrumab treatment is more effective than a standard treatment approach based on
lifestyle intervention.

Lifestyle interventions: Trials with anti-obesity agents have to demonstrate treatment
benefits on body weight/composition on a background of first line-therapy with lifestyle
interventions. The daily caloric deficit of 500 Kcal with approximately 45-50% calories
from carbohydrate, 20-25% from protein and 30% from fat is a standard approach and is
expected to induce weight loss over the treatment period. It may also enhance the effect of
bimagrumab on body composition and body weight. The American Diabetes Association
(ADA) walking program is tailored to the type of population in this study and is a gentle,
easy to implement approach for physical activity.
 Electronic methods to support participants in making behavioral 
changes to promote weight loss may also be utilized.

Adequate protein intake: Protein content of 1.2 g/kg/day is recommended to ensure
adequate dietary intake during the period of muscle growth.

Standard of care diabetes therapy: Subjects will remain on their standard of care
treatment for diabetes, enabling the evaluation of added treatment benefit with
bimagrumab on glycemic parameters. Anti-diabetes therapy is restricted to metformin
and/or DPP4 inhibitors, as these medications are less likely to affect body weight and thus
confound the study results.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Dose rationale
In healthy volunteers (HV) and sIBM patients, a 10 mg/kg dose of bimagrumab was shown to 
provide exposure levels (i.e. above 10 µg/mL) at which the anabolic effect is observed and 
maintained over dosing intervals of 4 weeks [CBYM338X2102 (N=6
subjects), 
CBYM338X2104 (N=47 subjects)], for up to six doses [CBYM338X2109 (N=35 subjects)] 
. The threshold for minimal 
target exposure for bimagrumab is approximately 10 µg/mL, a concentration below which 
nonlinear clearance is observed, suggesting loss of full receptor saturation and target-mediated 
drug disposition. In clinical studies to date, bimagrumab concentrations approximately at or 
above 10 µg/mL for at least 4 weeks in HV and more than one year in sIBM patients have 
been safe, well tolerated, and have demonstrated an increase in thigh muscle volume. 
The 26-week toxicology studies in cynomolgus monkeys showed a chronic exposure at 
NOAEL (300 mg/kg/week) of approximately 300-fold and 55-fold for AUC and Cmax,
respectively, when compared to human exposures at 10 mg/kg at steady state.
Dosing in this study is weight-based for subjects with body weight up to 120 kg, and is 
capped at 1200 mg for subjects with body weight between 120 kg and 140 kg. 
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Body-weight based dosing has proven to reduce variability in exposure in subjects/patients, 
and will be implemented as applicable. Capped dose is selected for body weights > 120 kg 
because of the uncertainty of the effect of large body weight and body composition (% fat 
mass vs. % lean mass) on the exposure and safety profile of bimagrumab. 
To date, the pharmacokinetic data is limited in obese subjects, and the maximal body weight 
in dosed subjects has been 116 kg, in studies conducted with bimagrumab in overweight to 
obese subjects with insulin resistance (N=10), and obese healthy subjects (N=6). 
The maximal amount of bimagrumab administered to-date is 3500 mg (at a dose of 30 mg/kg), 
given i.v. and as a single dose for a maximal body weight of 116 kg. This dose did not show 
over-exposure and caused no safety concerns. 
A capped dose for these subjects is selected to avoid over-exposure and to maintain 
bimagrumab levels around the threshold for safe anabolic effects over 4-week dosing intervals. 
Specifically, the selected amount of 1200 mg translates to a body weight based dose ranging 
from 10 to 8.6 mg/kg for the body weight range of 120-140 kg, which is predicted to result in 
exposure levels within the safe and efficacious range for bimagrumab and with minimal risk 
of over-exposure.
Rationale for duration of treatment
A treatment duration of 48 weeks is selected to capture the temporal profile as well as 
maximal effect of bimagrumab on body fat mass. While a ceiling effect is typically observed 
on lean mass gain with bimagrumab, the loss of fat mass does not seem to plateau over a 
period of 24 weeks and even up to 64 weeks (Internal data).
Rationale for follow-up period
An off-drug follow-up period is included to monitor the durability of treatment effect of 
bimagrumab on body fat mass, lean mass and glycemic control once off treatment. The EOS 
visit being performed 12 weeks after the last administration covers the wash-out period of 
bimagrumab exposure associated with anabolic effect (approximately 8 weeks).
3.4
Rationale for choice of comparator
A placebo will be used as a comparator in this study based on the following rationale:

A placebo comparator is needed to assess bimagrumab efficacy over the standard
treatment approach based on lifestyle intervention. Also a placebo comparator does allow
maintaining the double blind design.


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3.5
Rationale for choice of background therapy
This trial in overweight or obese patients with T2D has the primary goal of assessing the 
effect of bimagrumab on body composition. 
While improvement in glycemic control may occur as a result of improved body composition, 
subjects should maintain their background T2D therapy throughout to avoid deterioration in 
glycemic control. If, however, improvement in glycemic control is observed during the study, 
reduction in or discontinuation of anti-diabetic treatment is allowed under the guidance of a 
medical professional to prevent hypoglycemia as specified in Section 6.4. T2D treatment is 
restricted to specific anti-diabetes therapy for homogeneity of the study population and to 
enable interpretability of the data. Anti-diabetes therapy is restricted to classes with minimal 
effect on body weight, including metformin, a first line therapeutic agent, and/or DPP4 
inhibitors. Management of background therapy, including the potential need for managing 
worsening glycemic control, is presented in Section 6.4.
3.6
Purpose and timing of interim analyses/design adaptations
3.7
Risks and benefits
3.7.1
Potential benefits
Based on preliminary clinical data in a pre-diabetic population, bimagrumab is expected to 
result in improved body composition, with higher lean body mass and lower fat mass.  
Bimagrumab may also result in improved insulin sensitivity and glucose control during the 
trial. Although in a previous study in mostly overweight subjects, the effect of bimagrumab on 
body weight was neutral, in the presence of a negative energy balance and with a longer 
treatment period, bimagrumab may also induce body weight loss.  All subjects enrolled in the 
study may benefit from the lifestyle interventions including diet and physical activity, and 
regular monthly visits.
The risk to patients in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and stopping rules.
There may be unknown risks of bimagrumab, which may be serious.
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3.7.2
Bimagrumab related risks
Acne
Data from the prior proof of concept study in older adults with sarcopenia reported an 
incidence of acne in 10.5% (2/19) of patients administered two doses of 30 mg/kg 
bimagrumab. 
Program-wide, single and multiple dose studies in healthy volunteers and patients with 
sarcopenia, sIBM and COPD cachexia demonstrated the occurrence of diffuse, transient acne 
on the face and scalp and less frequently on the back and chest in 18.3% of the population. 
Earlier studies showed an increased incidence with the highest doses (Table 3-1). 
Conversely, acne was not observed in the multiple dose study (CBYM338X2102) after three 
i.v. doses of 3 or 10 mg/kg every 4 weeks.
Acne has been confirmed in these studies by dermatology consult and biopsy. Treatment has 
been successful with good skin hygiene using a 4-10% benzoyl peroxide wash and over the 
counter topical treatments. On occasion, a prescription, topical or oral antibiotic 
(i.e., minocycline 100 mg bid), was recommended. However, early standard of care 
intervention is recommended in participants when acne presents.
Further analysis of skin reactions and their association with preexisting conditions, 
bimagrumab PK parameters, time to appearance from dosing and time to resolution will be 
performed in current and future studies. A possible mechanistic link between bimagrumab and 
skin reactions remains unclear.
Table 3-1
Skin reactions considered possibly related to bimagrumab from 
unblinded data*
Muscle Symptoms
Involuntary muscle contractions, referred to as cramps, spasms or twitches, have been 
reported by participants in early studies receiving single or multiple doses of bimagrumab 
(Table 3-2). 
The dose-frequency of muscle symptoms is not linear. In the multiple dose study, spasms 
were reported by one (of six) subjects receiving three i.v. doses of 3 mg/kg, and six (of six) 
receiving 10 mg/kg and four (of six) in the combination i.v. and s.c. cohort (greatest drug 
exposure). Most muscle spasms throughout the clinical study program have been mild in 
intensity, transient, painless, of short duration, and did not require medical treatment. Several 
cases of muscle spasms were moderate in severity.
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In early studies, a smaller percentage of muscle symptoms were seen in older healthy 
volunteers 70-83 years of age than in young and middle aged adults. A case of spasm was 
reported by one subject (of 6) that received 3 mg/kg, while no cases were reported in the 
group receiving 30 mg/kg.
The etiology and clinical meaning of these observations are not known. Similar symptoms 
have been reported with at least one other anabolic molecule, a beta-2 adrenergic agonist 
(Tomlinson et al 1990) and are commonly reported by adults performing muscle building 
exercise. Data on twitches and the effects on people receiving bimagrumab are detailed in the 
Investigator’s Brochure.
Table 3-2
Muscle symptoms considered possibly related to bimagrumab from 
unblinded data*
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Reproductive organs
Data from CBYM338X2108 demonstrate no clinically or statistically significant effect of 
bimagrumab on circulating testosterone levels and no effect on the pituitary-gonadal or 
pituitary-adrenal axes in either gender. Suppression of FSH levels in postmenopausal women 
and premenopausal women of non-childbearing potential has been observed with no 
associated safety risk identified. All effects were transient and resolved after bimagrumab 
exposure ended. Semen analysis data from the multiple dose study suggest that three doses of 
10 mg/kg have no effect on sperm count or quality in males. 
Women of childbearing potential may participate in this study as long as they use highly 
effective contraception as detailed in Section 4.2 (Exclusion criteria).
Immunogenicity
It is possible that anti-drug antibodies could develop against bimagrumab, which could 
neutralize or clear the drug more rapidly and attenuate its efficacy. A treatment related 
anti-drug antibody response has been observed in subjects treated with bimagrumab although 
it should be noted that high exposure to bimagrumab may mask the presence of an immune 
response. Nevertheless, there was no evidence of an infusion or hypersensitivity reaction that 
could be related to immunogenicity or any sign of immune complex formation in the clinical 
trials performed so far. No positive signal in the immunogenicity assay was accompanied by a 
change in the bimagrumab PK profile.
Lipase and amylase elevations
Observations of dose-dependent, transient, sub-clinical elevations of lipase and/or amylase 
have been identified in several studies in the bimagrumab clinical program. The biological 
explanation for this temporal rise in pancreatic enzymes seen in some individuals is not yet 
fully understood.
As of 1 September 2018 there have been two confirmed cases of acute pancreatitis among 
approximately 1038 participants administered bimagrumab. There is no known association
among participants receiving bimagrumab between the temporary elevations in lipase and/or 
amylase and an increased risk for pancreatitis. However, to reduce the potential risk of 
elevated pancreatic enzymes to study participants, volunteers with elevated amylase and 
lipase will be excluded as per Section 4.2.
Participants will be monitored throughout the study as detailed in the Assessment schedule.
Safety monitoring guidance for participants who experience elevated lipase and/or amylase 
during the study is provided in Section 9.4.
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3.7.3
Blood sample volumes
A maximum of 500 mL of blood is planned to be collected from each subject during the study 
over a period of 392 days (56 weeks). Additional samples for monitoring of any safety 
findings are not included. Blood collection is not considered to be a risk for this population.
During the collection of blood samples, subjects may experience pain and/or bruising at the 
insertion site of the needle/catheter. Although rare, localized clot formation, infections and 
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.
Timings of blood sample collection are outlined in the Assessment Schedule, Section 8.1. 
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage and shipment information. 
See Section 8.9 regarding the potential use of residual samples. 
3.7.4
Trial-related risks
Infusion risks
Infusion-related reactions can occur with monoclonal antibodies. Hypersensitivity reactions 
can manifest as fever, chills, urticaria, dyspnea, headaches, myalgia and/or hypotension. 
A serious infusion reaction that results in anaphylaxis is a rare event in monoclonal antibody 
therapy. If a severe hypersensitivity reaction occurs, administration of bimagrumab should be 
discontinued and appropriate therapy initiated.
Diet-related
The daily caloric deficit of 500 Kcal with approximately 45-50% calories from carbohydrate, 
20-25% from protein and 30% from fat is a standard approach and is expected to induce
weight loss of approximately 450 gr (1 pound) per week over the treatment period. It may also
enhance the effect of bimagrumab on body composition and body weight. The anabolic effect
of bimagrumab requires adequate protein intake. Given the daily caloric deficit, the protein
intake is increased to 1.2 g/kg/day to ensure an adequate protein supply for increasing lean
mass.
A daily multivitamin/multimineral supplement is also recommended to ensure adequate intake 
of micronutrients involved in protein synthesis and glucose regulation.  Over-the-counter 
supplements will be recommended at doses commonly consumed and recommended by
recognized authoritative scientific bodies (for example, the US Institutes of Medicine). 
No adverse effects are anticipated.


