Conditions: Obesity
Keywords: Obesity disease Over weight T2DM interventional study Weight loss
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 126
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the efficacy, tolerability and safety of LIK066 to support dose selection for Phase 3 development in Japanese adults with obesity disease.

Detailed description:

Arms:
arm 1: Eligible patients randomized to this arm will receive LIK066 2.5 mg orally daily for 12 weeks. arm 2: Eligible patients randomized to this arm will receive LIK066 10 mg orally daily for 12 weeks. arm 3: Eligible patients randomized to this arm will receive LIK066 25 mg orally daily for 12 weeks. arm 4: Eligible patients randomized to this arm will receive LIK066 50 mg orally daily for 12 weeks. arm 5: Eligible patient randomized to this arm will receive LIK066 matching placebo orally daily for 12 weeks.

Interventions: intervention 1: LIK066 intervention 2: Placebo
Intervention descriptions: intervention 1: LIK066 will be supplied in different doses as tablets to be taken orally daily. intervention 2: Placebo will be supplied as tablets to be taken daily orally.

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine
LIK066
Clinical Trial Protocol CLIK066B1201 / NCT03320941
A randomized, double-blind, dose-finding study to evaluate 
the change in weight after 12 weeks treatment with 4 doses 
of LIK066 compared to placebo in Japanese patients with 
obesity disease
Document type:
Clinical Trial Protocol
Version number:
01 (clean)
Clinical trial phase:
IIb
Release date:
30-Oct-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 1 ...........................................................................................................................12
Protocol summary..............................................................................................................14
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................17
2
Study objectives and endpoints .........................................................................................18
2.1
Objectives and related endpoints...........................................................................18
3
Investigational plan ...........................................................................................................19
3.1
Study design...........................................................................................................19
3.1.1
Epoch 2 (run-in)....................................................................................19
3.1.2
Epoch 3 (treatment)...............................................................................20
3.2
Rationale for study design .....................................................................................21
21
3.4
Rationale for choice of comparator .......................................................................22
3.5
Purpose and timing of interim analyses/design adaptations..................................22
3.6
Risks and benefits..................................................................................................23
4
Population..........................................................................................................................24
4.1
Inclusion criteria ....................................................................................................24
4.2
Exclusion criteria...................................................................................................25
5
Treatment...........................................................................................................................28
5.1
Study treatment......................................................................................................28
5.1.1
Investigational and control drugs..........................................................28
5.1.2
Additional treatment..............................................................................28
5.2
Treatment arms......................................................................................................28
5.3
Treatment assignment and randomization.............................................................28
5.4
Treatment blinding.................................................................................................29
5.5
Treating the patient................................................................................................29
5.5.1
Patient numbering .................................................................................29
5.5.2
Dispensing the study drug.....................................................................30
5.5.3
Handling of study and additional treatment..........................................30


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5.5.4
Instructions for prescribing and taking study treatment........................31
5.5.5
Permitted dose adjustments and interruptions of study treatment ........31
5.5.6
Rescue medication ................................................................................31
5.5.7
Concomitant medication .......................................................................32
5.5.8
Prohibited medication ...........................................................................32
5.5.9
Emergency breaking of assigned treatment code..................................33
5.6
Study completion and discontinuation...................................................................33
5.6.1
Study completion and post-study treatment..........................................33
5.6.2
Discontinuation of study treatment .......................................................34
5.6.3
Withdrawal of informed consent...........................................................35
5.6.4
Loss to follow-up ..................................................................................35
5.6.5
Early study termination by the sponsor.................................................35
6
Visit schedule and assessments .........................................................................................36
6.1
Information to be collected on screening failures..................................................40
6.2
Patient demographics/other baseline characteristics .............................................40
6.3
Treatment exposure and compliance .....................................................................40
6.4
Efficacy..................................................................................................................40
6.4.1
Weight...................................................................................................40
6.4.2
Waist circumference..............................................................................41
6.4.3
HbA1c ...................................................................................................41
6.4.4
FPG .......................................................................................................41
6.4.5
BP..........................................................................................................41
6.4.6
Fasting lipid profile & inflammation biomarkers .................................42
6.4.7
Uric acid................................................................................................42
6.4.8
Urine albumin and Urine albumin to creatinine ratio ...........................42
6.4.9
VFA and SFA........................................................................................42
6.4.10
Appropriateness of efficacy assessments..............................................42
6.5
Safety.....................................................................................................................42
6.5.1
Physical examination ............................................................................42
6.5.2
Vital signs..............................................................................................43
6.5.3
Laboratory evaluations..........................................................................43
6.5.4
Electrocardiogram (ECG) .....................................................................44
6.5.5
Pregnancy and assessments of fertility .................................................44
6.5.6
Appropriateness of safety measurements..............................................44
6.6
Other assessments..................................................................................................45
45
6.6.2
Resource utilization...............................................................................45


