A Randomized, Placebo-controlled, Participant-and-investigator- Blinded, Sponsor Open-label Study to Evaluate the Safety, Tolerability, and Efficacy With Different Dosing Regimens of Subcutaneously Administered MBL949 in Obese Participants With or Without Type 2 Diabetes Mellitus
Phase: PHASE2
Conditions: Obesity
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
MBL949
Clinical Trial Protocol CMBL949A12201
ClinicalTrials.gov Identifier: NCT05199090
A randomized, placebo-controlled, participant-and 
investigator-blinded, sponsor open-label study to evaluate 
the safety, tolerability, and efficacy with different dosing 
regimens of subcutaneously administered MBL949 in 
obese participants with or without type 2 diabetes mellitus
Document type:
Amended Protocol Version
EUDRACT number:
2021-004449-19
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
12-Jan-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020

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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................6
List of abbreviations ............................................................................................................7
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................16
1
Introduction........................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose...................................................................................................................21
2
Objectives and endpoints...................................................................................................21
3
Study design.......................................................................................................................23
4
Rationale ............................................................................................................................29
4.1
Rationale for study design......................................................................................29
4.2
Rationale for dose/regimen and duration of treatment...........................................30
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................31
4.4
Purpose and timing of interim analyses/design adaptations ..................................31
4.5
Risks and benefits ..................................................................................................31
4.5.6
Injection site reaction ............................................................................34
4.5.7
Hypoglycemia........................................................................................34
4.5.9
Blood sample volume............................................................................35
4.5.10
Potential risk associated with the COVID-19 pandemic.......................35
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4.5.11
New diagnosis of T2DM .......................................................................35
4.7
Rationale for Public Health Emergency mitigation...............................................36
5
Study Population................................................................................................................36
5.1
Inclusion criteria ....................................................................................................36
5.2
Exclusion criteria ...................................................................................................37
6
Treatment...........................................................................................................................40
6.1
Study treatment ......................................................................................................40
6.1.1
Investigational and control drugs ..........................................................40
6.1.2
Additional study treatments...................................................................41
6.1.3
Treatment arms/group ...........................................................................41
6.2
Other treatment(s) ..................................................................................................41
6.2.1
Concomitant therapy .............................................................................41
6.2.2
Prohibited medication............................................................................42
6.2.3
Restriction for study participants...........................................................42
6.3
Participant numbering, treatment assignment, randomization...............................43
6.3.1
Participant numbering ...........................................................................43
6.3.2
Treatment assignment, randomization...................................................43
6.4
Treatment blinding.................................................................................................44
6.5
Dose escalation and dose modification..................................................................46
6.6
Additional treatment guidance...............................................................................46
6.6.1
Treatment compliance ...........................................................................46
6.6.2
Recommended treatment of adverse events ..........................................46
6.6.3
Emergency breaking of assigned treatment code ..................................47
6.7
Preparation and dispensation .................................................................................48
6.7.1
Handling of study treatment and additional treatment ..........................48
6.7.2
Instruction for prescribing and taking study treatment..........................49
7
Informed consent procedures.............................................................................................49
8
Visit schedule and assessments..........................................................................................50
8.1
Screening................................................................................................................57
8.1.1
Eligibility screening...............................................................................57
8.1.2
Information to be collected on screening failures .................................58
8.2
Participant demographics/other baseline characteristics........................................58
8.3
Efficacy..................................................................................................................58
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8.3.1
Appropriateness of efficacy assessments ..............................................59
8.3.2
Body weight and central obesity ...........................................................59
8.4
Safety .....................................................................................................................61
8.4.1
Laboratory evaluations..........................................................................62
8.4.2
Electrocardiogram (ECG)......................................................................63
8.4.3
Pregnancy and assessments of fertility..................................................64
8.4.4
Appropriateness of safety measurements ..............................................64
8.4.5
Injection/infusion site reaction ..............................................................65
8.5
Additional assessments ..........................................................................................65
9
Study discontinuation and completion...............................................................................70
9.1
Discontinuation and completion ............................................................................70
9.1.1
Study treatment discontinuation and study discontinuation..................70
9.1.2
Discontinuation from study...................................................................71
9.1.3
Lost to follow-up...................................................................................71
9.1.4
Early study termination by the sponsor.................................................71
9.2
Withdrawal of informed consent/Opposition to use data/biological samples........72
9.3
Study stopping rules...............................................................................................72
9.4
Study completion and post-study treatment...........................................................73
10 Safety monitoring and reporting........................................................................................73
10.1
Definition of adverse events and reporting requirements......................................73
10.1.1
Adverse events.......................................................................................73
10.1.2
Serious adverse events...........................................................................75
10.1.3
SAE reporting........................................................................................76
10.1.4
Pregnancy reporting...............................................................................76
10.1.5
Reporting of study treatment errors including misuse/abuse ................77
10.2
Additional Safety Monitoring................................................................................77
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11 Data Collection and Database management ......................................................................78
11.1
Data collection .......................................................................................................78
11.2
Database management and quality control ............................................................78
11.3
Site monitoring.......................................................................................................79
12 Data analysis and statistical methods.................................................................................80
12.1
Analysis sets...........................................................................................................80
12.2
Participant demographics and other baseline characteristics.................................80
12.3
Treatments..............................................................................................................80
12.4
Analysis of the primary endpoint(s)/estimand(s)...................................................80
12.4.1
Definition of primary endpoint(s)/estimand(s)......................................80
12.4.2
Statistical model, hypothesis, and method of analysis ..........................81
12.4.3
Safety endpoints ....................................................................................81
12.4.5
Handling of missing values not related to intercurrent event................83
12.4.6
Sensitivity analyses for primary endpoint/estimand..............................84
12.4.7
Supplementary analysis.........................................................................84
12.4.8
Supportive analyses...............................................................................84
12.5
Analysis of secondary endpoints/estimands ..........................................................84
12.6
Analysis of exploratory endpoints .........................................................................85
12.7
Interim analyses .....................................................................................................86
12.8
Sample size calculation..........................................................................................87
12.8.1
Primary endpoint(s)...............................................................................87
13 Ethical considerations and administrative procedures.......................................................88
13.1
Regulatory and ethical compliance........................................................................88
13.2
Responsibilities of the investigator and IRB/IEC..................................................88
13.3
Publication of study protocol and results...............................................................88
13.4
Quality Control and Quality Assurance.................................................................89
13.5
Participant Engagement .........................................................................................89
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14 Protocol adherence.............................................................................................................89
14.1
Protocol amendments.............................................................................................90
15 References..........................................................................................................................91
16 Appendices.........................................................................................................................93
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................93
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements...........................................................................................................94
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up......97
16.3.1
Renal Event Follow-Up.........................................................................98
List of tables
Table 2-1
Objectives and related endpoints...........................................................21
Table 4-1
Rationale for study design.....................................................................29
Table 6-1
Investigational and control drug............................................................40
Table 6-2
Prohibited medication............................................................................42
Table 6-3
Blinding levels.......................................................................................45
Table 8-1
Assessment Schedule.............................................................................52
Table 8-2
Safety Assessments ...............................................................................61
Table 8-3
Laboratory evaluations..........................................................................63
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................77
Table 16-1
Liver event and laboratory trigger definitions.......................................94
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms...............................................................................................94
Table 16-3
Follow up requirements for liver laboratory triggers ............................96
Table 16-4
Specific Renal Alert Criteria and Actions.............................................97
Table 16-5
Renal Event Follow-Up.........................................................................98
List of figures
Figure 3-2
Enrollment Flow....................................................................................26
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List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
BLRM
Bayesian Logistic Regression Model
BMI
body mass index: weight kg / height m2
BUN
Blood Urea Nitrogen
CD-ROM
Compact Disc – Read Only Memory
CDP
Clinical Development Plan
CDS
Core Data Sheet
CK
Creatinine Kinase
CMO&PS 
Chief Medical Office and Patient Safety
CO
Country Organization
CO2
carbon dioxide
COA
Clinical Outcome Assessment
COVID-19
Coronavirus Disease-19
CQA
Clinical Quality Assurance
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Terminology Criteria
CV
coefficient of variation
DBP
Diastolic Blood Pressure
DIN
Drug Inducted Nephrotoxicity
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DPP-4
Dipeptidyl Peptidase 4
DQF
Data Query Form
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCOA
Electronic Clinical Outcome Assessment
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
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EOS
End Of Study
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
FDA
Food and Drug Administration
FIH
First in Human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GDF-15
Growth Differentiation Factor-15
GFRAL
Glial-derived neurotrophic Factor Receptor Alpha-Like
GGT
Gamma-glutamyl transferase
h
Hour
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HED
Human Equivalent Dose
HEOR
Health Economics & Outcomes Research 
HFpEF
Heart Failure with preserved Ejection Fraction
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
IntraUterine Device 
LDH
lactate dehydrogenase
LFT
Liver function test 
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
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mL
milliliter(s)
MRSD
Maximum Recommended Starting Dose
MTD
Maximum Tolerated Dose
NCDS
Novartis Clinical Data Standards
NOVDD
Novartis Data Dictionary
OHP
off-site Healthcare Professional
PA
posteroanterior
PC
Personal Computer
PPD
Premature Participant Discontinuation
PSD
Premature Subject Discontinuation
PT
prothrombin time
PTT
Partial Thromboplastin Time 
QD
Once a day
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RAP
The Report and Analysis Plan 
RBC
red blood cell(s)
RDC
Remote Data Capture
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
subcutaneous
sCR
serum creatinine
SD
standard deviation
SGLT-2
Sodium-Glucose coTransporter-2
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
T2DM
Type 2 Diabetes Mellitus
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TD
Study Treatment Discontinuation
TZD
Thiazolidinedione
ULN
upper limit of normal
UTI
Urinary Tract Infection
VAS
Visual Analogue Scale
WBC
white blood cell(s)
WHO
World Health Organization 
WHR
Waist to Hip Ratio
WoC
Withdrawal of Consent
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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as 
described in the protocol, but not as an investigational medicinal 
product (e.g. any background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant 
Cohort
A specific group of participants fulfilling certain criteria and generally 
treated at the same time
Control drug
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last 
participant or at a later point in time as defined by the protocol
Enrollment
Point/time of participant entry into the study at which informed consent 
must be obtained 
eSource (DDC)
eSource Direct Data Capture (DDC) refers to the capture of clinical 
study data electronically, at the point of care. eSource 
Platform/Applications combines source documents and case report 
forms (eCRFs) into one application, allowing for the real time collection 
of clinical trial information to sponsors and other oversight authorities, 
as appropriate
Estimand 
A precise description of the treatment effect reflecting the clinical 
question posed by the trial objective. It summarizes at a population-
level what the outcomes would be in the same patients under different 
treatment conditions being compared. Attributes of an estimand include 
the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are 
addressed and a population-level summary for the variable.
Intercurrent events
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the 
clinical question of interest.
Investigational drug/ 
treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
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Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy)
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for the 
participant and should be used to identify the participant throughout the 
study for all data collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually in 
analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples.
Premature participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned
Randomization number
A unique identifier assigned to each randomized participant
Screen Failure
A participant who did not meet one or more criteria that were required 
for participation in the study
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant
Study treatment
Any drug or combination of drugs   or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) 
prior to the defined study treatment completion date (if any) for any 
reason; may or may not also be the point/time of study discontinuation 
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the 
combination, and may consist of 1 or more cohorts.
Treatment of interest
The treatment of interest and, as appropriate, the alternative treatment 
to which comparison will be made. These might be individual 
interventions, combinations of interventions administered concurrently, 
e.g. as add-on to standard of care, or might consist of an overall
regimen involving a complex sequence of interventions. This is the
treatment of interest used in describing the related clinical question of
interest, which might or might not be the same as the study treatment.
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event.
C
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Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a participant 
does not want to participate in the study any longer and does not allow 
any further collection of personal data  
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation.
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal 
reason than consent.