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Exercise-related
The ADA walking program is tailored to the type of population in this study and is a gentle, 
easy to implement approach for physical activity. 
No adverse effects are anticipated.
Imaging
Dual-Energy X-ray Absorptiometry (DXA)
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 effective dose of a DXA whole body scan on an adult is 2.1 microSv. Therefore, the total 
amount of radiation exposure per subject from five DXA scans will be about 10.5 microSv. 
This amount of radiation is equivalent to approximately 14 days of background exposure 
(approx. 0.03 microSv per hour at sea level). For effective radiation doses under 3 mSv 
(300 mrem), the risk is considered to be minimal (Albanese et al 2003). Therefore, the 
radiation exposure in this study involves minimal risk and is necessary to obtain the research 
information desired (Stabin 2008). DXA measures are described as having no observable or 
biological effect and are similar to natural background levels of radiation in most countries; 
the study scans pose no safety risk. 
4
Population
Approximately sixty-eight (68) overweight/obese men and women 18-75 years old (inclusive) 
with type 2 diabetes will be enrolled in the study.
The investigator must ensure that all subjects being considered for the study meet the 
eligibility criteria. No additional criteria should be applied by the investigator, in order that 
the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening 
and baseline. A relevant record (e.g., checklist) of the eligibility criteria must be stored with 
the source documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
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4.1
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female, age 18 to 75 years (inclusive), in stable health condition as determined
by past medical history, physical examination, vital signs, electrocardiogram, and
laboratory tests at screening.
3. Type 2 diabetes, with an HbA1c between 6.5% and 10% (inclusive) at screening.
4. On one of the following anti-diabetes regimens with stable treatment for approximately
3 months prior to randomization: 1) metformin monotherapy; 2) DPP4 inhibitor agent
monotherapy; 3) combination therapy of metformin and DPP4 inhibitor agent; 4) no
anti-diabetes therapy.
5. Body mass index (BMI) of 28.0 to 40.0 kg/m2 (inclusive) at screening.
6. Body weight between 65 and 140 kg (inclusive) at screening, and with a stable body
weight (±5 kg) by history (patient report) and stable physical activity within 3 months
prior to screening by history (patient report).
7. Able to communicate well with the investigator; to understand and comply with the
requirements of the study.
4.2
Exclusion criteria
Conditions related to safety: 
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception until the termination of gestation, and confirmed by a positive hCG
laboratory test at screening.
2. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant unless they are using highly effective methods of contraception during
dosing and for 6 months after stopping of investigational drug. Highly effective
contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred
and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods
of contraception.

Female sterilization (surgical bilateral oophorectomy with or without hysterectomy),
total hysterectomy or tubal ligation at least six weeks before taking investigational
drug.  In case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects in the
study, the vasectomized male partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception.
In the case of oral contraception, women should be stable on the same pill for a minimum 
of 3 months before taking the investigational drug.


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Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age-appropriate, history of vasomotor symptoms) or have been sterilized as specified 
above. 
3. Any chronic active infection (e.g., HIV, hepatitis B or C, tuberculosis, etc) or has received
anti-HCV treatments within the previous 6 months. Patients receiving chemoprophylaxis
for latent tuberculosis infection are eligible for the study.
4. History of or known hypersensitivity to monoclonal antibodies or drugs similar to the
study drug.
5. History of multiple and recurring allergies or allergy to the investigational
compound/compound class being used in this study.
6. Chest pain, severe shortness of breath, or occurrence of other safety concerns during the
screening or baseline assessments.
Diabetes related conditions: 
7. Diabetes other than type 2, such as type 1 diabetes, surgically induced-diabetes, "brittle"
type 2 diabetes as per investigator judgment, history of severe hypoglycemic episodes in
the year preceding screening, known hypoglycemic unawareness.
Liver or pancreas related conditions:
8. Abnormal liver function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase,
or serum bilirubin (except Gilbert’s Disease), or abnormal lipase and/or amylase.
The investigator should be guided by the following criteria:
a.
Any single transaminase may not exceed 3x the upper limit of normal (ULN).
b. A single parameter elevated up to and including 3x ULN should be re-checked
as soon as possible, and always prior to enrollment/randomization, to rule out
any laboratory error.
c.
If the total bilirubin concentration is increased above the ULN, total bilirubin
should be differentiated into the direct and indirect reacting bilirubin. In any
case, serum bilirubin should not exceed the value of 1.6 mg/dL (27μmol/L).
d. Screening or baseline levels of lipase and/or amylase ≥ 2x ULN are
exclusionary. Initial tests in either lipase or amylase of ≥ 2x ULN should be re-
checked as soon as possible to confirm lab values, and must be available prior
to randomization. Patients with confirmed lipase and/or amylase ≥ 2x ULN at
screening or baseline are excluded.
9. Known history or presence of severe active acute or chronic liver disease (e.g., cirrhosis)
or conditions with hepatotoxic potential (e.g. known gallbladder or bile duct disease, acute
or chronic pancreatitis, or exocrine pancreatic insufficiency).


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Other conditions:
12. Any medical condition or laboratory finding during screening (e.g. an unexplained or
clinically significant laboratory result), which, in the opinion of the investigator, may
interfere with participation in the study, might confound the results of the study, or pose
an additional safety risk in administering bimagrumab.
13. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin), treated or untreated, within the past 5 years, regardless of whether there is
evidence of local recurrence or metastases.
14. Active alcohol or drug abuse, or participation in an alcohol or drug treatment program
within 1 year prior to screening.  Subjects having successfully completed an alcohol or
drug treatment program > 1 year prior to screening with sustained abstinence may be
eligible.
15. Confirmed diagnosis of current, significant psychiatric disease (e.g. dementia,
Alzheimer’s disease, schizophrenia, depression or bipolar disorder).  Individuals with
adequately treated depression and stable treatment at least 3 months prior to screening are
eligible for enrollment.
16. Chronic kidney disease [estimated glomerular filtration rate (GFR) < 30 mL/min].
17. Patient plans to move out of the study area within 12 months, or be out of the study area
for > 4 weeks, continuously.
18. History of any type of bariatric procedure.
Temporary Exclusion criteria:
Subjects excluded for one of the temporary medical conditions listed below may be 
rescreened after a period that is considered clinically relevant by the investigator.  The subject
will need to re-sign informed consent and the full screening visit must be repeated under a 
new subject number.
20. Use of prohibited medications (found in Section 5.2).
21. Significant acute illness such as urinary tract infection or upper respiratory tract infection
which has not resolved within two (2) weeks prior to screening.
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22. Men with low fasting morning testosterone (<250 ng/dl) at screening; men receiving
testosterone replacement therapy for low testosterone are eligible if on a stable dose of
testosterone for a minimum of 3 months and if their testosterone level is in the normal
range on 2 consecutive tests at least one month apart and not more than 6 months apart,
the second one being performed at screening.
23. Systolic blood pressure > 180 or < 90 mmHg or diastolic blood pressure > 100 or
< 50 mmHg at screening or baseline.
24. Currently enrolled in, or discontinued within the last 30 days (or 5 half-lives of enrollment
or until PD effect is expected to return to baseline, whichever is longer, or longer if
required by local regulations) from a clinical trial involving an investigational drug or off-
label use of a drug, or are concurrently enrolled in any other type of medical research
judged to be scientifically or medically incompatible with this study.
25. Uncontrolled thyroid disease.  Hypothyroid subjects with euthyroidism on stable thyroid
replacement therapy for at least 3 months prior to screening are allowed.
26. Significant change in cigarette smoking within 3 months of screening, as judged by the
investigator.
27. Use of any anti-obesity medications, nutritional supplements or over the counter products
for weight loss within 3 months of screening. Use of medications known or suspected to
induce weight gain, such as some anticonvulsant and psychotropic medications (excluding
anti-depressant medication, refer to point 15) within 3 months of screening.
28. Use of skeletal muscle anabolic agents in any form such as medications, hormones
(except stable testosterone replacement therapy for at least 3 months for hypogonadal
men), over the counter products and nutritional supplements (other than protein) that are
labeled as muscle anabolic agents for 3 months prior to screening.
29. Any dietary intervention, new exercise regimen or lifestyle modifications targeted for
weight loss or diabetes control started within 3 months of screening.
Refer to Section 8.3 (Subject Screening) for information regarding re-screening. 
Refer to Section 8.6 for a complete list of safety assessments.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the restrictions outlined in this section.
5.1
Contraception requirements
Women of childbearing potential are eligible for this study if they use highly effective 
methods of contraception during dosing and for 6 months after stopping study medication. 
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods)
and withdrawal are not acceptable methods of contraception.


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
Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), total
hysterectomy or tubal ligation at least six weeks before taking study treatment.  In case of
oophorectomy alone, only when the reproductive status of the woman has been confirmed
by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects in the study,
the vasectomized male partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of an
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception. In case of use of oral contraception,
women should be stable on the same contraceptive medication for a minimum of 3 months
before taking study treatment.
Men are not required to use contraception because of the large size of the antibody which does 
not penetrate the blood-testes barrier.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered or continue in the study.
5.2
Prohibited treatment

Use of skeletal muscle anabolic agents in any form such as medications, hormones, over
the counter products and nutritional supplements (other than protein) that are labeled as
muscle anabolic agents.