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6.6.3
Pharmacokinetics ..................................................................................45
7
Safety monitoring..............................................................................................................46
7.1
Adverse events.......................................................................................................46
7.2
Serious adverse events...........................................................................................47
7.2.1
Definition of SAE .................................................................................47
7.2.2
SAE reporting........................................................................................48
7.3
Liver safety monitoring .........................................................................................49
7.4
Renal safety monitoring.........................................................................................50
7.5
Reporting of study treatment errors including misuse/abuse ................................50
7.6
Pregnancy reporting...............................................................................................51
7.7
Prospective suicidality assessment ........................................................................51
7.8
AEs of special interest ...........................................................................................51
7.8.1
Ketoacidosis ..........................................................................................51
7.8.2
Hypoglycemia .......................................................................................51
8
Data review and database management.............................................................................52
8.1
Site monitoring ......................................................................................................52
8.2
Data collection.......................................................................................................53
8.3
Database management and quality control............................................................53
8.4
Data Monitoring Committee..................................................................................54
8.5
Adjudication Committee........................................................................................54
9
Data analysis......................................................................................................................54
9.1
Analysis sets ..........................................................................................................54
9.2
Patient demographics and other baseline characteristics.......................................55
9.3
Treatments .............................................................................................................55
9.4
Analysis of the primary variable(s) .......................................................................56
9.4.1
Primary Variable(s)...............................................................................56
9.4.2
Statistical model, hypothesis, and method of analysis..........................56
9.4.3
Handling of missing values/censoring/discontinuations.......................58
9.4.4
Sensitivity analyses ...............................................................................58
9.5
Analysis of secondary variables ............................................................................58
9.5.1
Efficacy variables..................................................................................58
9.5.2
Safety variables .....................................................................................60
9.5.3
Resource utilization...............................................................................61
9.5.4
Pharmacokinetics ..................................................................................61
9.5.5
DNA......................................................................................................61
61
61


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9.7
Interim analyses.....................................................................................................62
9.8
Sample size calculation..........................................................................................62
10 Ethical considerations........................................................................................................63
10.1
Regulatory and ethical compliance........................................................................63
10.2
Informed consent procedures.................................................................................63
10.3
Responsibilities of the investigator and IRB/IEC..................................................63
10.4
Publication of study protocol and results...............................................................64
10.5
Quality Control and Quality Assurance.................................................................64
11 Protocol adherence ............................................................................................................64
11.1
Protocol amendments.............................................................................................64
12 References .........................................................................................................................65
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................66
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................67
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................69
List of tables
Table 2-1
Objectives and related endpoints ..........................................................18
Table 5-1
Rescue criteria for FPG (subjects with T2DM) ....................................32
Table 6-1
Assessment schedule.............................................................................37
Table 6-2
Fasting lipid profile, TG & inflammation biomarkers..........................42
Table 6-3
Hematology evaluations........................................................................43
Table 6-4
Clinical chemistry .................................................................................43
Table 6-5
Urinalysis ..............................................................................................44
44
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................51
Table 9-1
Power for detecting a significant dose response signal*.......................62
Table 13-1
Vital signs notable range deviations .....................................................66
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................67
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...67
Table 15-1
Specific Renal Alert Criteria and Actions.............................................69


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List of figures
Figure 3-1
Study design..........................................................................................21
Figure 9-1
Dose-response curve of candidate models ............................................57


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List of abbreviations
ACEi
angiotensin-converting enzyme inhibitor
ACR
albumin creatinine ratio
AE
Adverse Event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARB
angiotensin receptor blocker
AST
aspartate aminotransferase
AUC
area under the curve
BL
baseline
BMI
body mass index
BP
blood pressure
β-hCG
β-human chorionic gonadotropin
CFR
US Code of Federal Regulations
CPO
country pharma organization
CRF
Case Report/Record Form (paper or electronic)
CT
computer tomography
CYP3A
cytochrome P450 3A4
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl peptidase -4
ECG
electrocardiogram
ED50
effective dose 50
EDC
Electronic Data Capture
eGFR
estimated glomerular filtration rate
ENR
enrolled set
eSource
electronic source
EU
European Union
FAS
full analysis set
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GI
gastro-intestinal
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
hsCRP
high sensitive C-reactive protein
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization