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Protocol summary
Protocol number
CMBL949A12201
Full Title
A randomized, placebo-controlled, participant-and-investigator- blinded, 
sponsor open-label study to evaluate the safety, tolerability, and efficacy 
with different dosing regimens of subcutaneously administered MBL949 in 
obese participants with or without type 2 diabetes mellitus
Brief title
Study to assess safety, tolerability and efficacy of SC administered MBL949 
in obese participants with or without T2DM
Sponsor and Clinical 
Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
This Phase II study is designed to assess the safety, tolerability, and efficacy 
for body weight reduction of different MBL949 regimens in obese 
participants with or without T2DM. Data from this study will support the 
future development of MBL949 for these disorders.
Primary Objective(s) 
To evaluate the safety and tolerability of MBL949 in obese participants with 
or without T2DM by monitoring safety endpoints including adverse events 
and SAEs.
To evaluate the efficacy for body weight reduction of MBL949 in obese 
participants with or without T2DM.
Study design
The study comprises a screening/baseline period of up to 35 days (5 
weeks), a 14-week treatment period in which participants will receive 8 
doses of MBL949 or placebo at bi-weekly intervals starting on Day 1 and a 
10 week follow-up period.
Each participant will be randomized to 1 of 5 MBL949 arms or placebo and 
will receive eight dose administrations biweekly over 14 weeks. Refer to 
Section 4.2 for dosing rationale. 
MBL949 Arm 1: 
MBL949 Arm 2: 
MBL949 Arm 3: 
MBL949 Arm 4: 
MBL949 Arm 5:
The enrollment flow is described in Figure 3-2. First, participants will be 
enrolled into MBL949 arm 1, MBL949 arm 2, and placebo arm with a 1:1:1 
ratio in each randomization stratum. Upon completion, each arm will have 12 
participants who complete week 16 weight assessment. After successful 
enrollment of MBL949 arm 1, MBL949 arm 2, and placebo, participants will 
be enrolled into MBL949 arm 3, MBL949 arm 4 and placebo arm with a 1:1:1 
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ratio in each stratum. MBL949 arm 3 and MBL949 arm 4 will each have 12 
participants who complete week 16 weight assessment; and an additional 12 
participants will be added to placebo arm. MBL949 dosing arm 5 will be 
triggered if MBL949 dosing arm 1 is tolerated (i.e., 7 treated participants 
complete week 8). Participants will be enrolled into MBL949 arm 5 and 
placebo arm independently with a ratio of 2:1 in each stratum. MBL949 arm 
5 will have 12 participants and 6 participants added in the placebo 
arm. Decisions on whether the study enrollment will be continued or 
discontinued will be based on ongoing safety and tolerability assessments 
throughout the study.
Study population
The study population will be comprised of obese (BMI ≥ 32 kg/m2) adult 
males and females between 18 and 60 years old with or without 
T2DM. 
approximately 106 participants will be randomized based on an estimated 
dropout rate of 15% in order to achieve 90 total completers.
Key Inclusion criteria
ALL participants:
Participants must be between 18 to 60 years of age inclusive

At screening participants must have:

Body mass index (BMI) ≥ 32 kg/m2, BMI = body weight (kg) / [Height
(m)]2

Weight ≥ 77 kg, stable weight i.e., less than 1.5 kg self-reported change
within 90 days and/or 3 kg self-reported weight loss within
6 months before screening
Participants with T2DM

Diagnosed diabetes duration less than 10 years

Hemoglobin A1C below ≤9%

C-peptide ≥ 0.2 ng/ml

If treated for T2DM, treatment may be limited to diet and exercise. In
addition, treatment with one of the following anti-diabetic agents is
permitted (stable for approximately 3 months prior to randomization):

Metformin

SGLT2 inhibitors (if prescribed as the first line i.e. single agent)

DPP4 inhibitors

Acarbose
Key Exclusion 
criteria
ALL participants: 
Participants with:

Systolic blood pressure less than 95 mmHg or greater than 155 mm Hg

Diastolic blood pressure less than 60 mgHg or greater than 95 mg Hg

Pulse rate less than 56 bpm or greater than 110 bpm

History or presence of symptomatic cardiovascular disease such as
angina pectoris, prior ASCVD events (including stroke, myocardial
infarction, heart failure, claudication), or prior coronary revascularization
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
Participation in an organized weight reduction program (e.g. Weight
Watchers, NutriSystem) or any investigational weight loss trial within 6
months before screening
Study treatment

MBL949

Placebo
Treatment of interest
The randomized treatment (MBL949 or placebo)
Efficacy 
assessments