Anti-obesity medications, nutritional supplements, dietary interventions other than
described in the protocol, or over the counter products for weight loss.

Chronic systemic steroid treatment or systemic steroids for > 7 consecutive days for
worsening of an underlying condition are not allowed during the study and within 4 weeks
of screening.

Any anti diabetic medication other than metformin or DPP4 inhibitor agent. Injectable
drugs such as exenatide or pramlintide are prohibited; insulin is allowed for up to one
week at a time to correct for acute hyperglycemia.

Any product or medication known or suspected to cause weight gain, unless it is a stable
anti-depressant therapy for at least 3 months before screening.
5.3
Dietary restrictions and smoking
Patients will be counseled to follow a modest calorie restricted diet with a daily deficit of 
approximately 500 kcal and approximately 45-50% calories from carbohydrate, 20-25% from 
protein and 30% from fat intake throughout the study, in keeping with guidelines for daily 
recommended 
protein 
intake 
(at 
least 
1.2 
g/kg/body 
weight) 
for 
anabolism 
(WHO guidelines 2015). The amount of calories will be determined by a dietitian or physician 
for every patient according to their height, weight and calculated basal metabolism. A copy of 


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the diet with content and nutritional information will be provided to the Sponsor prior to study 
start upon request.
Once enrolled and throughout the study period, site personnel will query study patients to 
determine if there has been a change in dietary habits and to encourage dietary intake that will 
promote weight loss.  Dietary monitoring will occur via:

Monthly dietary counseling visits at which time a 24 hour recall will be obtained

Collection of 3-day food records at 3 time points during the study

One telephone or in-person contact per month, approximately midway between counseling
visits, to obtain a 24-hour dietary recall and reinforce lifestyle intervention.
Subjects will be advised to consume a daily multivitamin/multimineral supplement.  
Smoking is discouraged but not prohibited for participation in this trial. Patients should refrain 
from smoking for one hour prior to study visits and during the study visits.
On Day 1, no breakfast will be provided. Meals should be similar in caloric content and 
macronutrient distribution for all patients on the day of dosing.
5.4
Other restrictions
On any visit day where fasting is required, patients should withhold their anti-diabetic 
medication until after study blood draws are completed, ideally before 10 AM.
Additionally, patients should restrict alcohol consumption for 24 hours prior to visits at which 
the lipid profile will be assessed. 
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual and Pharmacy Manual.
Refer to Section 5.3 ‘Dietary restrictions and smoking’ for details of dosing and food intake.
6.1.1
Investigational treatment and control drugs
The investigational drug, bimagrumab, 150 mg LIVI (liquid in vial), will be prepared by 
Novartis and supplied to the Investigator site as open labeled bulk medication. Study drug 
preparation will be detailed in a separate pharmacy manual. Placebo will be a D5W infusion 
supplied by the site. 
Table 6-1
Overview of study medication
Study drug name
Formulation 
Appearance (e.g., 
approximate size, color, etc.)
Packaging
Provided 
by 
BYM338 
(bimagrumab)
liquid in vial
water infusion
open labeled bulk 
medication
Novartis
Placebo
Liquid
water infusion
Site


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Study drugs must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secure location to which only the Investigator and 
designated staff have access. Upon receipt, the study drugs should be stored according to the 
instructions specified on the drug labels. Storage conditions must be adequately monitored 
and appropriate temperature logs maintained as source data. Appropriate documentation of the 
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 the patient.
Note: To maintain the blind, the investigational treatments will be prepared by an unblinded 
pharmacist/designee, the bags will be covered by an opaque sleeve, and the investigational 
treatment will only be administered by study personnel blinded to patient treatment 
allocation.
All drug supplies are to be used only for this protocol and not for any other purpose. 
Unless specifically instructed by Novartis, the Investigator must not destroy any drug labels, 
or any partly used or unused drug supply. Only after receiving a written authorization by 
Novartis, the Investigator/designee will send all the unused and partly used drug supplies, as 
well as the empty containers, to the address provided at the time of authorization for 
destruction.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.1.2
Additional study treatment
Not applicable.
6.2
Treatment arms
Patients will be assigned to one of the following 2 treatment arms in a ratio of 1:1.
Study treatments are defined as:

Bimagrumab 10 mg/kg up to maximum 1200 mg, every 4 weeks (12 doses)
Placebo, every 4 weeks (12 doses)
6.3
Permitted dose adjustments and interruptions of study treatment
Dose adjustments are not permitted.
6.4
Background therapy dose adjustments
Adjustments of T2D background therapy are allowed, according to the standard of care, but 
are restricted to the following: 

Either increased or decreased dosage, or discontinuation, of current medication is allowed
under the guidance of a medical professional;

The add-on of a second medication is allowed but restricted to metformin or
DPP4-inhibitor;

Insulin, as an acute treatment for severe or uncontrolled hyperglycemia, such as during an
acute illness, is allowed but restricted to one week only;


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The Investigator must emphasize to the subjects the importance to communicate ANY change 
in the background medication. In particular, the Investigator must inform the subjects that 
ANY change in the anti-diabetes medication that IS NOT LISTED above, will cause the 
subject to discontinue study treatment. Any modification to the background therapy during 
study participation must be reported by the Investigator.
6.5
Treatment assignment and randomization
Treatment is assigned by stratified randomization for two strata based on the patient’s
baseline BMI. The strata have the following randomization numbers: 

BMI between 28.0 kg/m2 and 33.0 kg/m2 (inclusive): 5101 – 5150

BMI between 33.1 kg/m2 and up to 40.0 kg/m2 (inclusive): 5201 – 5250
The randomization number is used to identify which strata the patient belonged to at 
randomization and which treatment the patients have been randomized to receive.  
The Patient number assigned to a patient at screening remains the unique identifier for the 
patient throughout the study.  For information on patient numbering, please see ‘Subject 
numbering’ section in the SOM.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A randomization list will be produced by, or under the responsibility of, Novartis Drug 
Supply Management using a validated system that automates the random assignment of 
treatment arms to randomization numbers in the specified ratio.
BMI was selected as a stratification parameter as it is an important predictor of response on 
parameters of body composition/body weight and HbA1c (internal data). The expected 
median value for BMI in this patient population is 33 kg/m2 (internal data); therefore, 2 strata 
above and below/inclusive of the median will ensure a balanced representation of patients 
between placebo and active drug in each strata, i.e. strata of approximately similar size 
between the 2 arms. Equal size strata will not be enforced, but a minimal size of 10 will be 
required for the smaller stratum in order to ensure adequate precision of treatment effect 
estimation in both strata.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.


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6.6
Treatment blinding
This is a subject- and investigator-blinded study. Subjects and investigators will remain 
blinded to study treatment throughout the study, except where indicated below.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.

Unblinded pharmacist
Unblinding a single patient at site for safety reasons (necessary for patient management) will 
occur via an emergency system in place at the site (see Section 6.8 Emergency breaking of 
assigned treatment code).
IMPORTANT: Drug product will be supplied in bulk. Due to the difference in preparation 
methods between the active and placebo treatments, an unblinded pharmacist or other 
qualified trained personnel, who is independent of the study team, will be required. 
This unblinded pharmacist will receive treatment allocation cards from Drug Supply 
Management with the appropriate treatment allocation numbers. Appropriate measures must 
be taken by the unblinded pharmacist to ensure that the treatment assignments are concealed 
from the rest of the site staff. Any potential visible difference in treatments will be concealed 
by the use of an opaque sleeve.
Sponsor staff
The following unblinded sponsor roles are required for this study:

Unblinded field monitor(s)

Unblinded clinical staff managing drug re-supply to site

Unblinded sample analyst(s) (PK blood)
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be 
unblinded through review of source documentation compiled by the unblinded pharmacist, 
which details treatment allocation to individual subjects. The unblinded monitors will also be 
able to review the treatment allocation cards/randomization list provided to the unblinded 
pharmacist. 
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly, but may be 
unblinded through communication of drug re-supply needs via the unblinded site pharmacists.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-2. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.


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Study programmers and other personnel involved in study data analysis (e.g. biomarker 
expert) are allowed to access treatment assignment information for the purpose of conducting 
interim analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at 
the time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-2
Blinding levels
Role
Time or Event
Randomization list 
generated
Treatment 
allocation & 
dosing
Safety event (single 
subject unblinded)
Interim 
Analysis 
Subjects
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff (see text for 
details) 
B
UI
UI
UI
Drug Supply and Randomization 
Office
UI
UI
UI
UI
Unblinded sponsor staff (see text 
for details)
B
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
UI
Independent committees used for 
assessing interim results
B
UI
UI
UI
All other sponsor staff not 
identified above
B
B
UI
UI
B Remains blinded
NA Not applicable
UI Allowed to be unblinded on individual patient level
6.7
Treating the subject
Bimagrumab or placebo will be administered to the subject via the following route of 
administration: i.v. by infusion pump.
Administrations will be performed at the study site. See the Site Operations Manual for 
further details.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.


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6.8
Emergency breaking of assigned treatment code
Emergency unblinding must only be undertaken when it is essential to treat the subject safely 
and efficaciously. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. A complete set of emergency code break cards will be provided to the investigator 
site(s) and a complete set will be available at Novartis. All code break cards must be retained 
until the end of the study and returned to Novartis. They must be stored in a secure place but 
be accessible to the investigator 24 hours per day in case of emergency. The investigator will 
receive a blinded code break card for each subject, with the details of study treatment covered 
by a removable, scratch-off cover. In an emergency, the scratch-off cover can be removed to 
determine the treatment. The scratch-off covers are not to be removed for any reason other 
than an emergency. When the investigator removes the scratch-off cover he/she must note the 
date, time, and reason for removing it and retain this information with the case report form 
documentation. The unblinded treatment code must not be recorded on the CRF.
The investigator must also immediately inform the study monitor that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the code break cards at any time in case of emergency.   The investigator will 
need to provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
un-blinding to assess whether or not study treatment should be discontinued for a given 
subject and, if applicable, whether the subject can continue into the next trial phase (e.g., an 
unblinded extension).
6.9
Treatment exposure and compliance
Subjects 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.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with bimagrumab, as detailed in Section 8.7.


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6.10
Recommended treatment of adverse events
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.
Acne may be treated with a face wash containing 4-10% benzoyl peroxide and over the 
counter topical treatments. If needed, a prescription topical treatment (i.e., antibiotics) or oral 
antibiotic (i.e., minocycline 100 mg bid) may be recommended at the Investigator’s discretion. 
Early intervention is recommended when acne presents.
Diarrhea may be treated with over the counter remedies. In cases of prolonged occurrence, 
other treatments may be used at the Investigator’s discretion.
Although not expected, any acute allergic reactions should be treated as needed using 
conventional counter measure therapies as indicated (including but not limited to epinephrine, 
antihistamine, corticosteroid, intravenous supplies, crystalloid, an oral airway, bag and mask, 
and supplemental oxygen). In the case of a serious adverse event in which decreasing the 
systemic concentration of bimagrumab may be of clinical benefit, the investigator should 
consider plasmapheresis. Study sites should not feel constrained in any way from providing 
necessary medical intervention.
Adverse events related to underlying disease of T2D:  hypoglycemia or hyperglycemia events 
that are clinically significant based on the judgment of the principal investigator should be 
treated and managed according to local diabetes treatment guidelines and standard of care.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
Elevated lipase and amylase levels that meet AE criteria should be monitored and managed
according to Section 9.4.
6.11
Rescue medication
Not applicable.
6.12
Concomitant treatment
The investigator should instruct the subject to notify the study site about any NEW and 
changes to current medications he/she takes AFTER the start of the study. 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, 
must be recorded on the Concomitant medications/ Significant non-drug therapies section of 
the eCRF. 
Should a subject have an incidental and limited need for a medication to be taken within the 
restricted pre-dose timeframe (e.g., ibuprofen for a headache, antibiotic prophylaxis prior to 
dental surgery, etc.), the sponsor should be advised, as administration of any concomitant 
medication may require the subject to be discontinued. 