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IEC
Independent Ethics Committee
IN
investigator notification
INR
international normalization ratio
IRB
Institutional Review Board
LDL
low density lipoprotein
LFT
liver function test
LS
least squares
MAR
missing at random
MDRD
modified diet in renal disease
MedDRA
Medical dictionary for regulatory activities
NIRT
Novartis Interactive Response Technology
NOAEL
no-observed-averse-effect-level
NOEL
no-observed-effect-level
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
OC/RDC
Oracle Clinical/Remote Data Capture
OGTT
oral glucose tolerance test
PCR
protein creatinine ratio
PK
pharmacokinetics
PPS
per-protocol set
PT
prothrombin time
qd
quaque die (once a day)
RAN
randomized set
SAE
Serious Adverse Event
SAF
safety set
SBP
systolic blood pressure
SBW
standard body weight
SD
standard deviation
SFA
subcutaneous fat area
SGLT1
sodium-glucose co-transporter 1
SGLT2
sodium-glucose co-transporter 2
SUSAR
Suspected Unexpected Serious Adverse Reactions
SU
sulfonylurea
T2DM
type 2 diabetes mellitus
TD
study treatment discontinuation
TG
triglycerides
TSH
thyroid stimulating hormone
UGE
urinary glucose excretion
UGT
uridine-5'-diphosphoglucoronosyltransferase
ULN
upper limit of normal
UTI
urinary tract infection
VFA
visceral fat area
VLDL
very low density lipoprotein


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WBC
white blood cell
WHO
World Health Organization


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Glossary of terms
Dosage
Dose of the study treatment given to the patient 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.
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures described 
in the protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits.
eSource 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.
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Subject ID
A unique number assigned to each patient upon signing the informed 
consent
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Rescue medication
Rescue medication is medication that can be used to treat those
subjects with type 2 diabetes mellitus (T2DM) whose glycemic control is
deteriorating. In this protocol a dipeptidyl-peptidase-4 (DPP-4) inhibitor
or insulin should be used as rescue medication.
Run-in period
In this study, the run-in period is Epoch 2, where subjects who were
successfully screened will receive placebo medication.
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.
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study


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Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
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Amendment 1
Amendment rationale
The protocol is being amended to provide information related to a new risk recently identified
from data of the SGLT-2 inhibitor canagliflozin where more cases of lower limb amputations
(mainly of the toe) have been observed in the canagliflozin group compared to the placebo
group. No lower limb amputations have been seen in LIK066 studies, but this risk may
constitute a possible class-effect. Patients with a history of lower limb amputation will be
excluded from enrollment into the study.
As a precautionary measure, patients with any history of ketoacidosis, lactic acidosis, or
hyperosmolar coma will be excluded from enrollment into the study as well.
Furthermore, some minor changes and corrections of inconsistencies and typographical errors
have been done.
Changes to the protocol
Protocol summary and Section 3.1 have been amended regarding the duration of Epoch 1 and 
Epoch 2, as these epochs are now approximately 2 and 4 weeks respectively.
Section 3.6 has been updated to add a newly identified risk (lower limb amputation) observed
with the SGLT-2 inhibitor canagliflozin and preventive measures are provided; this was also
updated in other sections of the protocol (e.g. Section 6.5.1).
The exclusion criterion on ketoacidosis, lactic acidosis or hyperosmolar coma in Protocol 
summary and Section 4.2 was amended to also exclude any history of the condition. 
Furthermore, a typo was corrected in this section with regards to the units for hemoglobin, 
and in addition history of lower limb amputation was added to the exclusion criteria as a 
precautionary measure.
In Section 5.5.2 overlapping sentence was deleted.
In Section 5.5.4 package was corrected.
Section 5.5.5 was changed to clarify that dose adjustments are not permitted but that 
interruptions can be done for safety reasons.
In Section 5.6.2 lower limb amputation was added as a condition when study treatment has to
be discontinued.
In Table 6-1 some minor typographical corrections were made.
In Section 6.4.1 Subjects must be in underwear or use a hospital gown when their weight is 
being assessed.
In Section 6.4.4 the definition of overnight fast was updated.
In Section 6.4.5 the use of alternative blood pressure devices is now allowed if an automated
device cannot be used (for instance when the cuff on the automated device is too small for the
subject’s arm).


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Section 7.8.2 was improved and clarifications were provided.
In Section 8.3 some minor processes were corrected.
In Section 9 some minor typographical corrections were made.
In Section 10.5 the old name of the audit department was updated to the new name (Global
Development Quality Audit).
In Section 12 new references have been added.
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are substantial and require IRB/IEC approval
prior to implementation.