Weight (kg)
Key safety 
assessments

Adverse Events

Serious Adverse Event
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Data analysis
The primary endpoint for efficacy is change in weight from baseline to week 
16. Primary endpoints for safety and tolerability include frequency and
severity of adverse events. 
Key words
Phase 2 study, Obese participants with or without type 2 diabetes mellitus, 
MBL949
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1
Introduction
1.1
Background
Excess weight poses increased risk for a number of substantial co-morbidities. The most 
significant is type 2 diabetes mellitus (T2DM). Additional co-morbidities include, but are not 
limited to, excess risk for all forms of cardiovascular disease, liver disease, cognitive decline 
and several malignancies including hepatocellular carcinoma. Risk increases with weight as 
individuals progress from an overweight body mass index to class I obesity (BMI 30 to ≤ 34.9) 
to class II obesity (BMI 35 to ≤ 39.9) and class III obesity (BMI ≥ 40).
Rates of obesity in the United States have risen dramatically over the past two decades. The 
2020 Centers for Disease Control report on obesity shows that there are 99 million obese 
individuals in the United States of which 9 million have class III obesity. In parallel, rates of 
diabetes have risen and in the United States to an estimated 34.2 million individuals, 
26.8 million diagnosed and 7.3 million undiagnosed (DeFronzo et al 2015). The risk of diabetes 
increases with increasing weight. (Narayan et al 2007). The worldwide estimate for obesity 
associated diabetes is 463 million individuals.
Weight loss ameliorates the complications of obesity and can lead to complete remission and 
in some cases reversal of some of the comorbidities, including T2DM and non-alcoholic fatty 
liver disease (Gadde et al 2018). Short term calorie restriction leads to rapid improvements in 
insulin sensitivity (Kirk et al 2009). In individuals with diabetes, significant improvements are 
seen with weight loss in fasting glucose, insulin and hemoglobin HbA1c, are noted after 5% 
weight loss and improve as weight loss increases (Petersen et al 2005) (Wing et al 2011). 
Weight loss, especially of 15 kilograms and above can lead to remission of T2DM 
(Zhang et al 2018, Lean et al 2019), regardless of whether weight loss is achieved through 
surgery, diet or pharmacologic intervention.
Multiple classes of medications aimed at achieving weight loss are available, however generally 
efficacy is limited (Khera et al 2016). Surgical approaches such as bariatric surgery are 
effective in achieving significant and durable weight loss and remission of T2DM 
(le Roux and Heneghan 2018, Zhang et al 2018). Eligibility is reserved for individuals with a 
BMI of 40 kg/m2 or greater or 35 kg/m2 in the case of a co-morbidity. This leaves a substantial 
unmet medical need for a more effective pharmacotherapy for those who do not meet the criteria 
or do not want surgery. In addition, pharmacotherapy may benefit those with other 
obesity-associated disorders such as heart failure with preserved ejection fraction (HFpEF).
The paucity of effective weight lowering agents that could be used for the potential remission 
of T2DM led to substantial interest in the discovery that growth differentiation factor 15 
(GDF15/MIC1) was elevated in conditions of significant weight loss and loss of appetite. 
Furthermore, in pre-clinical studies, treatment with a long acting analogue of GDF15 associated 
with reduction in weight. (Tsai et al 2014, Tsai et al 2016). The nature of this pathway remained 
elusive until the receptor – designated GFRAL, a member of the glial cell derived neurotrophic 
factor family, was identified and found to be expressed in the central nervous system. This 
discovery was soon followed by reports that the GFRAL receptor was required for the action 
of GDF15 defining the central nervous system as a site of GDF15 action (Emmerson et al 2017, 
Hsu et al 2017, Mullican et al 2017, Yang et al 2017).

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1.2
Purpose
The purpose of this study is to assess the safety, tolerability, efficacy, 
 of subcutaneous (SC) MBL949 in obese participants with or without T2DM on weight 
loss. Data from this study will be used to inform the future development plans for MBL949 to 
reduce weight in obesity-associated disorders such as T2DM.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To evaluate the safety and tolerability of
different dosing regimens of MBL949 in
obese participants with or without T2DM

Frequency and severity of adverse events
(AEs)

To evaluate the effect of different dosing
regimens of MBL949 on weight in obese
participants with or without T2DM at week
16

Weight
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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Objective(s)
Endpoint(s)
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3
Study design
This is a multi-center, randomized, placebo-controlled, participant-and-investigator-blinded, 
sponsor open-label study in obese participants with or without T2DM. The study comprises a 
screening/baseline period of up to 35 days (5 weeks), a 14-week treatment period in which 
participants will be administered MBL949 or placebo at 8 biweekly intervals starting on Day 1 
and a 10-week follow-up period.
Approximately106 participants will be enrolled to ensure at least 90 participants complete week 
16 to assess the primary objectives of safety, tolerability, and efficacy.
Participants will be randomized to one of five MBL949 arms (shown below), or placebo, 
administered by subcutaneous (SC) injection every 2 weeks during the treatment period 
(8 doses):
MBL949 Arm 1:
MBL949 Arm 2:
MBL949 Arm 3:
MBL949 Arm 4:
MBL949 Arm 5:
Enrollment into MBL949 dose arms will be staggered as described below under Enrollment 
Flow and in Figure 3-2.
Participants will be evaluated for safety, tolerability, efficacy, 
 during the treatment and 
follow-up period as described below and shown in the assessment schedule (Table 8-1).
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Screening (Days -35 to -15)
Consented participants will undergo a screening visit between Day -35 and Day -15 to 
determine their eligibility for the study (see inclusion/exclusion criteria Section 5). Participants 
who meet eligibility criteria will be scheduled for baseline assessments.
Baseline (Days -14 to -1)
Prior to dosing (Day 1), participants who are eligible for enrollment following screening will 
return to the clinic to undergo baseline assessments as defined in Section 8 (Assessment 
Schedule). To facilitate study conduct, participants may come to the clinic on multiple days to 
complete the required assessments prior to Day 1,
 
Randomization and Dosing (Day 1)
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Eligible participants, based on screening and baseline assessments, will be randomized into 
MBL949 arms 1-5 and placebo arm 
On Day 1, participants will come to the clinic after an overnight fast of at least 10 hours to 
complete the Day 1 assessments as defined in Assessment schedule Table 8-1 prior to dosing. 
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Administration of MBL949 or placebo will be given via a SC injection according to 
instructions provided in the Pharmacy Manual. Dosing will be followed by an observation 
period of at least one hour post dose administration.
Participants may be discharged from the site when the Investigator judges them to be medically 
stable, in general good health, and not needing further observation.
Treatment period (Days 1 - 99)
Following Day 1, the study treatment will be administered SC at biweekly intervals for a total 
of eight dose administrations over 14 weeks. Participants will be evaluated regularly 
throughout the treatment period for safety, tolerability, efficacy, 
 The specific 
assessments for each visit are detailed in Table 8-1 (Assessment Schedule).  Participants in 
consultation with the Investigator may elect to have selected visits throughout the study, as 
specified on the Assessment Schedule, be conducted at home by a visiting nurse or at the study 
site. 
Follow Up (Days 100 - 169)
Participants will have a 10-week follow-up period (Day 100 to Day 169) 
 in which they will continue to be monitored for safety, tolerability, 
efficacy, 
 The specific assessments for the follow-up and end of study visits are detailed 
in Table 8-1.
Enrollment Flow
The enrollment flow is described in Figure 3-2 . First, participants will be enrolled into MBL949 
arm 1, MBL949 arm 2, and placebo arm with a 1:1:1 ratio in each randomization stratum. Upon 
completion, each arm will have 12 participants who complete week 16 weight assessment. After 
successful enrollment of MBL949 arm 1, MBL949 arm 2, and placebo, participants will be 
enrolled into MBL949 arm 3, MBL949 arm 4 and placebo arm with a 1:1:1 ratio in each stratum. 
MBL949 arm 3 and MBL949 arm 4 will each have 12 participants who complete week 16 
weight assessment; and an additional 12 participants will be added to placebo arm. MBL949 
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dosing arm 5 will be triggered if MBL949 dosing arm 1 is tolerated (i.e., 7 treated participants 
complete week 8). Participants will be enrolled into MBL949 arm 5 and placebo arm 
independently with a ratio of 2:1 in each stratum. MBL949 arm 5 will have 12 participants and 
6 participants added to the placebo arm. Decisions on whether the study enrollment will be 
continued or discontinued will be based on ongoing safety and tolerability assessments 
throughout the study.
The ratio of obese only to obese T2DM individuals will be examined and consideration given 
to expanding enrollment to include additional participants with T2DM.
Figure 3-2
Enrollment Flow
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4
Rationale
4.1
Rationale for study design
Table 4-1
Rationale for study design 
Study Design Aspect
Rationale
Overall
This is a randomized, placebo-controlled, 
participant-and investigator-blinded, sponsor 
open-label study to evaluate the safety, 
tolerability, and efficacy of different MBL949 
dosing regimens in obese participants with or 
without T2DM. In this study, a subcutaneous 
injection of MBL949 or placebo is planned at 
biweekly dosing intervals for 14 weeks to study 
the effect of MBL949 on weight loss. The design 
(5 different MBL949 treatment arms and 
placebo) allows assessment of the safety, 
tolerability and efficacy of different up titration 
regimens modelled to reach three different 
steady state plasma concentrations. This will 
help determine the optimal dosing regimen for 
MBL949. The randomized and blinded study 
design was chosen to minimize bias.  
Randomization
 
The 
randomization strategy as defined in Section 3 
will maximize the statistical power for detecting 
differences in each strata while avoiding 
allocation bias.
Blinding
Blinding of participants and the investigator 
allows for an unbiased assessment of study 
endpoints, particularly for participant readouts 
such as adverse events and patient-reported 
outcomes. The blinding table, as detailed in 
Table 6-3 and will improve the accuracy of 
safety-related decisions during trial conduct, if 
needed.
Duration of study periods
Participants will be treated over a period of 14 
weeks. The treatment period of 14 weeks 
followed by a 10 week evaluation period will 
allow adequate safety and efficacy data to be 
collected to assess the future potential of 
MBL949 in obesity-related disorders. This trial 
duration is comparable to the early assessment 
of weight loss efficacy identified in studies of 
weight loss agents. 
 