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Administration of acetaminophen on an occasional basis is acceptable, but must be 
documented. Medication entries should be specific to trade name, the single dose and unit, the 
frequency and route of administration, the start and discontinuation date and the reason for 
therapy.
Medications allowed in the study as chronic therapy:

Low dose aspirin is allowed.

Oral anti-diabetic therapy (limited to metformin and/or DPP4 inhibitor agent), with stable
treatment for approximately 3 months prior to randomization, for diabetes management
during the trial. Insulin is allowed for one week only in case of acute deterioration of
glycemic control.

Stable regimen of testosterone replacement therapy for at least 3 months prior to
randomization.

Thyroid replacement therapy that is stable for at least 3 months prior to randomization.

Antihypertensive medication must be on a stable regimen for at least 3 months prior to
randomization.

Medications for dyslipidemia must be stable for at least 3 months prior to randomization.

Vitamin D and multivitamin/mineral supplementation (see below)

Antidepressant medications must be stable for at least 3 months prior to randomization.

Chronic therapy for hyperuricemia must be stable for at least 3 months prior to
randomization.

Other chronic therapy medications not listed above require Sponsor approval
6.13
Vitamin and mineral supplementation

The subject must consume an oral multivitamin/multimineral supplement.

In subjects with 25-OH vitamin D level between 12.0 and 50.0 ng/mL inclusive at
screening:

Daily administration of vitamin D as part of the multivitamin/multimineral supplement
(800 IU to 4000 IU, D3 preferable but D2 also acceptable per local availability); or,

Equivalent weekly or monthly formulation if deemed to be of advantage for the
individual subject’s compliance.

In subjects with 25-OH vitamin D level ≥50.0 ng/mL at screening: supplementation
recommendations may be made at the investigator’s discretion.

In subjects with 25-OH vitamin D level <12.0 ng/mL at screening and with no symptoms
of osteomalacia or low serum calcium: administration of loading dose of oral vitamin D
(recommended minimum 50 000 IU of vitamin D3, but according to local guidance) will
be allowed. Different formulations of vitamin D3 are allowed based on the approved
therapy in the subject’s country. Vitamin D2 is permitted where D3 is not available.


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7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. Study completion is defined as when the last 
subject completes their Study Completion visit, and any repeat assessments associated with 
this visit have been documented and followed-up appropriately by the Investigator, or in the 
event of an early study termination decision, the date of that decision.
If subjects discontinue early and are not able to return for their End of Treatment and End of 
Study visits, they should have a safety follow-up call conducted 30 days after the last dosing
visit, per Section 7.2. The information collected is kept as source documentation.  All SAEs 
reported during this time period must be reported as described in Section 9.2 and the Site 
Operations Manual.  Documentation of attempts to contact the subject should be recorded in 
the source documentation.
7.2
Discontinuation of study treatment
Subjects may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would be detrimental to the subject's well-being.
Study treatment must be discontinued for an individual subject under the following 
circumstances:

Withdrawal of consent

An infusion reaction that is considered severe

One or more symptomatic hypoglycemic events necessitating third party rescue and
suspected to be related to study drug; if diabetes medication can be appropriately reduced,
the study drug may be resumed after stabilization of FPG at the Investigator's discretion

A serious adverse event (SAE) thought to be related to study drug

Pregnancy: a positive urine pregnancy test after start of study treatment requires
immediate interruption of study treatment until serum hCG is performed and found to be
negative

Any protocol deviation that results in a significant risk to the subject’s safety

Emergence of one or more adverse events that in the judgment of the investigator, taking
into account the subject’s overall status, prevent the subject from safely continuing in the
study
Investigational treatment may be discontinued under the following circumstances:

Breaking of the blind (inadvertently or for emergency reasons)

Use of prohibited treatment as described in the protocol
Subjects who discontinue study treatment should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent. They should return approximately 4 weeks after 
their last dose for the EoT visit (Visit 113). The EoS visit (Visit 199) should be scheduled 


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4 weeks after EoT. If they fail to return for these assessments for unknown reasons, every 
effort should be made to contact them as specified in Section 7.4.
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her consent 
and record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment schedule (Table 8-1).
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
For US: All biological samples not yet analyzed at the time of withdrawal may still be used 
for further testing/analysis in accordance with the terms of this protocol and of the informed 
consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, 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 subject cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred.
7.5
Study Stopping rules
If any of the following situations occur, the study will be placed on hold and, upon review of 
study data by the clinical trial team and the safety team and discussion with the investigators,
may be terminated or the dose level re-evaluated.

Data from this study is judged by the Investigators and Sponsor to indicate a clinically
significant risk of using bimagrumab in the diabetic obesity patient population.


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
Two or more subjects develop at least one event of symptomatic hypoglycemia
necessitating rescue that is not self-administered, and judged to be related to study drug.

Two or more subjects develop a significant hypersensitivity reaction (grade severe)
believed to be related to bimagrumab treatment.

The Sponsor unilaterally requests a stoppage.
7.6
Early study termination by the sponsor
The study may be terminated by Novartis at any time for any reason. This may include 
reasons related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
patients must be seen as soon as possible and treated as a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient's interests. The investigator 
will be responsible for informing IRBs/IECs of the early termination of the trial.
8
Procedures and assessments
8.1
Assessment schedule
After the Screening period, visits are scheduled every 4 weeks, except during the first month 
of the treatment period since a visit needs to be performed at Week 2 to comply with the 
safety monitoring for circulating amylase and lipase.
The Assessment Schedule below lists all of the assessments and indicates with an “x” the 
visits when they are performed. All data obtained from these assessments must be supported 
in the patient’s source documentation. Assessments marked with an “S” should be assessed 
and documented in the patient’s source documentation but no data needs to be entered into the 
eCRF. 
Patients should be seen for all visits on the designated day as specified in the Assessment 
Schedule. Until randomization, the visits should be calculated relative to the calendar date of 
the previous visit. After randomization, visits should be calculated relative to the calendar 
date of the randomization visit.


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Table 8-1
Assessment schedule
Epoch
Screening
Treatment and Primary Follow-Up
Visit Name
Screening
Baseline1
Treatment
Visit Numbers
1
2
101
115
102
103
104
105
106
107
Days
-21 to -8
-7 to -1
1
14
28
56
84
112
140
168
Time (post-dose)
-
-
Pre-dose
0min
45min6
-
-
-
-
-
-
Pre-dose
0min
45min6
Informed consent
X
Genetic Informed Consent
X
Inclusion / Exclusion criteria
S
S2
Subjects domiciled3
S
Study drug administration
X
X
X
X
X
X
X
Demography
X
Medical history/current medical conditions
X
Concomitant therapies
X
X
X
X
X
X
X
X
X
X
Body Height
X
Body Weight
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
Hip measurement
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Physical Examination
S
S
S
ECG evaluation
X
X
Alcohol Test and Drug Screen 
S
Hepatitis and HIV Screen
S
Pregnancy test
X
X
X
X
X
X
X
X
X
Fasting insulin and glucose5
X
X
HbA1c
X
X
X
Mixed Meal Tolerance Test5
See Table 8-2 below
Blood chemistry5
X
X
X
X
X
X
X
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Epoch
Screening
Treatment and Primary Follow-Up
Visit Name
Screening
Baseline1
Treatment
Visit Numbers
1
2
101
115
102
103
104
105
106
107
Days
-21 to -8
-7 to -1
1
14
28
56
84
112
140
168
Time (post-dose)
-
-
Pre-dose
0min
45min6
-
-
-
-
-
-
Pre-dose
0min
45min6
Hematology
X
X
X
Urinalysis
X
X
25-Hydroxy Vitamin D
X
X
Testosterone
X
TSH
X
FSH LH
X
X
Immunogenicity
X
X
PK blood collection
X
X
X
X
X
DXA scan
X
X
X
Adverse events
X
Dietary Counseling8
X
X
X
X
X
X
X
X
X
3-day Food Record
S
S
24-hour recall dietary assessment10
X
X
X
X
X
X
X
X
Study completion information
Comments
X
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Epoch
Treatment & Primary Follow-up
Visit Name
Treatment
Follow-Up
End Of Study
Visit Numbers
108
109
110
111
112
1139
114
199
Days
196
224
252
280
308
336
364
392
Time (post-dose)
-
-
-
-
Pre-dose
0min
45min6
-
-
-
Informed consent
Genetic Informed Consent
Inclusion / Exclusion criteria
Subjects domiciled3
Study drug administration
X
X
X
X
X
Demography
Medical history/current medical conditions
Concomitant therapies
X
X
X
X
X
X
X
X
Body Height
Body Weight
X
X
X
X
X
X
X
X
Waist circumference
X
X
Hip measurement
X
X
Vital Signs
X
X
X
X
X
X
X
X
Physical Examination
S
S
ECG evaluation
X
Alcohol Test and Drug Screen 
Hepatitis and HIV Screen
Pregnancy test
X
X
X
X
X
X
X
Fasting insulin and glucose5
X
X
HbA1c
X
X
Mixed Meal Tolerance Test5
See Table 8-2 below
Blood chemistry5
X
X
Hematology
X
X
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Epoch
Treatment & Primary Follow-up
Visit Name
Treatment
Follow-Up
End Of Study
Visit Numbers
108
109
110
111
112
1139
114
199
Days
196
224
252
280
308
336
364
392
Time (post-dose)
-
-
-
-
Pre-dose
0min
45min6
-
-
-
Urinalysis
X
X
25-Hydroxy Vitamin D
X
Testosterone
TSH 
FSH LH
X
X
Inflammatory markers
X
X
Immunogenicity
X
X
PK blood collection
X
X
X
X
X
X
DXA scan
X
X
Adverse events
X
Dietary Counseling8
X
X
X
X
X
X
3-day Food Record
S
24-hour recall dietary assessment10
X
X
X
X
X
X
Study completion information
X
Comments
X
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1 Assessments expected at Baseline can be done on separate days between Day -7 and Day -1
2 Criteria that have to be re-checked at baseline (refer to Section 4.2)
3 Optional to be domiciled prior to day 1 to facilitate
 DXA
4 
5 Assessments need to be performed after a fast of approximately 12 hours
6 Time point should be calculated based on the start of the infusion
7 
8 Assessment to be conducted in-person
9 In the event of subject early discontinuation, visit assessments to be performed for the End of Treatment (EoT) visit
10See Table 8-3 for schedule of 24-hour recall dietary assessments performed in between monthly site visits
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Table 8-2
Mixed Meal Tolerance Test
Epoch
Visit Name
Visit Numbers
Days
Time
Glucose and Insulin
Treatment And Primary Follow-Up
Treatment
101
1
0min*
X
30min
X
60min
X
90min
X
120min
X
150min
X
180min
X
107
168
0min*
X
30min
X
60min
X
90min
X
120min
X
150min
X
180min
X
113
336
0min*
X
30min
X
60min
X
90min
X
120min
X
150min
X
180min
X
* Sample collection must be performed while subject is fasted prior to start of meal ingestion
Table 8-3
24-hour dietary recall
Epoch
Treatment And Primary Follow-Up
Visit Name
Treatment
Days
14
42 70 98 126 154 182 210 238 266 294 322
24-hour recall dietary assessment via
telephone call or in-person visit
x
x
x
x
x
x
x
x
x
x
x
x