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Protocol summary
Protocol number
CLIK066B1201
Full Title
A randomized, double-blind, dose-finding study to evaluate the change in 
weight after 12 weeks treatment with 4 doses of LIK066 compared to 
placebo in Japanese patients with obesity disease
Brief title
A dose-finding study to evaluate the change in weight after treatment with 
LIK066 compared to placebo in Japanese patients with obesity disease.
Sponsor and Clinical 
Phase
Novartis 
Phase 2b
Investigation type
Drug
Study type
Interventional
Purpose and rationale
To evaluate the efficacy, tolerability and safety of LIK066 to support dose 
selection for Phase 3 development in Japanese adults with obesity 
disease.
Primary Objective(s)
To examine the dose-response relationship of LIK066 as measured by 
percent change from baseline (BL) in body weight relative to placebo after 
12 weeks of treatment
Secondary Objectives

To assess the responder rates according to percent decrease in body 
weight either ≥3%, ≥5% or ≥10%, from BL at Week 12, for the overall 
population and each of the subgroups [dysglycemic subjects and 
subjects with type 2 diabetes mellitus (T2DM)]

To assess the dose-response relationship for weight loss in 
dysglycemic subjects and subjects with T2DM after 12 weeks of 
treatment

To evaluate the effect of all LIK066 doses vs placebo for the overall 
population and by subgroups (dysglycemic subjects and subjects with 
T2DM) after 12 weeks of treatment on:

Waist circumference at umbilical level

Hemoglobin A1c (HbA1c)

Fasting plasma glucose (FPG)

Systolic blood pressure (SBP) and diastolic blood pressure (DBP)

Fasting lipid profile and high sensitivity C-reactive protein (hsCRP)

Uric acid

Urine albumin and urine albumin to creatinine ratio

Visceral fat area (VFA) and subcutaneous fat area (SFA) by
computer tomography (CT)

To evaluate safety (adverse events (AEs) and laboratory parameters) 
and tolerability of LIK066 over 12 weeks of treatment

To evaluate the pharmacokinetics (PK) of LIK066
Study design
This is a multi-center, randomized, double-blind, parallel-group dose-
finding study evaluating the effect on weight, tolerability and safety of 4
doses of LIK066 vs placebo.
Following a screening visit (Visit 1) and a screening period of 
approximately 2 weeks (Epoch 1), subjects meeting all eligibility criteria 
will enter the run-in Epoch 2 at Visit 101.
Population
130 female and male patients with obesity disease ≥20 and ≤75 years 
old.


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Key Inclusion criteria

Male and female, age 20 to 75 years old, both inclusive

Patients with obesity disease and inadequately controlled body weight 
with diet and/or exercise

Body mass index (BMI) ≥25 kg/m2 combined with at least two 
obesity-related comorbidities

BMI ≥35 kg/m2 at least one obesity-related comorbidity

Waist circumference at umbilical level ≥85 cm for male, ≥90 cm for 
female

Visceral fat area ≥100 cm2

Agreement to comply with the study-required life-style intervention and 
treatment during the full duration of the study
Key Exclusion criteria

Use of pharmacologically active weight-loss medications, glucagon-like 
peptide-1 (GLP-1) agonists or sodium-glucose co-transporter 2 
(SGLT2) inhibitors, within 3 months of screening, or between screening 
and randomization.

Use of alpha glucosidase inhibitors within 3 months of Visit 1, or 
between screening and randomization.

Bariatric surgery

Lack of compliance with lifestyle intervention (defined as weight gain 
during run-in (Epoch 2)) or with study medication (defined as < 80%
study drug intake during Epoch 2), assessed at randomization.

History of ketoacidosis, lactic acidosis, or hyperosmolar coma, or any 
of these occurring between Visit 1 and Visit 199/201 (randomization).

Symptomatic genital infection or urinary tract infection (UTI) in the 4 
weeks prior to screening, or screening and randomization.

Gastro-intestinal (GI) disorders associated with chronic diarrhea.

Congestive heart failure, New York Heart Association (NYHA) class III 
or IV.
Study treatment

LIK066

Placebo
Efficacy assessments

Body weight

Waist circumference

HbA1c

FPG

Blood pressure

Fasting lipid profile and hsCRP

Uric acid

Urine albumin and urine albumin to creatinine ratio

Visceral fat area and subcutaneous fat area
Key safety 
assessments

Physical examinations

Vital signs

Monitoring of laboratory markers in blood and urine

Electrocardiogram

AE monitoring

Liver & renal safety monitoring


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Other assessments

PK (trough)
Data analysis
The primary analysis of this study aims to detect a dose response signal 
for the percentage reduction in body weight after 12 weeks treatment 
using data from all doses (including placebo) to model the dose-response 
curve and to provide sufficient information to choose the doses for the 
further development of the drug.
Hence, the following null and alternative hypotheses will be tested:

H0: There is no dose-response relationship for LIK066 (i.e. the dose 
response relationship is flat).