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Study Design Aspect
Rationale
Placebo comparator
The use of placebo as a comparator is to 
provide a comparison group for the collection 
and assessment of safety, tolerability, and 
efficacy data while avoiding historical 
comparisons and helps to distinguish time-
effects from drug effects.
4.2
Rationale for dose/regimen and duration of treatment
All 5 proposed dosing arms consist of a total of 8 bi-weekly SC injections over 14 weeks, 
followed by a 10 week follow-up period with primary endpoint evaluation at week 16. 
 
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4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The use of a placebo comparator allows for a comparison group of safety 
 
effects. An excipient matched placebo will be used to evaluate the benefit of MBL949 beyond 
any potential physiologic effect of the excipients, 
 
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
There may be a benefit of weight loss and improvement in metabolic parameters for participants 
in this study. 
 
It is hoped that this study will benefit 
individuals with obesity through weight loss and thereby lead to a new therapeutic approach to 
treat obesity related comorbidities.
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Risks to participants are minimized by the appropriate eligibility criteria and specific 
dose-limiting toxicity definitions, as well as specific guidelines for dosing holidays as well as 
stopping rules, and are included in this protocol.
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4.5.6
Injection site reaction
4.5.7
Hypoglycemia
The risk of hypoglycemia in participants with T2DM in this study is low. Weight loss itself is 
not associated with hypoglycemia. Medications that increase the risk of hypoglycemia with 
weight loss are those that induce insulin secretion such as sulfonylureas and insulin. These are 
excluded in this study.
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4.5.9
Blood sample volume
The total volume of blood collected over a period of approximately 27 weeks is smaller than 
the volume of a typical blood donation. This sampling will be performed in each participant of 
the study. Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the assessment schedule Table 8-1.
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage and shipment information are also available in the laboratory manual.
See the Section 8.5.3.1 on the potential use of residual samples.
4.5.10
Potential risk associated with the COVID-19 pandemic
Novartis is committed to supporting the safety and well-being of our study participants, 
investigators, and site staff. All local regulations and site requirements are being applied in the 
countries that are affected by the COVID-19 pandemic, including COVID-19 testing of 
participants if applicable. The Novartis clinical trial team will review the situation in each 
participating country and work with investigators to continue to ensure the safety of participants 
during the conduct of the trial. A benefit/risk assessment has been made and has been 
determined to be positive for the participants to be enrolled. As the COVID-19 situation evolves, 
investigators must use their best judgement to minimize risk to participants during the conduct 
of the study. Study specific details of vaccination of COVID-19 is provided in Section 8.1.1.3 
of the protocol.
MBL949 is not an immunosuppressive agent, and is not expected to compromise participants’ 
immune systems.
4.5.11
New diagnosis of T2DM
Per standard of care, typically individuals with a new diagnosis of T2DM receive counseling 
on diet and exercise through their health care provide and dietitian. Evaluation of diet and 
exercise usually proceeds for 3-4 months after which initiation of an anti-diabetes drug is 
typically prescribed if diet and exercise therapy are ineffective. Thus enrollment in the study 
would not materially change or delay T2DM management.
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4.7
Rationale for Public Health Emergency mitigation
In 
 the event of a Public 
Health emergency as declared by Local or Regional authorities i.e., pandemic, epidemic or 
natural disaster, additional mitigation procedures to ensure participant safety and trial integrity 
may be implemented. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or additional visits by OHPs to the 
participant´s home, can replace onsite study visits (in addition to the already planned off-site 
visits), for the duration of the disruption until it is safe for the participant to visit the site again.
Notification of the Public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures and permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate.
5
Study Population
The study population will include obese (BMI >/= 32 kg/m2) men and women between 18 and 
60 years of age with or without T2DM. To account for 15% drop out rate, approximately 106 
participants are planned to be randomized to achieve 90 total completers. The Investigator must 
ensure that all participants being considered for the study meet the following eligibility criteria. 
No additional criteria should be applied by the Investigator, in order that the study population 
will be representative of all eligible participants. Participant selection is to be established by 
checking through all eligibility criteria at both screening, baseline, and prior to randomization 
as applicable. A relevant record (e.g., checklist) of the eligibility criteria must be stored with 
the source documentation at the site. Deviation from any entry criterion excludes a participant 
from enrollment into the study.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
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ALL PARTICIPANTS
1. Written informed consent must be obtained before any assessment is performed.
2. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
3. At screening, men and women must be between 18 and 60 years of age inclusive
4. At screening, participants must have a body mass index: ≥ 32 kg/m2, weight ≥ 77 kg, 
stable body weight i.e., less than 1.5 kg self-reported change within 90 days and/or 3 kg 
self-reported change within 6 months prior to screening [BMI = Weight (kg) / [Height 
(m)]2
PARTICIPANTS WITH T2DM 
5. Diagnosed T2DM as documented by medical history and confirmed by Investigator and
with diagnosed duration < 10 yrs, HbA1c ≤ 9%, and fasting C-peptide ≥ 0.2 ng/ml
6. If treated for T2DM, treatment must be limited to diet and exercise and treatment with one 
of the following anti-diabetic agents is permitted (stable for 90 days prior to 
randomization):

Metformin

SGLT2i inhibitors (if prescribed as the first line, i.e. single agent)

DPP4 inhibitors

Acarbose
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
ALL PARTICIPANTS
1. At screening, vital signs (blood pressure and pulse rate) will be assessed in the sitting 
position (see Table 8-2 for detailed description on vital signs methodology). The sitting 
vital signs defined below are exclusionary:

systolic blood pressure less than 95 mm Hg or greater than 155 mm Hg

diastolic blood pressure less than 60 mg Hg or greater than 95 mm Hg

pulse rate less than 56 or greater than 110 bpm
2. History of bariatric surgery, Roux-en-Y Gastric Bypass, Sleeve Gastrectomy, gastric 
banding, and any other intra abdominal procedures designed for weight loss at screening
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3.
4. History of myocardial infarction within 2 years of screening
5.
6.
7.
8.
9. Diet attempts using herbal supplements or over-the-counter medications within 90 days 
before screening
10. Participation in an organized weight reduction program (e.g. WeightWatchers, 
NutriSystem) or any investigational weight loss trial within 6 months before screening
11.
12.
13.
14.
15.
16.
17.
18.
19.
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20.
21.
22.
23.
24.
25.
26.
27.
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28.
PARTICIPANTS WITH T2DM
29.
30.
31.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering, prescribing/dispensing, and taking study treatment are 
outlined in the Pharmacy Manual.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug 
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
MBL949 10 
mg/mL
Solution for 
injection
Subcutaneous 
Use
Open label; bulk 
supplies
Sponsor (global)
Placebo 0 mg/mL
Solution for 
injection
Subcutaneous 
Use
Open label; bulk 
supplies
Sponsor (global)
The investigational drug, MBL949 10 mg/mL and placebo, will be prepared by Novartis and 
supplied to the Investigator as an open labeled medication to be dispensed by the unblinded 
pharmacist or designated staff at the investigator site according to the randomization schedule. 
Study medication will be administered by an unblinded staff at the site.
MBL949 drug product is formulated for subcutaneous injection as 10 mg/mL liquid in vial. 
Details of the dose administration can be found in the Pharmacy Manual.
Each vial of MBL949 contains 10 mg of drug product formulated as a solution for injection. 
In addition to the active substance, each vial contains the following excipients: 
 
 A 20% overfill is provided to allow the 
withdrawal of the designated amount of 10 mg/mL MBL949 upon administration.
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MBL949 10 mg solution for injection is packaged in glass vials with coated rubber stoppers 
sealed with aluminum caps with plastic flip-off disks, which are in common use for packaging 
of parenteral products.  
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Participants will be assigned to one of five arms in this study; MBL949 dosing arms 1-5 and 
placebo arm. MBL949 Arm 1, MBL949 arm 2 and placebo to be enrolled in a 1:1:1 ratio in 
each randomization stratum. MBL949 arm 3 and MBL949 arm 4 and placebo will be enrolled 
in a 1:1:1 ratio in each randomization stratum. If triggered, MBL949 dosing arm 5 will be 
randomized in a 2:1 ratio of MBL949 or placebo. Refer to Section 3 for study design in 
Figure 3-1 and enrollment flow Figure 3-2.
Study treatments are defined as:

Once every other week SC injection of MBL949 mg, for dosing details refer to Section 4.2

Once every other week SC injection of Placebo 0 mg
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
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already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.
Medications allowed in the study as chronic therapy:

Oral anti-diabetic therapy (limited to metformin and/or DPP4 inhibitor or acarbose), with 
stable treatment for 90 days prior to randomization, for diabetes management during the 
trial.