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8.2
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.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents. 
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the patient agrees to future research.  
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Novartis will review the investigator’s proposed informed consent form to ensure it complies 
with the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for 
this study. Any further changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the patient.
Ensure subjects are informed of the contraception requirements outlined in Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Subject screening
In general it is permissible to re-screen a subject if s/he fails the initial screening; however, 
each case must be discussed and agreed with the Sponsor on a case-by-case basis.
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Information on what data should be collected for screening failures is outlined in the Site 
Operations Manual.
Inclusion/exclusion criteria assessment will not be entered in the CRF, however, data should 
be available as Source data.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects and 
include: date of birth, age, sex, race, predominant ethnicity.  Relevant medical history/current 
medical conditions data will also be collected until signature of informed consent.  Details are 
outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
Alcohol Test and Drug Screen 
Subjects will be tested for substances of abuse (e.g., alcohol, amphetamines, barbiturates, 
benzodiazepines, cocaine, cannabinoids, and opiates). 
Results will be available as source data and will not be recorded within the eCRF.
8.4.2
Hepatitis and HIV Screen
All subjects must be tested for Hepatitis B, Hepatitis C, and HIV at the screening visit. 
Hepatitis B will be evaluated using the Hepatitis B surface antigen (HBsAg). Screening for 
Hepatitis C will be based on HCV antibodies and if positive, HCV RNA levels should be 
determined. Evaluation for HIV positive status should be performed, and, if positive, 
confirmation by a second technique available at the laboratory site, e.g., Western blot or as 
specified by local regulation.
Results will be available as source data and will not be recorded within the clinical database.
8.4.3
Testosterone and TSH
The following hormones will be measured at screening only: total testosterone (for males 
only) and thyroid stimulating hormone (TSH). If TSH is abnormal, free thyroxine (free T4 -
not total T4) should be reported. For testosterone refer to Exclusion criteria for more details.
8.5
Efficacy / Pharmacodynamics
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the Site Operations Manual (SOM). Assessments will be 
performed/samples collected at the time point(s) defined in the Assessment schedule.
 DXA images will be centrally read by a CRO.
Pharmacodynamic (PD) samples will be obtained and evaluated in all patients.
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8.5.1
Diabetes parameters
8.5.1.1
Fasting insulin and glucose
Samples for fasting insulin and glucose will be collected after a fast of approximately 
12 hours at time points specified in the Assessment schedule. 
The Homeostatic model assessment 2 – insulin resistance index (HOMA2-IR) is a derived 
insulin resistance index that must be calculated by the sites and entered in the CRF. 
Please refer to the SOM for the details on the calculation.
The quantitative insulin-sensitivity check index (QUICKI) is another insulin resistance index 
that will be calculated at the end of the study and will not be entered in the CRF
(Yokoyama et al 2004; Hrebícek et al 2002).
8.5.1.2
HbA1c
HbA1c will be measured at time points defined in the Assessment schedule. 
8.5.1.3
Meal Tolerance test and Matsuda Index
The meal tolerance test will be performed in the morning, after a fast of approximately 12 hours.  
The meal will consist of a mixed liquid-solid food and frequent blood sampling will be conducted as 
indicated in Table 8-2 and in the SOM.  The meal tolerance test will be conducted at time 
points defined in the Assessment schedule and results will be used at the end of the study to 
calculate Matsuda Index and other insulin sensitivity parameters (Matsuda and DeFronzo 1999).
8.5.2
Imaging
8.5.2.1
DXA Scan
Dual energy X-ray absorptiometry (DXA) will be used to assess changes in body composition, 
including total fat and lean body mass (FBM and LBM) and appendicular skeletal fat and 
muscle mass (aFBM and aLBM). DXA instruments contains a source that generates x-rays
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%.
Quality assurance is an important issue in the use of DXA scans to determine body 
composition. DXA instrument manufacturer and model should remain consistent and their 
calibration should be monitored throughout the study. Use of a standardized scan acquisition 
protocol and appropriate and unchanging scan acquisition and analysis software is essential to 
achieve consistent results. Likewise, because of variability in interpretation of the scans, it is 
important to utilize centralized scan analysis by experienced staff.
Data collection and processing is explained in the imaging charter written by the imaging 
CRO supporting the study. DXA data need to remain blinded to investigator and patient until 
database lock.


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8.5.3
Anthropometric measurements

Height

Body weight

Waist circumference

Hip circumference

Waist to hip ratio will be calculated at the end of the study

Body mass index (BMI) will be calculated by the site (Body weight (kg)/ [Height (m)]2)
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8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed.
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8.6.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, and vascular and neurological systems. If indicated based on medical history 
and/or symptoms, additional 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 at baseline 
and all follow-up visits due to the previously noted increased incidence of acne in people 
treated with bimagrumab. Information for all physical examinations must be included in the 
source documentation at the study site and will not be recorded in the CRF. Significant 
findings that are present prior to informed consent are included in the Relevant Medical 
History CRF. Significant findings observed after informed consent signature which meet the 
definition of an Adverse Event must be appropriately recorded on the Adverse Event CRF.
8.6.2
Vital signs

Body temperature

Blood pressure (BP)

Pulse rate
All readings should be recorded on the CRF.
8.6.3
Pregnancy test
Serum pregnancy test is required at screening for all female subjects regardless of reported 
reproductive/menopausal status. 
Urine pregnancy tests will be used at other visits as per the Assessment Schedule and will be 
performed in women of child-bearing potential only. The result of this test must be received 
before the patient may be dosed at the current visit.
8.6.4
ECG evaluation
A standard 12-lead ECG will be performed with the subject in a supine position. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG and in the ECG section of the CRF. Each ECG tracing should be labeled with the study 
number, patient initials, patient number and date, and kept in the source documents at the 
study site. Clinically significant abnormalities should be recorded on the relevant medical 
history CRF page prior to informed consent signature and on the Adverse Events page 
thereafter. Clinically significant findings must be discussed with the sponsor.
The CRF will contain:

date and time of ECG

PR interval

QT interval

QTcF

QRS duration

RR interval


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The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
As applicable, QTcF may be calculated in-house. Unless auto-calculated by the ECG 
machine, the investigator must calculate QTcF at the Screening and/or Baseline visit(s) 
(as applicable) to assess eligibility. See the Site Operations Manual for additional details.
Original ECG tracings, appropriately signed, will be archived at study site.
8.6.5
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential
(e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes), erythrocyte sedimentation 
rate,  platelet count, aPTT, PT, INR will be measured.
8.6.6
Blood chemistry
Blood chemistry should be assessed after a fast of approximately 12 hours. Blood chemistry 
will include: Sodium, potassium, calcium, magnesium, bicarbonate/HCO3, chloride, 
phosphate or phosphorus, creatinine, BUN or urea, uric acid, albumin, total protein, alkaline 
phosphatase, total bilirubin, LDH, γGT, AST, ALT, amylase, lipase, CK (CK-MM, CK-MB), 
myoglobin.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
Additional safety labs may be performed at the Investigator’s discretion
for 
clinically/medically significant abnormalities in glycemic control.
8.6.7
Urinalysis
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments. Required assessments 
include: occult blood, pH, specific gravity, ketones, glucose, protein, bilirubin, nitrite and 
leukocytes.
8.7
Pharmacokinetics (PK)
PK samples will be collected at the time points defined in the Assessment schedule
(Section 8.1). Follow instructions outlined in the Site Operations Manual regarding sample 
collection, numbering, processing and shipment. See Section 8.9 regarding the potential use of 
residual samples.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol. 
PK samples will be obtained and evaluated in all patients.
Concentrations will be expressed in mass per volume units.  
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For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol.
The following PK parameters will be determined from the serum concentration-time data 
using the actual recorded sampling times and non-compartmental method(s) with Phoenix 
WinNonlin (Version 6.2 or higher):

On Day 1, 168 and 308: Cmax, Tmax

On Days 84, 168, 252, 308 and 336: Ctrough
8.8
Other assessments
8.8.1
3 day food record
Subjects will be asked to keep a 3-day food record at time points indicated in the 
Assessment schedule, and according to guidance provided in the SOM.  These records will 
provide detailed information regarding dietary intake over the course of the study. Results will 
be available as source data and will not be recorded within the clinical database.
8.8.2
24 hour dietary recall assessment
A 24 hour dietary recall will be used at time points defined in the Assessment schedule to 
monitor the dietary intake and guide the dietary counseling. 
Dietitians may contact the subject prior to a scheduled visit in order to collect the data, and will also 
contact subjects once between monthly in-person counseling visits as defined in Table 8-3. 
Subjects will be asked to report: time of day, food/beverage, method of preparation, portion 
size/amount consumed and details of the item, as defined in the Site Operations Manual.
Data will be entered in the CRF as total amount of calories, protein (g/kg and % calories), fat 
(g and % calories), and carbohydrate (g and % calories).
8.8.3
Immunogenicity
Immunogenicity (IG) samples will be collected at the time points defined in the 
Assessment schedule and analyzed by a Novartis CRO.
Further details on sample collection, numbering, processing and shipment can be found in the 
SOM.
A validated bridging enzyme-linked immunosorbent assay (ELISA) will be used for screening 
and confirmation of the presence of anti-bimagrumab antibodies in human serum. 
Confirmed immunogenicity samples will be further characterized for presence of neutralizing 
antibodies using a validated ligand binding assay. The detailed method description to assess 
immunogenicity of bimagrumab will be described in the bioanalytical raw data of the study 
and in the respective Bioanalytical Data Report (BDR).
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IG samples remaining after immunogenicity analysis may be used for exploratory assessment or 
other bioanalytical purposes (e.g., cross check between different sites). Given the exploratory nature 
of the work, the analytical method used for those assessments will not be validated. 
8.9
Use of residual biological samples
Residual blood and urine samples may be used for another protocol specified endpoint.
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an AE irrespective if a clinical event has occurred. See Section 9.6 for an overview 
of the reporting requirements.
The occurrence of AE must be sought by non-directive questioning of the patient at each visit 
during the study. AEs also may be detected when they are volunteered by the patient during or 
between visits or through physical examination finding, laboratory test finding, or other 
assessments.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patients and identifying AEs. Alert ranges for liver and kidney related events are included in 
Appendix 1 and Appendix 2, respectively. Other laboratory values to check are markers of 
muscle distress (CK, myoglobin) and pancreatic enzymes (amylase and lipase).
AEs must be recorded on the Adverse Events CRF under the signs, symptoms or diagnosis 
associated with them, and accompanied by the following information:
1. The severity:

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:

Yes or

No
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not
recovered/not resolved must be reported.
4. Whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which
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5. Action taken regarding investigational treatment.  All AEs must be treated appropriately.
Treatment may include one or more of the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. Its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the informed consent 
and should be discussed with the patient during the study as needed.  Once an adverse event is 
detected, it must 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 investigational drug, the interventions required to 
treat it, and the outcome.
The investigator must also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
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 diarrhea-like events.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any AE (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition (any diabetic-related complications)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study  and has not worsened since the start of study drug

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


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
social reasons and respite care in the absence of any deterioration in the subject’s
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention.
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 (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per 
Section 9.2.2.
9.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.
Note: SAEs reported by patients deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the Site 
Operations Manual.
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 
on the paper SAE Report Form. The investigator must assess the relationship to each specific 
component of study treatment (if study treatment consists of several drugs) complete the SAE 
Report Form in English, and send the completed, signed form by fax within 24 hours after 
awareness of the SAE to the local Novartis Drug Safety and Epidemiology Department, 


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notifying the Clinical Trial Leader. Contact information is listed in the Site Operations 
Manual.
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the source documentation at the study site. Follow-up information should be provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
SAEs (initial and follow-up) that are recorded electronically in the Electronic Data Capture 
system should be entered, saved and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. These data will automatically be submitted to Novartis Drug 
Safety & Epidemiology immediately after investigator signature or 24 hours after entry, 
whichever occurs first. Study site personnel must also inform the Clinical Trial Leader.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
patient continued or withdrew from study participation. Each recurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study 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 study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to 
Novartis within 24 hours of the investigator learning of its occurrence/receiving follow-up 
information.
9.3
Liver safety monitoring
To ensure subject safety, 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 15-1-Appendix 1 for complete definitions of liver events.


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Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 15-2-Appendix 1. 

Repeating liver chemistry tests (ALT, AST, TBL, PT, INR, ALP and γGT) to confirm
elevation within 48-72 hours.

Repeat laboratory test results must be reported as appropriate via an electronic data
transfer (if applicable), or entered on the appropriate unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the patient will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to  Section 7.2 (Discontinuation of study
treatment), if appropriate

Hospitalization of the patient if appropriate.

Causality assessment of the liver event.

Thorough follow-up of the liver event should include:

Repeating liver chemistry tests two or three times weekly. Testing should include
ALT, AST, ALP, PT, INR, and γGT. If total bilirubin is elevated > 2 x ULN,
fractionation into direct and indirect bilirubin is required. To rule out muscular origin
of transaminase elevations, CPK should be measured along with liver chemistry tests.
Frequency of retesting can decrease to once a week or less if abnormalities stabilize
or the study drug has been discontinued and the patient is asymptomatic.
Retesting should be continued up to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications
and herbal and dietary supplement preparations), alcohol use, recreational drug use,
and special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate.

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.


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9.4
Lipase and amylase elevations
To ensure subject safety and enhance reliability in determining the potential for pancreatic 
events with bimagrumab, a standardized process for identification, monitoring and evaluation 
of pancreatic events should be followed (Table 9-1).
Table 9-1
Safety monitoring guidance for amylase and lipase elevations
Event
Follow up monitoring
Lipase and/or amylase < 3x ULN

If asymptomatic, follow up at discretion of investigator.

If clinical symptoms (e.g., abdominal pain, nausea, diarrhea)
suggest pancreatic involvement, re-check enzymes
(amylase, lipase) and inflammatory markers (C-reactive
protein) and consider pancreatic imaging (i.e., CT or MRI) to
evaluate for presence of pancreatitis.
Lipase and/or amylase ≥ 3x ULN

Re-check enzymes (amylase, lipase) and inflammatory
markers (C-reactive protein) independent of presence of
clinical symptoms.

Assess subject for clinical symptoms.

Conduct pancreatic imaging (i.e., CT or MRI) to evaluate for
presence of pancreatitis.

Study drug interruption based on findings of additional
assessments and at discretion of investigator.
Medically significant pancreatic events which are considered as serious adverse events 
(SAEs) should follow the standard procedures for SAE reporting as described in
Section 9.2. Every pancreatic event reported as an SAE should include a causality assessment 
of the event via exclusion of alternative causes (e.g., gallstones, co-medication).
An investigation of the pancreas needs to be followed up until resolution. A gastroenterology 
consult can be included at the investigator’s discretion. All follow-up information, and the 
procedures performed, should be recorded in the appropriate CRFs.
9.5
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2.
9.6
Reporting medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.


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All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF.  Study treatment errors are only to be 
reported to Novartis Drug Safety and Epidemiology department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Drug Safety and Epidemiology. As such, 
instances of misuse or abuse are also to be reported using the SAE form/CRF. Table 9-2
summarizes the reporting requirements.
Table 9-2
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose
Administration (DAR) CRF
Document in AE 
CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see Section 9.1
and Section 9.2, respectively.
9.7
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
The study drug must be discontinued immediately, though the patient may stay in the study, 
if she wishes to do so. All assessments that are considered as a risk during pregnancy must not 
be performed. The patient may continue all other protocol assessments. Pregnancy must be 
recorded on the Pharmacovigilance Pregnancy Form and reported by the investigator to the 
local Novartis Drug Safety and Epidemiology Department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to 
the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
9.8
Early phase safety monitoring
The Investigator will monitor AEs in an ongoing manner and inform the Sponsor of any 
clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations 
may occur verbally, but the outcome and key discussion points will be summarized in writing 
(e-mail) and made available to both Sponsor and all Investigator(s). Criteria pertaining to 
stopping the study/treatment or adapting the study design are presented above.


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When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis. 
Additionally, a central analytics organization may analyze data and identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility 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 patients will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms 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 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. 


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After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule and can be recorded directly on the CRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff or CRO working on behalf of Novartis who will make the correction to 
the database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
For laboratory samples processed centrally, the results will be sent electronically to Novartis 
(or a designated CRO).
The imaging CRO will collect all imaging data (DXA 
) from sites. The analysis 
results are then collected by the imaging CRO and then transformed into a format according 
to a Novartis data transfer specification. The transformed output will then be sent to Novartis 
data management for incorporation into the CSR. The imaging CRO will be responsible for 
all image data clarification forms and missing data at all sites.
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
Biostatistics NIBR Franchise Head and the relevant NIBR TA Head.
DNA samples (optional):
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10.4
Data Monitoring Committee
An independent, program-wide DMC is instituted for bimagrumab with focus on safety.
The DMC will periodically review the safety information throughout the study to monitor the 
trial’s progress for unexpectedly large differences of toxicity between treatment groups. 
The DMC for the study will be composed of individuals with experience and expertise in the 
management of patients with muscle wasting diseases, and in the monitoring of randomized 
clinical trials as well as a DMC statistician. None of the DMC members will be involved in 
the operational conduct of the study or any other bimagrumab clinical or pre-clinical study, 
except as a member of the DMC.
The mission of the DMC is to independently review and evaluate the unblinded safety data 
generated during the study as defined in this protocol. The DMC will ensure that study 
participants are not exposed to unnecessary or unreasonable risks and that the study is 
conducted with high scientific and ethical standards. As needed, the DMC will make
recommendations to the Sponsor on actions to be taken regarding the study, which may 
include the following:

Discontinuation of the study.

Suggested modifications to the study protocol and/or the informed consent document.

Continuation of the study according to the protocol and the relevant amendments.
The DMC is accountable to the Sponsor for appropriate monitoring of the study data.
Although the DMC may make recommendations to the Sponsor about changes in the conduct 
of the study, final decisions will be made by Novartis. In the case of early termination, 
consultation with Health Authorities may be required.
Members of the DMC will not share any unblinded or semi-blinded information with anyone 
outside of the DMC. Particularly, the Sponsor will remain fully blinded to any results 
throughout the study unless the DMC recommends changes in the conduct of the study (for 
example, early termination due to negative safety findings).
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 semi-blinded reports before sending to the DMC.
The frequency of the DMC meetings will be determined by the members and ratified in the 
DMC Charter. 
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10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all patient data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
The PK analysis set will include all patients with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact PK data.
The PD analysis set will include all patients with available PD data and no protocol deviations 
with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
patient. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and patient.
11.4
Analysis of the primary variable(s)
The primary aim of the study is to assess the effect of bimagrumab on fat mass at Week 48 of 
the treatment period. 
11.4.1
Variable(s)
The primary efficacy variable is the change from baseline in fat mass (kg) at Week 48.
Since the week 48 visit is the scheduled EOT visit, and since the EOT assessments are also 
performed in subjects who discontinue early (see Section 7.2), only EOT assessments on 
subjects who completed a full treatment regimen (i.e., those who did not discontinue early) 
will be included in the primary analysis.


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11.4.2
Statistical model, hypothesis, and method of analysis
The study design enables evaluation of efficacy based on the following dual criteria 
1) statistical significance (superior treatment effect, 1-sided 10% level) in fat mass; and
2) clinical relevance of the change in fat mass (estimated median treatment effect of 5% or
more). Weight loss of 5% has been shown to translate into clinical benefit in an
overweight/obese population with T2D (Franz et al 2015). Fat mass loss of a similar
magnitude to the weight loss is expected to translate into similar clinical benefits (such as on
glycemic control) in a similar population.
The randomization will be stratified by BMI category (>=28.0 kg/m2 and <=33.0 kg/m2, 
>33.1 kg/m2 to <=40.0 kg/m2) in order to achieve an approximate balance of BMI distribution
across the two treatment groups. The cutoff value of 33 kg/m2 represents the expected median
BMI in that population (based on internal data); therefore the two randomization strata are
expected to be of similar size. However, equal size strata will not be enforced. A minimum of
10 patients will be targeted for enrollment in the smaller stratum to ensure accurate precision
on the treatment effect in both strata (see Section 11.7).
The primary endpoint will be analyzed using a mixed effects model. This model will have 
change from baseline in kg fat mass as the dependent variable, treatment arm,  time, 
time*treatment interaction as fixed effects, and a  subject level random intercept. Baseline fat 
mass and baseline BMI value may be included in the model as covariates. Data collected from 
both randomization strata (BMI category at randomization) will be included in the model. The 
change from baseline (absolute) in kg fat mass at Week 48 will be estimated from that model 
and will be summarized graphically and in tabular form. No transformation (logarithmic or 
otherwise) of body weight will be done for analysis. An unstructured within-subject 
covariance will be used.
The evaluation of efficacy is based on the following dual criteria:
1. statistical significance (superior treatment effect, 1-sided 10% level) in fat mass; and
2. clinical relevance of the change in fat mass (estimated median treatment effect of 5% or
more) at Week 48.
11.4.3
Handling of missing values/censoring/discontinuations
The primary analysis model described above is valid under the assumption of data missing at 
random. If the dropout rate is greater than 10% in any arm, other analysis methods will be 
used to assess the sensitivity of the results to different methods for missing data handling. 
11.4.4
Sensitivity analyses
Other models may be used (such as pattern-mixture models) if the dropout rate is higher than 
expected, in order to assess sensitivity of the primary efficacy conclusions to missing data. If 
a treatment effect in fat mass or HbA1c materializes, then it will be investigated whether this 
finding is robust under an assumption of informative drop-out; that the subjects who drop out 
would likely not have experienced a treatment benefit.