H1: There is a dose-response relationship for LIK066 (i.e. as dose 
increases, the percent weight decreases).
The Multiple Comparison Procedure-Modeling methodology will be used to 
analyze the primary endpoint of percent change from BL in body weight at 
Week 12, in order to test these dose-response hypotheses and determine 
the dose-response relationship.
A set of the dose-response candidate models were defined. In order to 
preserve the family-wise error rate at one-sided significance level of 2.5%, 
the optimal contrasts derived from the model candidate set will be 
individually compared to the critical value derived using a multiplicity 
adjustment that accounts for all tests of comparing LIK066 doses to 
placebo simultaneously. The rejection of the null hypothesis will be 
achieved using the maximum test statistic from each estimated contrast 
test in the candidate set.
The analysis to derive the test statistics is based on an analysis of 
covariance (ANCOVA) model with the percent change in body weight from 
BL to Week 12 as a response variable, treatment (placebo and all LIK066 
doses) and stratification factor (dysglycemic or T2DM) as factors and BL 
weight as a covariate.
Model averaging approach will be used to estimate the dose-response.
The primary analysis will be conducted on the full analysis set (FAS). 
Missing values of body weight at Week 12 will be imputed using the 
multiple imputation approach under a missing at random (MAR) 
assumption.
Key words
Obesity disease, T2DM, interventional study, weight loss


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1
Introduction
1.1
Background
Obesity represents a rapidly growing threat to the health of populations worldwide. Obesity 
raises the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes mellitus (T2DM), 
coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory 
problems, and some cancers. Obesity is also associated with increased risk in all-cause and 
cardiovascular disease mortality. The biomedical, psychosocial, and economic consequences 
of obesity have substantial implications for the health and well-being of the person with 
obesity (AACE 2016). Similar to Western countries, obesity remains an unmet medical need 
in Asian countries including Japan with increasing numbers of obese patients in recent years. 
Although obesity is less severe as assessed by body mass index (BMI) in Japan than Western 
countries, the prevalence of several obesity related diseases is comparable due to 
accumulation of visceral fat and/or fatty organ dysfunction. Based on that, obesity disease is 
defined as BMI ≥25 kg/m2 with comorbidities in the guidelines in Japan.
Diet and exercise therapies have been shown to be useful in producing clinically relevant, but 
modest weight loss leading to amelioration of comorbid medical problems. However clinical 
challenges remain with the magnitude of weight reduction (at least ≥3%) and the 
maintenance of the achieved weight loss by behavior modification. Weight loss medication is 
recommended for obese patients who are inadequately controlled with diet and exercise 
therapies, but the only drugs available in Japan are mazindol (only approved for severely 
obese patients with BMI ≥35 kg/m2) or the recently approved cetilistat. Weight loss drugs
also have limitations for long term use due to central nervous system adverse effects. 
Therefore, there is a substantial opportunity and real need to develop weight loss medicines 
which will be more effective and better tolerated.
LIK066 is an inhibitor of the sodium-glucose co-transporter-1 (SGLT1) and sodium-glucose 
co-transporter-2 (SGLT2). The
dual mechanism (renal and intestinal) to reduce 
re-absorption/absorption of glucose leads to loss of calories (calorie-loss enhancer). It also has 
the potential to reduce food intake via central mechanisms mediated by an increase in incretin 
hormones (glucagon-like peptide-1 (GLP-1) and peptide YY). 
 
 
 
The current study is designed to evaluate the efficacy, tolerability and safety of a dose-range 
of LIK066 as part of a development program for the use of LIK066 in adults with obese 
disease.
1.2
Purpose
The purpose of the study is to evaluate the efficacy, tolerability and safety of LIK066 to 
support dose selection for Phase 3 development in Japanese adults with obesity disease.


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2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To examine the dose-response relationship of 
LIK066 (2.5 mg qd, 10 mg qd, 25 mg qd and 
50 mg qd) as measured by percent change 
from baseline (BL) in body weight relative to
placebo after 12 weeks of treatment
Endpoint(s) for primary objective(s)

Percent change from BL in body weight at 
Week 12
Secondary Objective(s)

To assess the responder rates according to 
percent decrease in body weight either ≥3%, 
≥5% or ≥ 10%, from BL at Week 12, for the 
overall population and each of the subgroups 
(dysglycemic subjects and subjects with 
T2DM).
Endpoint(s) for secondary objective(s)

Responder rates according to percent change 
in body weight ≥3%, ≥5%, ≥10% from BL at 
Week 12 (see Section 9.5.1)

To assess the dose-response relationship for 
weight loss in dysglycemic subjects and 
subjects with T2DM after 12 weeks of 
treatment.