Treatment with SGLT2i (permitted if first line agent)
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed per the prohibition period 
below.
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
Over the counter anti-obesity 
medications, nutritional 
supplements, dietary 
interventions particularly 
chromium picolinate and 
sodium vanadate (other than 
described in protocol) or over 
the counter products of weight 
loss
Within 90 days prior to 
randomization and through 
duration of study
Discontinue study treatment
Prescription anti obesity agents 
and GLP1 receptor agonists 
such as (e.g., semaglutide, 
exenatide, liraglutide, 
lixisenitide, albiglutide, 
dulaglutide) Refer to 
Section 5.2
Sulfonylureas or 
thiazolidinediones
Insulin
Within 6 months prior to 
randomization and through 
duration of study
Discontinue study treatment
6.2.3
Restriction for study participants
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section.
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6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6.3.2
Treatment assignment, randomization
Randomization for this study will be managed by Novartis Interactive Response Technology 
(IRT). The randomization numbers will be generated using the following procedure to ensure 
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that treatment assignment is unbiased and concealed from participants and investigator staff. 
A participant randomization list will be produced by the IRT provider, or by a delegate under 
Novartis supervision, using a validated system that automates the random assignment of 
participant numbers to randomization numbers. These randomization numbers are linked to the 
different treatment arms.
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This is a participant-and investigator-blinded, sponsor open-label study. Participants and 
investigators will remain blinded to study treatment throughout the study, except where 
indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
With the exception of any unblinded site staff listed below, all site staff (including study 
investigator, study nurse, 
) will be blinded to study treatment throughout the study.

Designated unblinded site staff,
 for dose administration: required due to 
the range of different dose levels and to maintain the investigator and site staff blinding.

Unblinded pharmacist who is independent of the study team will be required in order to
manage drug product supplied in bulk and prepare doses.
This unblinded pharmacist will receive a randomization assignments via IRT. Appropriate
measures must be taken by the unblinded pharmacist to ensure that the treatment
assignments are concealed from the rest of the site staff, with the exception of the
designated unblinded site staff who will administer the dose.
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via the IRT system.
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

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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 participants. The unblinded monitors will also be able to 
review the treatment allocation cards/randomization list provided to the unblinded pharmacist. 
The names of the unblinded monitor(s) are detailed in the monitoring plan.
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 study statistician will be able to access the randomization list at any time throughout the 
study and is allowed to share unblinded information with the rest of the clinical team including 
an unblinded study lead and Trial Medical Expert as appropriate for internal decision purposes, 
as outlined in Table 6-3.
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 6-3
Blinding levels
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
dose escalation
Subjects/Patients
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
UI
UI
UI
All other sponsor staff not 
identified above
B
UI
UI
UI
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B Remains blinded
UI Allowed to be unblinded on individual patient level
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments or modifications are not permitted. 
6.6
Additional treatment guidance
6.6.1
Treatment compliance
MBL949 will be administered by clinical personnel at the site 
 under delegation 
of the Investigator following the procedures outlined in the Pharmacy manual. 
6.6.2
Recommended treatment of adverse events
This is the first study of MBL949 in obese participants with or without T2DM receiving repeat 
doses of MBL949, therefore, careful management of potential adverse events is essential. 
 All medications required or recommended to manage adverse events 
associated with study drug should be recorded. Medication used to treat AEs must be recorded 
on the Concomitant medications/Significant non-drug therapies CRF.
Management of injection site reactions
If a participant experiences mild injection site discomfort, the Investigator may attempt 
applying a cold compress.
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Management of hypoglycemia
1. In participants on anti-diabetic medication, the investigator should monitor glucose levels
closely by recommending frequent blood glucose monitoring as per standard diabetes care
guidelines.
2. If symptomatic hypoglycemia occurs:

The investigator should provide standard of care to maintain glucose balance. This
may involve reducing or discontinuing anti-diabetic medication.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Blinding codes may also be broken after a participant discontinues treatment 
due to unmanageable adverse events if deemed necessary by the site PI and Sponsor. Most often, 
study treatment discontinuation and knowledge of the possible treatment assignments are 
sufficient to treat a study participant who presents with an emergency condition. Emergency 
treatment code breaks are performed using the IRT. When the investigator contacts the system 
to break a treatment code for a participant, he/she must provide the requested participant 
identifying information and confirm the necessity to break the treatment code for the participant. 
The investigator will then receive details of the investigational drug treatment for the specified 
participant and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team 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 IRT at any time in case of emergency. The investigator will provide:

protocol number

participant number
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In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1). MBL949 will be administered to the participant via 
subcutaneous injection. Refer to the Pharmacy Manual for further details.
A unique medication number is printed on the study medication label.
Unblinded investigator staff will identify the treatment to dispense to the participant by 
contacting the IRT and obtaining the treatment assignment. As per the treatment assigned to the 
participant, unblinded investigator staff will select the study treatment to dispense to the 
participant and record the batch number on the accountability logs accordingly.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance.
Study treatment must be prepared by an unblinded pharmacist to ensure treatment masking. 
Please refer to the Pharmacy Manual for complete preparation instructions.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. If study treatment is 
administered off site, the unblinded OHP study personnel will be asked to return all unused 
study treatment and packaging at the end of the study or at the time of discontinuation of study 
treatment.
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site.

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6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
MBL949 or placebo will be administered to the participant via subcutaneous injection at the 
site 
. Please refer to the Pharmacy Manual 
for detailed instructions.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (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 participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed 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 
participant informed consent and should be discussed with the participant 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 participant.
The following informed consents are included in this study:
Main study consent, which also includes:



As applicable, Pregnancy Outcomes Reporting Consent for female participants or the
female partners of any male participants who took study treatment

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 requirements.
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Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
A copy of the approved version of all consent forms used at each site must be provided to 
Novartis after IRB/IEC approval.
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
8
Visit schedule and assessments
The Assessment Schedule Table 8-1 lists all of the assessments when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
Table 8-1 or as close to the designated day/time as possible as per described visit window. 
Missed or rescheduled visits should not lead to automatic discontinuation. Participants who 
discontinue from study treatment are to return for an end of treatment (EoT) visit (Day 99), as 
soon as possible and if able, attend the follow up visits on days 100, 103, 108, 112, 140 and 
169 week visits for safety.
Participants who discontinue from the study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time the assessments listed for the final visit should be performed. At this 
final visit the adverse event and concomitant medications not previously report must be 
recorded on the CRF.
If unable to complete the final visit, the participant will be asked to have the following 
assessments performed. See details on study discontinuation in Section 9.1.1