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11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, patient, and visit and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit.
ECG evaluations
All ECG data will be listed by treatment group, patient and visit; abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, patient, and visit and if normal ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and visit.
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Adverse events
All information obtained on adverse events will be displayed by treatment group and patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A patient with multiple adverse events 
within a body system is only counted once towards the total of this body system.
Other safety evaluations
11.5.3
Pharmacokinetics
Bimagrumab serum concentration data will be listed by treatment, patient, and visit/sampling 
time point.
PK parameters will be listed by treatment group, patient, visit/sampling time, and dose 
number.  Descriptive summary statistics will include mean (arithmetic and geometric), SD, 
and CV (arithmetic and geometric), median, minimum, maximum and 90% CI. A geometric 
mean will not be reported if the dataset includes zero values. An exception to this is Tmax 
where median, minimum and maximum will be presented. Summary statistics will include 
mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum.
11.5.4
Pharmacokinetic / pharmacodynamic interactions
Graphical exploration of bimagrumab PK parameters versus fat mass will be provided. Other 
graphical exploration may be done as appropriate.
11.5.5
Other assessments
Immunogenicity
All immunogenicity results will be listed by treatment group, subject and visit.
11.6
Analysis of exploratory variables
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11.7
Sample size calculation
A sample size of 68 recruited subjects (34 receiving active treatment and 34 placebo) is 
selected to enable at least 48 completers, assuming a dropout rate of maximum 30%.
A sample size of 24 completers per group (total of 48 patients) provides about 70% power 
(see Table 11-1) to pass the criteria described above for fat mass (significant reduction at the 
1-sided 10% level (compared to placebo) and an estimated median placebo-adjusted reduction
of at least 5%).  Assumptions used for these calculations include a true placebo-adjusted fat
loss of 6% (standard deviation 6.5%, CBYM338X2206). The associated type I error is about
1% (Table 11-1).
Because weight loss interventions in overweight/obese diabetic patients result in ~ 15% lower 
magnitude of response compared to overweight/obese non-diabetic patients (Franz et al 2007), 
we made the assumption that bimagrumab could have a 6% true effect on fat loss in 
overweight and obese diabetic patients (this is about 15% lower than the 7.2% effect observed 
in overweight and obese pre-diabetics (CBYM338X2206)).
11.8
Power for analysis of key secondary variables
The power to pass the criteria for HbA1c (significant reduction and an estimated median 
placebo-adjusted reduction of at least 0.5%) is about 73%. Assumptions used for these 
calculations include a true placebo-adjusted HbA1c reduction of 0.7% (standard deviation 
1.11%, internal data). The associated type I error is about 6%.
11.9
Interim analyses
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12
Ethical considerations
12.1
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.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must 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, patient recruitment 
procedures (e.g. advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis 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.
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For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
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.
13
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 is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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.
13.1
Protocol Amendments
Any change 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.
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 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
Albanese CV, Diessel E, Genant HK (2003) Clinical Applications of Body Composition 
Measurements Using DXA. Journal of Clinical Densitometry, vol. 6, no. 2, 75–85.
Apovian CM, Aronne LJ, Bessesen DH, et al (2015) Pharmacological management of obesity: 
an endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. p. 342-62.
Arterburn D, Sofer T, Boudreau DM, et al (2016) Long-term weight change after initiating 
second-generation antidepressants.  J Clin Med 5(4):48
DeFronzo RA, Tripathy D, Schwenke DC, et al (2011) Pioglitazone for diabetes prevention in 
impaired glucose tolerance. N. Engl. J. Med. p. 1104-15.
Fournier B, Murray B, Gutzwiller S, et al (2012) Blockade of the activin receptor IIb activates 
functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative 
metabolism. Mol. Cell. Biol. p. 2871-9.
Franz MJ, VanWormer JJ, Crain AL, et al (2007) Weight-loss outcomes: a systematic review 
and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet 
Assoc. 107(10):1755-67
Franz MJ, Boucher JL, Rutten-Ramos S, et al (2015) Lifestyle weight-loss intervention 
outcomes in overweight and obese adults with type 2 diabetes: A systematic review and meta-
analysis of randomized clinical trials. J. Acad. Nutr. Diet. p. 1447-1463.
Goldstein DJ (1992) Beneficial health effects of modest weight loss. Int J Obes Relat Metab 
Disord. 16(6):397-415.
Hrebícek J, Janout V, Malincíková J, et al (2002) Detection of insulin resistance by simple 
quantitative insulin sensitivity check index QUICKI for epidemiological assessment and 
prevention. J. Clin. Endocrinol. Metab. p. 144-7.
Knowler WC, Barrett-Connor E, Fowler SE, et al (2002) Reduction in the incidence of type 2 
diabetes with lifestyle intervention or metformin. N. Engl. J. Med. p. 393-403.
Lim SS, Vos T, Flaxman AD, et al (2012) A comparative risk assessment of burden of disease 
and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a 
systematic analysis for the Global Burden of Disease Study 2010. Lancet p. 2224-60.
Marena S, Montegrosso G, De Michieli F, et al (1992) Comparison of the metabolic effects of 
mixed meal and standard oral glucose tolerance test on glucose, insulin and C-peptide 
response in healthy, impaired glucose tolerance, mild and severe non-insulin-dependent 
diabetic subjects. Acta Diabetol. 29(1):29-33.
Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose 
tolerance testing: comparison with euglycemic insulin clamp. Diabetes Care p. 1462-70
Mechanick JI, Hurley DL, Garvey WT (2016) Adiposity-based chronic disease as a new 
diagnostic term: american association of clinical endocrinologists and the american college of 
endocrinology position statement. Endocr Pract In-Press


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Rijkelijkhuizen JM, Girman CJ, Mari A, et al (2009) Classical and model-based estimates of 
beta-cell function during a mixed meal vs. an OGTT in a population-based cohort. Diabetes 
Res. Clin. Pract. p. 280-8.
Stabin MG (2008) Radiopharmaceuticals for nuclear cardiology: radiation dosimetry, 
uncertainties, and risk. J. Nucl. Med. p. 1555-63.
Suzuki ST, Zhao B, Yang J (2008) Enhanced muscle by myostatin propeptide increases 
adipose tissue adiponectin, PPAR-alpha, and PPAR-gamma expressions. Biochem. Biophys. 
Res. Commun. p. 767-73.
Tomlinson B, Cruickshank JM, Hayes Y, et al (1990) Selective beta-adrenocceptor partial
agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatinine
kinase changes in healthy subjects. Brj J Pharmac; 30: 665-672.
U.S. Department of Health and Human Services (2008) 2008 physical activity guidelines for 
Americans. 
Van Gaal LF, Mertens IL, Ballaux D (2005) What is the relationship between risk factor 
reduction and degree of weight loss? Eur Heart J Suppl;7:L21–L26
Vidal J (2002) Updated review on the benefits of weight loss. Int J Obes Relat Metab Disord. 
26 Suppl 4:S25-8.
Wallace TM, Levy JC and Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes 
Care, 27, 1487–1495
Weiss EP, Fields DA, Mittendorfer B, et al (2008) Reproducibility of postprandial lipemia 
tests and validity of an abbreviated 4-hour test. Metab Clin Exp. 57:1479–85
World Health Organization (2015) World Health Organization obesity and overweight fact 
sheet.
Yokoyama H, Emoto M, Fujiwara S, et al (2004) Quantitative insulin sensitivity check index 
and the reciprocal index of homeostasis model assessment are useful indexes of insulin 
resistance in type 2 diabetic patients with wide range of fasting plasma glucose. J. Clin. 
Endocrinol. Metab. p. 1481-4.


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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase in ALP
to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue,
abdominal pain, nausea, or vomiting, or rash, or eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤8 x ULN

3 x ULN < ALT/AST ≤5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 × 
ULN

If confirmed, consider interruption or discontinuation of
study drug

If elevation persists for more than 2 weeks, discontinue the
study drug

Establish causality

Complete CRFs per liver event guidance
Isolated ALT or AST elevation > 3 to ≤ 5 × 
ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if >50%
is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance
Any AE potentially indicative of liver toxicity

Consider study treatment interruption or discontinuation

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance


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Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, γGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia,
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin


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16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase
25 – 49% compared to baseline

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase > 50%

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 
3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset glucosuria on urine dipstick (unless 
related to concomitant treatment, diabetes)
Assess & document:

Blood glucose (fasting)

Serum creatinine

Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:

Urine sediment microscopy

Assess sCr and urine albumin-creatinine ratio

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Whenever a renal event is identified, a detailed patient history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain,
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic
failure, contrast media or other known nephrotoxin administration, or other potential
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case 
Report Form (CRF) or via electronic data load. 
Review and record possible contributing factors 
to the renal event (co-medications, other co-
morbid conditions) and additional diagnostic 
procedures (MRI etc) in the CRF.