Dose response relationship for weight loss
among subgroups (dysglycemic, T2DM) at 
Week 12 (see Section 9.5.1)

To evaluate the effect of all LIK066 doses vs
placebo for the overall population and by 
subgroups (dysglycemic subjects and subjects 
with T2DM) after 12 weeks of treatment.
Change from baseline at Week 12 on (see 
Section 9.5.1):

Waist circumference at umbilical level

Hemoglobin A1c (HbA1c)

Fasting plasma glucose (FPG)

Systolic blood pressure (SBP) and diastolic 
blood pressure (DBP)

Fasting lipid profile and high sensitivity 
C-reactive protein (hsCRP)

Uric acid

Urine albumin and urine albumin to creatinine 
ratio

Visceral fat area (VFA) and subcutaneous fat 
area (SFA) by computer tomography (CT)

To evaluate safety (adverse events (AEs) and 
laboratory parameters) and tolerability of 
LIK066 over 12 weeks of treatment.

AEs including events of special interest

Laboratory parameters

Vital sign

Electrocardiogram (ECG) (see Section 9.5.2)

To evaluate the pharmacokinetics (PK) of 
LIK066

PK (trough) (see Section 6.6.3 and 
Section 9.5.4).


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3
Investigational plan
3.1
Study design
This is a multi-center, randomized, double-blind, parallel-group dose-finding study evaluating 
the effect on weight, tolerability and safety of 4 doses of LIK066 vs placebo (see Figure 3-1 & 
Section 5.2). Following a screening visit (Visit 1) and a screening period of approximately
2 weeks (Epoch 1), subjects meeting all eligibility criteria will enter the run-in Epoch 2 at 
Visit 101.
3.1.1
Epoch 2 (run-in)
Subjects meeting the eligibility criteria defined in Section 4 will enter the placebo run-in 
(Epoch 2). During the approximately 4 weeks duration of Epoch 2, subjects will receive the 
placebo run-in medication as described in Section 5.1.
At Visit 101, the subject's volume status must be assessed (see Section 6.5.1) and 
hypovolemia must be corrected during the run-in in the elderly, in subjects with low SBP, or 
if on diuretics, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor 
blockers (ARBs).
At the start of Visit 101, all subjects will receive the following advice for lifestyle intervention 
(Japan Society for the Study of Obesity 2016):

Subjects with BMI ranging from ≥25 to < 35 kg/m2 will be advised to follow a 
'25 × standard body weight (SBW)' kcal/day; subjects with BMI ≥35 kg/m2 will be 
advised to follow a '20 × SBW' to '25 × SBW' kcal/day diet. Consumption of 50 to 60% 
kcal from carbohydrate, 15 to 20% kcal from protein and 20 to 25% kcal from fat will be 
recommended.
Standard body weight (kg) = height (m)2 × 22

Subjects will be advised to gradually increase their physical activity to reach a goal of 
more than 150 min of moderate intensity physical activity per week, preferably distributed 
over the week.
Compliance with the lifestyle intervention shall be reviewed and re-enforced at every study 
visit.
Subjects with T2DM
Subjects with T2DM will continue their usual treatment, except for subjects taking 
sulfonylurea (SU) or insulin. These subjects may be at an increased risk of hypoglycemia due 
to the combination of the SU or insulin and weight loss, with or without consequent treatment 
with LIK066 in Epoch 3. Therefore:


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
The dose of SUs for subjects with T2DM (see Section 3.1.2 & Section 5.3) using such 
medication (either as monotherapy or in combination with other oral anti-diabetic drugs 
(OADs)) may be reduced by up to 50%, or as close to 50% as possible based on dose 
options available locally, along with following thresholds; glimepiride > 2 mg/day to 
≤2 mg/day, glibenclamide > 1.25 mg/day to ≤1.25 mg/day and gliclazide > 40 mg/day to 
≤40 mg/day. In case of persistent deterioration in glycemic control, the concomitant 
background OAD should be initially escalated to the maximal approved dose, followed by 
addition of rescue medication when required (see Section 5.5.6). To limit the number of 
subjects with early deterioration of glycemic control who would meet the FPG rescue 
criteria early after randomization (see Section 5.5.6), an FPG randomization criterion is 
included in Section 4.2.

For subjects on insulin, initial dose reduction of the total daily insulin dose by 10% or 
more may be considered at investigator's discretion based on subject's total daily dose and 
glycemic control. In case of deterioration in glycemic control, insulin can be up-titrated 
(see Section 5.5.6).
3.1.2
Epoch 3 (treatment)
After the run-in Epoch 2, eligible subjects will be randomized in the ratio of 2:2:3:3:3 to one 
of the following regimes at Visit 201 (randomization):

2.5 mg qd LIK066

10 mg qd LIK066

25 mg qd LIK066

50 mg qd LIK066

Placebo.
At Visit 201, subjects will be randomized simultaneously to one of the five Epoch 3 treatment 
schedules.
At randomization, subjects will be stratified according to their glycemic status at screening 
using the following criteria (see also Section 5.3):

Dysglycemic: no prior clinical diagnosis of T2DM, FPG ≥110 mg/dL and/or
HbA1c ≥5.6% , except for HbA1c ≥6.5% and FPG ≥126 mg/dL at Visit 1 (screening).