Physical exam

ECG
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
Vitals

Weight

Safety labs
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The "S" in the table denotes the assessments that are only in the 
participant's source documentation and do not need to be recorded in the clinical database.
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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening Baseline Day 
1
Day 
22
Day 
52
Day 
72
Day 
102
Day 
15 / 
Week 
22
Day 
29 / 
Week 
42
Day 
43 / 
Week 
62
Day 
57 / 
Week 
82
Day 
71 / 
Week 
102
Day 85 
/ Week 
122
Day 
99/Week 
142
Day 
1002
Day 
1032
Day 
1052
Day 
1082
Day 
112/Week 
162
Day 
140/Week 
202
Day 
169/Week 
24/ EOS2
Visit Numbers1
1
20
100
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
1999
Days
-35 to -15
-14 to -1
1
2
5
7
10
15
29
43
57
±1
71
85
99
100
103
105
108
112
±1
140
169
Time (post-dose)
-
-
-
24h
±2
96h
±2
144h
±2
216h
±2
-
-
-
-
-
-
-
24h
±2
96h
±2
144 
h
±2 
216h
±2
312h
±2
984h ±6
1680 ±6
Informed consent
X
Inclusion / 
Exclusion criteria
X
X
X3
IRT 
X
X
Demography
X
Alcohol Test and 
Drug Screen 
S
HIV screen
S
Hepatitis screen
S
COVID-19 testing4
S
As required per COVID-19 at the site and per local regulations
Psychological 
evaluation
X
X
X
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Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening Baseline Day 
1
Day 
22
Day 
52
Day 
72
Day 
102
Day 
15 / 
Week 
22
Day 
29 / 
Week 
42
Day 
43 / 
Week 
62
Day 
57 / 
Week 
82
Day 
71 / 
Week 
102
Day 85 
/ Week 
122
Day 
99/Week 
142
Day 
1002
Day 
1032
Day 
1052
Day 
1082
Day 
112/Week 
162
Day 
140/Week 
202
Day 
169/Week 
24/ EOS2
Visit Numbers1
1
20
100
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
1999
Days
-35 to -15
-14 to -1
1
2
5
7
10
15
29
43
57
±1
71
85
99
100
103
105
108
112
±1
140
169
Time (post-dose)
-
-
-
24h
±2
96h
±2
144h
±2
216h
±2
-
-
-
-
-
-
-
24h
±2
96h
±2
144 
h
±2 
216h
±2
312h
±2
984h ±6
1680 ±6
Pregnancy and 
assessments of 
fertility
S
S
S
S
S
S
Medical 
history/current 
medical conditions
X
As Required
Concomitant 
therapies
X
As Required
Physical 
Examination
S5
S
S
S
S
S
S
Body Height
X
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
Electrocardiogram 
(ECG)
X
X
X
X
X
X
X
X
Hematology
X
X
X6
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X6
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
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Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening Baseline Day 
1
Day 
22
Day 
52
Day 
72
Day 
102
Day 
15 / 
Week 
22
Day 
29 / 
Week 
42
Day 
43 / 
Week 
62
Day 
57 / 
Week 
82
Day 
71 / 
Week 
102
Day 85 
/ Week 
122
Day 
99/Week 
142
Day 
1002
Day 
1032
Day 
1052
Day 
1082
Day 
112/Week 
162
Day 
140/Week 
202
Day 
169/Week 
24/ EOS2
Visit Numbers1
1
20
100
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
1999
Days
-35 to -15
-14 to -1
1
2
5
7
10
15
29
43
57
±1
71
85
99
100
103
105
108
112
±1
140
169
Time (post-dose)
-
-
-
24h
±2
96h
±2
144h
±2
216h
±2
-
-
-
-
-
-
-
24h
±2
96h
±2
144 
h
±2 
216h
±2
312h
±2
984h ±6
1680 ±6
Study drug 
administration
X
X
X
X
X
X
X
X
HbA1C
X
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Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening Baseline Day 
1
Day 
22
Day 
52
Day 
72
Day 
102
Day 
15 / 
Week 
22
Day 
29 / 
Week 
42
Day 
43 / 
Week 
62
Day 
57 / 
Week 
82
Day 
71 / 
Week 
102
Day 85 
/ Week 
122
Day 
99/Week 
142
Day 
1002
Day 
1032
Day 
1052
Day 
1082
Day 
112/Week 
162
Day 
140/Week 
202
Day 
169/Week 
24/ EOS2
Visit Numbers1
1
20
100
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
1999
Days
-35 to -15
-14 to -1
1
2
5
7
10
15
29
43
57
±1
71
85
99
100
103
105
108
112
±1
140
169
Time (post-dose)
-
-
-
24h
±2
96h
±2
144h
±2
216h
±2
-
-
-
-
-
-
-
24h
±2
96h
±2
144 
h
±2 
216h
±2
312h
±2
984h ±6
1680 ±6
Adverse Events
As Required
Study completion 
information
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2
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Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening Baseline Day 
1
Day 
22
Day 
52
Day 
72
Day 
102
Day 
15 / 
Week 
22
Day 
29 / 
Week 
42
Day 
43 / 
Week 
62
Day 
57 / 
Week 
82
Day 
71 / 
Week 
102
Day 85 
/ Week 
122
Day 
99/Week 
142
Day 
1002
Day 
1032
Day 
1052
Day 
1082
Day 
112/Week 
162
Day 
140/Week 
202
Day 
169/Week 
24/ EOS2
Visit Numbers1
1
20
100
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
1999
Days
-35 to -15
-14 to -1
1
2
5
7
10
15
29
43
57
±1
71
85
99
100
103
105
108
112
±1
140
169
Time (post-dose)
-
-
-
24h
±2
96h
±2
144h
±2
216h
±2
-
-
-
-
-
-
-
24h
±2
96h
±2
144 
h
±2 
216h
±2
312h
±2
984h ±6
1680 ±6
3 Final review of all eligibility criteria prior to dosing
4 As required per COVID-19 protocols at the site and local regulations
5 Complete Physical examination to be done. All other PEs will be abbreviated.
6 To be collected pre dose
7
8
9
10
11
12
13
14
15 To be administered fasting, before lunch, before dinner, and before bedtime 
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8.1
Screening
Screening
It is permissible to re-screen a participant if s/he fails the initial screening and reason for screen 
fail is reasonably expected to have resolved; however, each case must be discussed and agreed 
with the Sponsor on a case-by-case basis.
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the exclusion criteria, the assessment may be repeated once prior to randomization. If the 
repeat value remains outside of the specified ranges, the participant must be excluded from the 
study.
8.1.1
Eligibility screening
8.1.1.1
Diagnosis of T2DM at Screening
If diagnosed with diabetes at screening, enrolling in the study versus receiving medical care 
from participant’s healthcare provider should be discussed (see Section 4.5.11).
8.1.1.2
Hepatitis screen, HIV screen
All participants will be screened for Hepatitis B surface antigen (HBsAg) and, if standard local 
practice, Hepatitis B core antigen (HBcAg). Screening for Hepatitis C will be based in HCV 
antibodies and if positive, HCV RNA levels should be determined.
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site e.g. Western blot. Appropriate counseling will be made 
available by the Investigator in the event of a positive confirmatory test. Notification of state 
and federal authorities, as required by law, will be the responsibility of the Investigator.
8.1.1.3
COVID-19
COVID-19 testing and frequency of testing in this study will follow the local guidance and 
COVID-19 protocols according to the study site and/or OHP.
COVID-19 vaccination (single dose vaccine or two dose vaccine) is recommended prior to 
enrollment and at least 2 weeks before dosing and evidence of minimal side effects. 
At screening unvaccinated individuals will be encouraged to receive a COVID vaccine. 
Vaccination during the trial is permitted and careful review of potential side effects of 
vaccination that may include nausea and vomiting that may mimic AEs will require 
documentation. Novartis has adopted for this reason the MHRA guidelines last updated on 
16th March 2021 on how to manage clinical trials during Coronavirus pandemic which includes 
recommendations on risk assessment and reporting of an SAE in relation to the vaccine during 
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8.1.1.4
Alcohol test, Drug screen
Participants will be tested for substances of abuse (e.g. alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine and opiates).
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information and informed 
consent pages must also be completed for screen failure participants. No other data will be 
entered into the clinical database for participants who are screen failures, unless the participant 
experienced a serious adverse event during the screening phase (see SAE Section 10.1.2 for 
reporting details). If the participant fails to be randomized, the IRT must be notified within 
2 days of the screen fail that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form.
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Participant demographics: date or year of birth (if permitted, sex, race, predominant ethnicity 
(if permitted) and relevant medical history/current medical conditions (until date of signature 
of informed consent) will be recorded in the eCRF. Where possible, the diagnosis and not 
symptoms should be recorded. Participant race/ethnicity data are collected and analyzed to 
identify any differences in the safety and/or efficacy profile of the treatment due to these 
characteristics. In addition, we need to assess the diversity of the study population as required 
by Health Authorities.
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the protocol Section 6.2.1 Concomitant Therapy 
for further details on what information must be recorded on the appropriate page of the eCRF.
8.3
Efficacy
Efficacy will be assessed by changes in 
weight from Baseline and Day 112. 
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8.3.1
Appropriateness of efficacy assessments
This repeat dose study will 
expand our understanding of the effect on weight, 
in obese participants with our without T2DM over a 14 week treatment 
period followed, a two week evaluation. Additional evaluations for safety will be monitored for 
10 weeks after the last dose. 
8.3.2
Body weight and central obesity
Weight
Weight will be measured to the nearest 0.1 kg at visits indicated in the Assessment Schedule 
Table 8-1 on a calibrated scale per site specific standards. The measurement will be performed 
with the study participant dressed in light clothing or hospital gown and without shoes. 
Participants must void prior to having their weight measured.
Height
Height will be measured in centimeters without shoes.
Body mass index (BMI)
Body mass index (BMI) will be calculated using the following formula:
BMI = weight (kg) / [Height (m)]2
Rounding should be done to the nearest whole number.
The Screening Visit height measurement will be used for BMI calculation.
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8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.1.
Table 8-2
Safety Assessments
Assessment
Specification
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, vascular, and neurological. If 
indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and 
pelvic exams may be performed.
A short physical exam will include the 
examination of general appearance and vital 
signs (blood pressure [SBP and DBP] and 
pulse). A short physical exam will be performed 
at all visits starting from visit 3 except where a 
complete physical examination is required (see 
above).
Information for all physical examinations must 
be included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be recorded on the appropriate CRF that 
captures medical history. Significant findings 
made after signing informed consent which 
meet the definition of an Adverse Event must be 
recorded as an adverse event.
Vital signs
Vital signs will include the collection of body 
temperature (recorded in °C), blood pressure 
(BP) and pulse measurements.
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Assessment
Specification
After the participant has been sitting for 
approximately 3 minutes, with back supported 
and both feet placed on the floor, systolic and 
diastolic BP will be measured using an 
automated validated device, e.g. OMRON with 
an appropriately sized cuff. In case the cuff 
sizes available are not large enough for the 
participant's arm circumference, a 
sphygmomanometer with an appropriately sized 
cuff may be used. 
If vital signs are out-of-range at screening (see 
Inclusion Criteria Section 5.1 of the protocol for 
details), two additional readings can be 
obtained, so that up to three consecutive 
assessments can be made, with the participant 
seated quietly for approximately five minutes 
preceding each repeat assessment. The last 
reading must be within the ranges provided in 
the eligibility criteria in order for the participant to 
qualify.
Efforts should be made to allow for a quiet, 
relaxed environment for the participants to have 
vital sign measurements taken to avoid the 
"white coat syndrome".
In case of repeated vital assessments, the 
eCRF should contain the qualifying results.
Clinically notable vital signs are defined in 
Section 16.1of the protocol.
Psychological Evaluation
Assessment of mental health will be conducted 
by the Investigator or qualified health 
professional to determine the participant's ability 
to participate in the study at Screening and as 
specified on the Assessment Schedule.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all safety specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the central laboratory manual.
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant.
Clinically notable laboratory findings are defined in Section 16.1 (Appendix 1). Clinically 
significant abnormalities must be recorded as either medical history/current medical conditions 
or adverse events as appropriate.