Urine dipstick and sediment microscopy

Blood pressure and body weight

Serum creatinine, electrolytes (sodium,
potassium, phosphate, calcium), bicarbonate
and uric acid

Urine output
Monitor subject regularly (frequency at 
investigator’s discretion) until:

Event resolution: (sCr within 10% of baseline or
protein-creatinine ratio within 50% of baseline)
or

Event stabilization: sCr level with ±10%
variability over last 6 months or protein-
creatinine ratio stabilization at a new level with
±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive
metric for integrated kidney function that requires excellent tubular function. A high urinary osmolality
in the setting of an increase in sCr will point toward a “pre-renal” cause rather than tubular toxicity.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
BYM338/Bimagrumab
CBYM338X2211
A randomized, subject- and investigator-blinded,
placebo-controlled study to assess the safety,
pharmacokinetics and efficacy of intravenous bimagrumab in 
overweight and obese patients with type 2 diabetes
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final Amendment v03
Release date:
18-Mar-2019
Number of pages:
18
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Protected Personal Data


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Table of contents
Table of contents .................................................................................................................4
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Scope of document ..................................................................................................6
1.2
Study reference documentation ...............................................................................6
1.3
Study objectives.......................................................................................................6
1.3.1. Primary objective(s).......................................................................................6
1.3.2. Secondary objective(s)...................................................................................6
1.3.3. Exploratory objective(s) ................................................................................7
1.4
Study design and treatment......................................................................................8
2
First interpretable results (FIR) ...........................................................................................8
3
Interim analyses.................................................................................................................10
4
Statistical methods: Analysis sets......................................................................................10
5
Statistical methods for Pharmacokinetic (PK) parameters................................................11
5.1
Variables................................................................................................................11
5.2
Descriptive analyses ..............................................................................................12
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................12
6.1
Primary objective...................................................................................................12
6.1.1
Variables ...............................................................................................12
6.1.2
Descriptive analyses..............................................................................12
6.1.3
Statistical model, assumptions and hypotheses.....................................12
6.2
Secondary objectives .............................................................................................14
6.2.1
Variables ...............................................................................................14
6.2.2
Descriptive analyses..............................................................................14
6.2.3
Statistical model, assumptions and hypotheses.....................................14
6.3
Exploratory objectives...........................................................................................15
7
Statistical methods for safety and tolerability data............................................................16
7.1
Variables................................................................................................................16
7.2
Descriptive analyses ..............................................................................................16
7.3
Graphical presentation...........................................................................................17
9
Statistical methods for biomarker data..............................................................................17
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List of tables
Table 1:  
Operating characteristics for primary efficacy criterion based on 
DXA fat mass (placebo-corrected decrease statistically significant 
(1-sided p<0.1) and clinically relevant (estimated median 5 percent 
or more).................................................................................................10
Table 2
Protocol deviation codes and analysis sets............................................11
List of figures
Figure 1-1: Study Design............................................................................................................8


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CBYM338X2211”.
The Statistical Analysis Plan (SAP) describes the implementation of the statistical analyses 
planned in the protocol.
1.2
Study reference documentation
Final study protocol (v05) is available at the time of finalization of SAP.
1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives

To evaluate the treatment effect of
bimagrumab on total body fat mass

Body fat mass by DXA at Week 48
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To evaluate the treatment effect of
bimagrumab on total body fat mass
after 6 months of treatment

Body fat mass by DXA at Week 24

To evaluate the treatment effect of
bimagrumab on glycemic control and
parameters of insulin sensitivity

HbA1c, fasting glucose and insulin,
HOMA2-IR, QUICKI, Matsuda
index based on MTT at Week 24 and
Week 48

To evaluate the safety and
tolerability of bimagrumab in
overweight/obese patients with type
2 diabetes.

Adverse events, Vital Signs, ECG,
Laboratory Values, Immunogenicity

To evaluate the pharmacokinetics of
repeat doses of bimagrumab in
overweight/obese patients with type
2 diabetes.

PK samples – pre (Ctrough) and post
dose during treatment and follow-up
periods. Tmax and Cmax (Day 1,
Day 168 and Day 308) will be
derived.

To evaluate the immunogenic
response to repeat dosing of
bimagrumab in overweight and
obese patients with type 2 diabetes.

Anti-bimagrumab antibodies pre-
dose, during treatment and at the end
of study.


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
To evaluate the treatment effect of
bimagrumab on anthropometric body
measurements and on lean body
mass

Body weight, BMI, waist
circumference, waist-to-hip ratio,
lean body mass (LBM) by DXA at
Week 24 and at Week 48
1.3.3. Exploratory objective(s)
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1.4
Study design and treatment
This is a non-confirmatory, randomized, subject and investigator blinded, placebo-controlled,
parallel arms study, investigating a 48-week treatment period with intravenous bimagrumab
10mg/kg in overweight/obese patients with type 2 diabetes. Approximately 68 patients (34 
receiving active treatment and 34 placebo) are planned to be enrolled and randomized. The 
randomization will be stratified according to baseline BMI in two strata:

BMI between 28 kg/m2 and 33 kg/m2 (inclusive) and

BMI above 33 kg/m2 and up to 40 kg/m2 (inclusive),
in order to achieve an approximate balance of BMI distribution across the two treatment groups.
Figure 1-1: Study Design
Based on the latest version of protocol amendment, an additional visit at week 2 has been 
added coded as Visit 115.
2
First interpretable results (FIR)
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3
Interim analyses 
4
Statistical methods: Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
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The PK analysis set will include all patients with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced
no protocol deviations that impact PK data.
The PD analysis set will include all patients with available PD data, who received any study 
drug and experienced no protocol deviations with relevant impact on PD data. 
For subjects for which the actual treatment received does not match the randomized treatment, 
the treatment actually received will be used for the analysis. The analysis sets and protocol 
deviation codes are related as follows:
Table 2
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
Subjects are excluded from PK and PD analysis in case of these PDs:
Exclude subject from PK and 
PD analysis sets
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
5.1
Variables
The following pharmacokinetic parameters will be determined from the serum concentration-
time data using the actual recorded sampling times and non-compartmental method(s) with 
Phoenix WinNonlin (Version 6.2 or higher):

On Day 1, 168 and 308: Cmax, Tmax

On Days 84, 168, 252, 308 and 336: Ctrough


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5.2
Descriptive analyses
PK parameters will be listed by treatment group, patient and dose number. Descriptive summary 
statistics will include mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), 
median, minimum, maximum and 90% CI. A geometric mean will not be reported if the dataset 
includes zero values. An exception to this is Tmax where median, minimum and maximum will 
be presented.
6
Statistical methods for Pharmacodynamic (PD) parameters 
All subjects within the PD analysis set will be included in the PD data analysis.
6.1
Primary objective
The primary objective of this trial is to assess the effect of bimagrumab on fat mass at Week 48 
of the treatment period.
6.1.1
Variables 
The primary efficacy variable is the change from baseline in fat mass (kg) at Week 48 of the 
treatment period. No transformation of (logarithmic or otherwise) will be done for analysis.
Since the week 48 visit is the scheduled EOT visit, and since the EOT assessments are also 
performed in subjects who discontinue early, only EOT assessments on subjects who completed 
a full treatment regimen (i.e., those who did not discontinue early) will be included in the 
primary analysis.
6.1.2
Descriptive analyses
The individual fat mass assessments will be listed by treatment group, patient and visit/time. 
Summary statistics will be provided for raw, change from baseline, and percentage change from 
baseline by treatment group and visit/time. Summary statistics will include mean (arithmetic), 
SD, CV, median, minimum, maximum.
Graphical methods will be employed to show group and individual summary plots over time by 
treatment.
6.1.3
Statistical model, assumptions and hypotheses
The primary analysis will be analyzed using a longitudinal mixed effects model. This model 
will have change from baseline in kg fat mass as the dependent variable, treatment arm, time, 
and a time*treatment interaction as fixed effects. Baseline fat mass and baseline BMI value may 
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be included in the model as covariates. Time will be modeled as a categorical variable. An 
unstructured within-subject covariance will be used.
6.1.3.1
Handling of missing values/censoring/discontinuations
The primary analysis model described above is valid under the assumption of data missing at 
random. If the dropout rate is greater than 10% in any arm, other analysis methods will be used 
to assess the sensitivity of the results to different methods for missing data handling.
Since the week 48 visit is the scheduled EOT visit, and since the EOT assessments are also 
performed in subjects who discontinue early, only EOT assessments on subjects who completed 
a full treatment regimen (i.e., those who did not discontinue early) will be included in the 
primary analysis.  Thus, we will only include patients in the final analysis where the EOS visit 
is within 8 weeks +/- 10 days from the week 48 assessment and did not discontinue early.
6.1.3.2
Sensitivity analyses
Other models may be used (such as pattern-mixture models) if the dropout rate is higher than 
expected, in order to assess sensitivity of the primary efficacy conclusions to missing data. If a 
treatment effect in fat mass or HbA1c materializes, then it will be investigated whether this 
finding is robust under an assumption of informative drop-out; that the subjects who drop out 
would likely not have experienced a treatment benefit.
6.1.3.3
Supportive analyses
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6.2
Secondary objectives
6.2.1
Variables 
The secondary variables are the:
1. Body fat mass: change from baseline in fat mass after 6 months of treatment at Week
24
2. HbA1c: change from baseline will be used for inferential analysis at Week 24 and Week
48. Baseline for HbA1c is defined at the Day 1 assessment.
3. Fasting insulin and glucose at Week 12, Week 36, and EOS: Baseline for these
parameters is defined at the Screening assessment.
4. HOMA2-IR: homeostatic assessment model of insulin resistance at Week 12, Week 36,
and EOS
5. QUICKI: quantitative insulin sensitivity check, under fasting conditions at Week 12,
Week 36, and EOS. QUICKI index will be derived from glucose and insulin levels at
study completion using the following formula:
QUICKI =
1
{log(Fasting Insulin) + log(Fasting Glucose)}
6. Matsuda Index based on MTT at Week 24 and Week 48. Matsuda Index will be derived
from glucose and insulin levels using the following formula:
10000
1(Fasting Glucose × Fasting Insulin) × (Mean Glucose × Mean Insulin)
7. Anthropometric body measurements: body weight, BMI, waist circumference, waist-to-
hip ratio and lean body mass (LBM) as measured by DXA at Week 24 and Week 48.
6.2.2
Descriptive analyses
The variables will be listed by treatment group, patient and visit/time. Summary statistics will 
be provided for raw, change from baseline and percentage change from baseline by treatment 
group and visit/time. Summary statistics will include mean (arithmetic), SD, CV, median, 
minimum, maximum.
Graphical methods will be employed to show group and individual summary plots over time by 
treatment. Other secondary efficacy variables will be summarized graphically and in summary 
tables.
6.2.3
Statistical model, assumptions and hypotheses
HbA1c


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The secondary analysis of HbA1c will be analyzed using a mixed effects model with the same
structure as the analysis of the primary variable, in Section 6.1.3.
Other Secondary Variables
Similar to the analysis of HbA1c, an MMRM model may be used to compare values between 
active and placebo groups for the remaining secondary variables.
6.2.3.1
Supportive analyses
As a supportive analysis for metabolic changes, summaries of change in background anti-
diabetic medication may be done. A change in background anti-diabetic medication is defined 
as a change in daily dose, any discontinuation, or the addition of a second agent.
6.3
Exploratory objectives
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7
Statistical methods for safety and tolerability data
All subjects within the safety analysis set will be included in the safety data analysis.
7.1
Variables
Adverse events, vital signs (blood pressure, heart rate, body temperature), ECG intervals, 
clinical laboratory measurements, immunogenicity, hematology, blood chemistry as well as 
subject demographics, baseline characteristics, and treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
Demographic table will include a corresponding p-value for comparison of baseline values 
between BYM338 and placebo groups. T-test can be performed for continuous variables and 
chi-squared test for categorical variables. Demographic table will be generated for both sets of 
patients (completed/not completed treatment).
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time, and if ranges are available,
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit.
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ECG evaluations
All ECG data will be listed by treatment, subject and visit; abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit.
Clinical laboratory evaluations
All laboratory data will be listed by 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 will be provided by treatment and 
visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
Other safety evaluations
Immunogenicity
All immunogenicity results will be listed by subject and visit/time.
7.3
Graphical presentation 
Figures may be created, as needed, to explore safety data trends.
8
Statistical methods for Pharmacokinetic/Pharmacodynamic 
interactions
Scatterplots may be used to explore the relationships between systemic exposure to BYM338 
and selected safety/PD endpoints. Other graphical exploration may be done as appropriate.
9
Statistical methods for biomarker data
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