T2DM: prior diagnosis of T2DM, or subjects without prior diagnosis of T2DM with 
HbA1c ≥6.5% and FPG ≥126 mg/dL at Visit 1 (screening).
Following randomization, subjects will attend study visits in Epoch 3 (12 weeks) for 
assessment of efficacy, tolerability and safety parameters as defined in Table 6-1. During 
Epoch 3, subjects will take the study medication as described in Section 5.5.4.
The doses of antidiabetic and antihypertensive medications should be adjusted in patients who, 
according to the investigator, could be at a safety risk (e.g. repetitive or severe hypoglycemia, 
symptoms and signs of volume depletion, etc.).


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Figure 3-1
Study design
QD: once daily, W: week, V: visit
3.2
Rationale for study design
The study is designed as a standard placebo-controlled, parallel-group study to obtain efficacy, 
tolerability and safety data in an unbiased fashion and detect signals of the dose-response 
characteristics of the investigated drug. A single-blind placebo run-in period is included to 
facilitate the implementation of lifestyle measures, as well as assess the compliance with 
study treatment. Twelve weeks of treatment in Epoch 3 are considered sufficient to reach sub-
maximal or maximal weight loss, and also provide LIK066 safety and tolerability, with
collection of trough PK samples in all subjects (see Section 6.6.3). In addition, visceral fat 
area (VFA) and subcutaneous fat area (SFA) measurement by CT scan will be performed to 
enable characterization of the efficacy of LIK066 in the studied population.


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3.4
Rationale for choice of comparator
A placebo group is a standard comparator in Phase 2 studies and is included to account for 
study effect and the lifestyle interventions described in Section 3.1.1.
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.


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3.6
Risks and benefits
The risk to subjects in this study will be minimized by compliance with the eligibility criteria 
and study procedures, and close clinical monitoring.
Publications on SGLT2 inhibition in subjects with T2DM treated with selective SGLT2 
inhibitors reported higher incidences of urinary tract infections (UTIs) and genital mycotic 
infections compared with placebo (Bailey et al 2010, Nauck et al 2011, Nyirjesy et al 2012). 


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SGLT2 inhibition may result in hypotension in elderly subjects, in subjects with low blood 
systolic pressure, or if on diuretics, ACEi, or ARB. Patients with T2DM treated with 
antidiabetic agents, especially with sulphonylurea or insulin, may be at an increased risk of 
hypoglycemia, which can be more pronounced with significant weight loss. In rare cases 
treatment 
with 
SGLT2 
inhibitors 
may 
be 
complicated 
by 
ketoacidosis
(Rosenstock and Ferrannini 2015). 
 
 
 
 
 
 
 
 
Hematology and biochemistry tests will be monitored at each study visit after randomization 
and study drug can be discontinued for clinically significant laboratory change or abnormality 
as per investigator's judgment. Detailed criteria for follow-up in case of a liver event are 
defined in Section 7.3 and Appendix 2. To prevent UTIs and genital infections, subjects will 
be instructed to pay attention to genital hygiene and have appropriate hydration. If UTI and/or 
genital infections occur, treatment will be initiated as appropriate at the investigator's
discretion.
Benefits to participation in the study may include weight reduction and, potentially, 
improvement in some cardio-metabolic markers such as blood pressure (BP), lipids or blood 
glucose.
4
Population
The study population will consist of male and female subjects. Approximately 130 subjects 
will be randomized. A screening failure rate of about 30% is expected, hence about 190
subjects will be screened.
4.1
Inclusion criteria
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female, age 20 to 75 years old, both inclusive at Visit 1
3. Patients with obesity disease and inadequately controlled body weight with diet and/or 
exercise for three months prior to Visit 1

BMI ≥25 kg/m2 combined with at least two obesity-related comorbidities* at Visit 1 
and 201

BMI ≥35 kg/m2 at least one obesity-related comorbidity at Visit 1 and 201
*Obesity-related comorbidities are (Japan Society for the Study of Obesity 2016);

Glucose tolerance impaired (T2DM, impaired glucose tolerance etc.)