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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.
Table 8-3
Laboratory evaluations
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets,  White blood cells, 
Red blood cells
Chemistry
Albumin, Alkaline phosphatase, ALT , AST , Gamma-
glutamyl-transferase (GGT), Lactate dehydrogenase 
(LDH), Bicarbonate, Calcium, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatine kinase, Direct Bilirubin, Indirect 
Bilirubin, Total Bilirubin, Total Cholesterol, LDL, HDL, 
Total Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose 
(non-fasting unless specified otherwise)
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, 
Protein, Specific Gravity, Urobilinogen)
Coagulation
International normalized ratio [INR]), Partial 
thromboplastin time (PTT)
Hepatitis markers
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR 
(baseline)
Pregnancy Test
Serum (refer to Pregnancy and assessments of 
fertility Section 10.1.4)
8.4.2
Electrocardiogram (ECG)
ECGs must be recorded approximately after 10 minutes rest in the supine position to ensure a 
stable baseline. In the case of a series of assessments, ECG should be first assessment obtained 
while participant is at rest.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
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 according to the following 
formula:
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Single 12-lead ECGs are collected and results are entered into the appropriate eCRF page. The 
original ECGs on on non-heat-sensitive paper, appropriately signed, must be collected and 
archived at the study site.
Each ECG tracing must be labeled with study number, participant initials, participant number, 
date and time, and filed in the study site source documents. Investigator should document 
clinical evaluation in source. For any ECGs with participant safety concerns, two additional 
ECGs must be performed to confirm the safety finding. Clinically significant ECG findings at 
baseline must be discussed with the sponsor before administration of study treatment.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are capable of becoming pregnant and not surgically sterile 
will have regular pregnancy testing. Serum pregnancy testing will be done at Screening, on Day 
1 prior to the first dose, every month while in study, and at the end of the study. Additional 
pregnancy testing might be performed if requested by local requirements.
If participants cannot visit the site to have serum pregnancy tests during a Public Health 
emergency as declared by Local or Regional authorities, i.e., pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. Refer to Section 4.7.
It is important that participants are instructed to perform the urine pregnancy test first and only 
if the rest result is negative proceed with administration of the study treatment. 
A communication process should be established with the participant so that the site is informed 
and can verify the pregnancy test results (e.g., follow country-specific measures).
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.

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8.4.5
Injection/infusion site reaction
Any local tolerability symptoms/signs related to injection will be reported as adverse events 
and followed until resolution.
8.5
Additional assessments
No additional tests will be performed on participants entered into this study.
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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the participant or the investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment 
Section 6.2.2

Any situation in which study participation might result in a safety risk to the participant

If a liver or renal event occurs, follow guidelines outlined in Section 16 regarding 
discontinuation of study treatment.

Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, 
fever, chills, urticaria, dyspnea, headache, myalgia, hypotension

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study

Emergence of any medical or psychological issue in which in the PI assessment of the 
participant leads to the conclusion now has a risk of participating

Following emergency unblinding
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If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.2). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, and letter) should 
be made to contact the participant/pre-designated contact as specified in the lost to follow-up 
Section 9.1.3. This contact should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
9.1.2
Discontinuation from study
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason is not done.
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table refer to Section 8.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development

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In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. 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 participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Withdrawal of informed consent/Opposition to use 
data/biological samples
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore,
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.
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 participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment Table 8-1.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.3
Study stopping rules
Overall study stopping rules
Enrollment in the study will be placed on hold if any of the following occurs:

Two or more drug related-SAEs identified after Safety Review;

Two or more participants experience hypersensitivity reactions or injection reactions of 
moderate to severe intensity;

The Sponsor considers that the number and/or severity of AEs, abnormal safety 
monitoring tests, or abnormal laboratory findings justify putting the study on hold.

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
The Sponsor unilaterally requests it.
If any of the above stopping rules are met, the Competent Authorities and Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) will be informed of the temporary halt of 
study in accordance with local regulations. The study may resume following the safety review 
if the Sponsor and Lead Investigator agree it is safe to proceed and after approval to restart the 
study is obtained from the Competent Authorities and IRB/IECs.
9.4
Study completion and post-study treatment
Study completion is defined as when the last participant finishes 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 (e.g., each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them). All attempts to contact 
the participant should be met.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded by the Investigator/site staff under the signs, symptoms, or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

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2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e., progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
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 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose increased/Dose reduced

Drug interrupted/withdrawn
6. Its outcome (recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued until the end of study visit.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must 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 participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
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10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant 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 (please refer to the ICH-E2D Guidelines).

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 obesity-associated disorders 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

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

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
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 participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” 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 (please refer to the 
ICH-E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.

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10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the last study visit must be reported to Novartis safety 
within 24 hours of learning of its occurrence. Detailed instructions regarding the submission 
process and requirements are to be found in the investigator folder provided to each site.
1. Screen Failures: SAEs occurring after the participant has provided informed consent until 
the time the participant is deemed a Screen Failure must be reported to Novartis.
2. Treated Participants: SAEs collected between time participant signs ICF after the last 
study visit must be reported to Novartis safety within 24 hours of learning of its 
occurrence.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
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 CMO & PS 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.
Any SAEs experienced after the last study visit should only be reported to Novartis Safety if 
the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant 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.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the [study treatment] any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.

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After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
10.1.5
Reporting of study treatment 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, participant 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.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
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 the 
respective sections.
10.2
Additional Safety Monitoring
Not applicable.
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11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (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.
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Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDC or 
eCRFs) 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 field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & 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 participant 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 
participant's file.  The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.

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12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
The safety analysis set will include all participants that received any study drug.
The full analysis set (FAS) will include all randomized participants.
12.2
Participant demographics and other baseline characteristics
Baseline will be defined as the last non-missing assessment prior to the first dose of study drug, 
unless specified otherwise.
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for safety analysis set. Categorical data will be 
presented as frequencies and percentages. For continuous data, mean, standard deviation, 
median, minimum, and maximum will be presented. Relevant medical histories and current 
medical conditions at baseline will be summarized by system organ class and preferred term, by 
treatment group.
12.3
Treatments
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group for the FAS.
12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary objectives of the study include assessing the efficacy of MBL949 in reducing 
weight and evaluating its safety and tolerability.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary endpoint for efficacy is change-from-baseline in weight at week 16. Baseline 
weight is defined as the last weight measurement before dosing. Primary endpoints for safety 
and tolerability are occurrences and severities of adverse events.
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12.4.2
Statistical model, hypothesis, and method of analysis
12.4.3
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants having treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of treatment but 
increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, and other significant adverse events leading to discontinuation.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time.
12-lead ECG
PR, QRS, QT, QTcF, RR intervals and HR will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted locally.
Abnormal ECG, especially HR, will be flagged and listed by treatment group, participant and 
visit/time. Summary statistics of all ECG data will be provided by treatment and visit/time. 
Categorical analyses of QT/QTc, PR, QRS, QRS, RR intervals and HR data based on the 
number of participants meeting or exceeding predefined limits, in terms of absolute values or 
changes from baseline, will be presented. In addition, a listing of these participants will be 
produced by treatment group.
Clinical laboratory evaluations
If normal ranges are available, abnormal laboratory data will be flagged and listed by treatment 
group, participant, and visit/time. Summary statistics of select laboratory parameters will be 
provided by treatment group and visit/time. 
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12.4.5
Handling of missing values not related to intercurrent event
All participants with a baseline weight and at least one post-baseline weight measurement will 
be included in the primary analysis. 
 
 
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12.4.6
Sensitivity analyses for primary endpoint/estimand
12.4.7
Supplementary analysis
12.4.8
Supportive analyses
To evaluate the effect of intercurrent events on efficacy/safety results, primary analysis may be 
performed on FAS including/excluding some intercurrent events cases described in 
Section 12.4.4 as seen fit.
12.5
Analysis of secondary endpoints/estimands
None.
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12.6
Analysis of exploratory endpoints
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12.7
Interim analyses
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
At final analysis, MBL949 arms 1, 2, and 3 (if not terminated early) will each have 
12 participants, and the placebo arm will have at least 24 participants who complete week 16 
weight assessment. Therefore, MBL949 efficacy group will have a sample size of either 24 or 
36. Conservatively assuming that the efficacy group and placebo arm each has 24 participants, 
the power for efficacy criteria is still 95%.
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At final analysis, if MBL949 arm 5 has been triggered and completed, the weight change of this 
arm will be compared to MBL949 efficacy group.
Weight change in MBL949 arm 4 will be compared against placebo arm and MBL949 efficacy 
group, respectively. Assuming that the true weight change in MBL949 arm 4 is -2kg, there is 
at least a 77% probability of declaring MBL949 arm 4 having more weight loss than placebo, 
and at least a 99% probability of declaring MBL949 efficacy group having more weight loss 
than MBL949 arm 4, given sample sizes of 12, ≥ 24, and ≥24 in MBL949 arm 4, MBL949 
efficacy group, and placebo arm, respectively, where type I error rate is 0.1.
13
Ethical considerations and administrative procedures
13.1
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 CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
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, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
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posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13.5
Participant Engagement
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis.

Thank You letter

Plain language trial summary - after CSR publication
14
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 participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
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.

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14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for participant safety 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 participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
References
References are available upon request
Casadevall N, Nataf J, Viron B, et al (2002) Pure red-cell aplasia and antierythropoietin 
antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med; 
346(7):469-75.
DeFronzo RA, Ferrannini E, Groop L, et al (2015) Type 2 diabetes mellitus. Nat Rev Dis 
Primers; p. 15019.
Department of Health and Human Services and U.S Department of Agriculture (2015) 
2015-2020 Dietary Guidelines for Americans. 8th Edition; December 2015.
Emmerson PJ, Wang F, Du Y, et al (2017) The metabolic effects of GDF15 are mediated by 
the orphan receptor GFRAL. Nat Med; p. 1215-1219.
Fairlie WD, Moore AG, Bauskin AR, et al (1999) MIC-1 is a novel TGF-beta superfamily 
cytokine associated with macrophage activation. J Leukoc Biol; p. 2-5.
Fejzo MS, Sazonova OV, Sathirapongsasuti JF, et al (2018) Placenta and appetite genes 
GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nat Commun; 9(1):1178 p. 
1178.
Gadde KM, Martin CK, Berthoud HR, et al (2018) Obesity: Pathophysiology 
and Management. J Am Coll Cardiol; p. 69-84.
Hsu JY, Crawley S, Chen M, et al (2017) Non-homeostatic body weight regulation through a 
brainstem-restricted receptor for GDF15. Nature; p. 255-259.
Jarvis S, Nelson-Piercy C (2011) Management of nausea and vomiting in pregnancy. BMJ; p. 
3342:d3606.
Khera R, Murad MH, Chandar AK, et al (2016) Association of Pharmacological Treatments 
for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. 
JAMA; p. 2424-34.
Kirk E, Reeds DN, Finck BN, et al (2009) Dietary fat and carbohydrates differentially alter 
insulin sensitivity during caloric restriction. Gastroenterology; p. 1552-60.
Lean MEJ, Leslie WS, Barnes AC, et al (2019) Durability of a primary care-led weight-
management intervention for remission of type 2 diabetes: 2-year results of the DiRECT 
open-label, cluster-randomised trial. Lancet Diabetes Endocrinol; p. 344-355.
Moore AG, Brown DA, Fairlie WD, et al (2000) The transforming growth factor-ss 
superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in 
the serum of pregnant women. J. Clin. Endocrinol. Metab; 85(12):4781-8.
Mullican SE, Lin-Schmidt X, Chin CN, et al (2017) GFRAL is the receptor for GDF15 and 
the ligand promotes weight loss in mice and nonhuman primates. Nat Med; p. 1150-1157.
Narayan KM, Boyle JP, Thompson TJ, et al (2007) Effect of BMI on lifetime risk for diabetes 
in the U.S. Diabetes Care; p. 1562-6.

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O’Rahilly (2017) GDF15-From Biomarker to Allostatic Hormone; 26(6):807-808.
Petersen KF, Dufour S, Befroy D, et al (2005) Reversal of nonalcoholic hepatic steatosis, 
hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with 
type 2 diabetes. Diabetes; p. 603-8.
Petry CJ, Ong KK, Burling KA, et al (2018) Associations of vomiting and antiemetic use in 
pregnancy with levels of circulating GDF15 early in the second trimester: A nested case 
control study. p. Wellcome Open Res; 3:123.
Tsai VW, Lin S, Brown DA, et al (2016) Anorexia-cachexia and obesity treatment may be 
two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15. Int J Obes 
(Lond); p. 193-7.
Tsai VW, Manandhar R, et al (2014) "The anorectic actions of the TGFbeta cytokine MIC-
1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract." p. 9(6).
Wing RR, Lang W, Wadden TA, et al (2011) Benefits of modest weight loss in improving 
cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes 
Care; p. 1481-6.
Yang L, Chang CC, Sun Z, et al (2017) GFRAL is the receptor for GDF15 and is required for 
the anti-obesity effects of the ligand. Nat Med; p. 1158-1166.
Zhang C, Zhang J, Liu Z, et al (2018) More than an Anti-diabetic Bariatric Surgery, 
Metabolic Surgery Alleviates Systemic and Local Inflammation in Obesity. Obes Surg; p. 
3658-3668.
Le Roux CW, Heneghan HM (2018) Bariatric Surgery for Obesity. Med Clin North Am; p. 
165-182.

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Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Clinically notable values for vital signs are as follows:

Any significant increase or decrease in vital signs beyond inclusion/exclusion criteria:

Systolic blood pressure less than 95 mgHg or greater than 155 mgHg

Diastolic blood pressure less than60 or greater than 95 mgHg

Pulse rate less than 56 or greater than 110 bpm
If these clinically notable vital signs are observed, investigators should initiate appropriate, 
guideline directed clinical care and inform the Sponsor.

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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
 
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal at 
baseline:

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known 
bone pathology)

Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent 
term)

ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a 
liver toxicity*
If ALT or AST abnormal at baseline:

ALT or AST > 2x baseline or > 300 U/L 
(whichever occurs first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: 
upper limit of normal
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms 
 
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
 
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
Normal
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL
None

No change 
to study 
treatment

Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours.

Follow-up for 
symptoms.

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ALT
TBL
Liver Symptoms
Action
If normal at 
baseline:
ALT > 5 x ULN 
for more than two 
weeks
 
If elevated at 
baseline:
ALT > 3 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst) for 
more than two 
weeks
Normal
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL
None
 
If normal at 
baseline:
ALT > 8 x ULN
Normal
None
ALT increase with bilirubin increase:
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
TBL > 2 x ULN 
(or INR > 1.5)
For patients with 
Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin
None
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
Normal or 
elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain

Interrupt 
study drug

Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours.

Follow-up for 
symptoms.

Initiate close 
monitoring 
and workup 
for competing 
etiologies.

Study drug 
can be 
restarted only 
if another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline.

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Table 16-3
Follow up requirements for liver laboratory triggers 
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
 
 
>1.5 – 3.0 ULN

Maintain treatment

Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome)

Interrupt treatment

Repeat LFT within 48-72 
hours

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 10 x ULN

Discontinue the study 
treatment immediately

Hospitalize the participant

Establish causality

Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in 
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.

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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
Specific Renal Alert Criteria and Actions
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase ≥ 50%+ OR if <18 
years old, eGFR < 35 mL/min/1.73 m2

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 patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥ 3+ OR Protein-
creatinine ratio (PCR) ≥ 1g/g Cr (or mg/mmol 
equivalent as converted by the measuring 
laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset hematuria ≥ 3+ on urine dipstick
Assess & document:

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury

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16.3.1
Renal Event Follow-Up
Table 16-5
Renal Event Follow-Up
Assess, document and record in CRF:

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
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
Monitor patient regularly (frequency at investigator’s discretion) until - 

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or proteincreatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.

Analysis of urine markers in samples collected over the course of the DIN event