Dyslipidemia


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
Hypertension

Hyperuricemia and gout

Coronary artery disease: myocardial infarction and angina pectoris

Cerebral infarction: cerebral thrombosis and transient ischemic attack

Nonalcoholic fatty liver disease

Abnormality in menstruation and infertility

Obstructive sleep apnea syndrome and obesity-hypoventilation syndrome

Locomotive diseases: Osteoarthritis (knee, hip) and Spinal osteoarthritis, Finger 
osteoarthritis

Obesity related glomerulopathy
4. Patients with FPG ≥110 mg/dL and/or 5.6% ≤HbA1c ≤10.0%, or T2DM with HbA1c
≤10.0% at Visit 1
5. Waist circumference at umbilical level ≥85 cm for male, ≥90 cm for female at Visit 1
6. Visceral fat area ≥100 cm2 at Visit 102.
7. Agreement to comply with the study-required life-style intervention and treatment during
the full duration of the study
4.2
Exclusion criteria
Patients/subjects fulfilling any of the following criteria are not eligible for inclusion in this 
study. No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients/subjects.
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, 
whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
3.
History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients/subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree atrio-ventricular block 
without a pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
4.
Patients/subjects taking medications prohibited by the protocol (see Section 5.5.8)
5.
History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases.
6.
Pregnant or nursing (lactating) women
7.
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception


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
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 m prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps*). For United Kingdom: with spermicidal 
foam*/gel*/film*/cream*/ vaginal suppository*

Use of oral, (estrogen and progesterone), injected* or implanted* hormonal methods 
of contraception or other forms of hormonal contraception that have comparable 
efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal 
hormone contraception* or placement of an intrauterine device or intrauterine system.
*: not approved in Japan, approved methods should be used.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF

Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential.
8. Use of pharmacologically active weight-loss medications, GLP-1 agonists or SGLT2 
inhibitors, within 3 months of Visit 1, or between Visit 1 and Visit 199/201 
(randomization).
9. Use of alpha glucosidase inhibitors within 3 months of Visit 1, or between Visit 1 and 
Visit 199/201 (randomization).
10. Bariatric surgery.
11. Lack of compliance with lifestyle intervention (defined as weight gain during Epoch 2) or 
with study medication (defined as < 80% study drug intake during Epoch 2), assessed at 
Visit 199/201 (randomization).
12. History of ketoacidosis, lactic acidosis, or hyperosmolar coma, or any of these occurring 
between Visit 1 and Visit 199/201 (randomization).
13. Symptomatic genital infection or UTI in the 4 weeks prior to Visit 1, or between Visit 1 
and Visit 199/201 (randomization).
14. GI disorders associated with chronic diarrhea.
15. Congestive heart failure, New York Hart Association (NYHA) class III or IV.
16. Myocardial infarction, stroke, surgery for heart disease, percutaneous coronary 
intervention in the 6 months prior to Visit 199/201 (randomization).


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17. Unstable angina within 3 months of Visit 1, or between Visit 1 and Visit 199/201 
(randomization).
18. Acute or chronic liver disease (except liver steatosis), such as hepatitis, cirrhosis or portal 
hypertension at Visit 1 or Visit 199/201 (randomization).
19. History of hepatitis B or C, or Hepatitis A or B vaccination in the last 3 months prior to 
Visit 1, or between Visit 1 and Visit 199/201 (randomization).
20. Active substance abuse, alcohol abuse (as defined by consumption of more than 24 
alcohol units per week) or history of alcohol-related disease within the past 2 years.
21. Chronic treatment with medication which has a hepatotoxic potential.
22. Chronic use of anti-retroviral therapies.
23. Chronic use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (eg clarithromycin, 
telithromycin, itraconazole, ketoconazole, voriconazole or posaconazole) or chronic use of 
strong uridine-5'-diphosphoglucoronosyltransferase (UGT) inhibitors (eg probenecid, 
valproic acid or mefenamic acid).
24. Concurrent medical conditions that may interfere with the interpretation of efficacy and 
safety data.
25. Clinically significant thyroid stimulating hormone (TSH) outside of the normal range at 
Visit 1.
26. For subjects treated with SUs or insulin, self-measured FPG > 13.3 mM (240 mg/dL) on 2 
occasions within one week of Visit 199/201 (randomization).
27. Estimated glomerular filtration rate (eGFR, calculated via the modified diet in renal 
disease (MDRD) formula) < 60 mL/min/1.73 m2 at Visit 1.
28. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) more than two-fold 
above upper limit of normal (ULN) (> 2 × ULN), or total bilirubin/direct 
bilirubin > 1.5 × ULN) at Visit 1, confirmed by repeat measurement within 5 working 
days of the respective visit.
29. Hemoglobin < 12 g/dL in men, < 11 g/dL in women at Visit 1 (screening).
30. Platelet count < 100 000/µL and/or white blood cell (WBC) count < 4000/µL at Visit 1 
(screening).
31. Hematuria determined by dipstick measurement at Visit 1 (screening).
32. Elevated fasting triglycerides (TGs) > 5.6 mM (500 mg/dL), at Visit 1 (screening), 
confirmed by repeat measurement within 3 working days of the respective visit.
33. Clinically significant laboratory abnormalities which, in the opinion of the investigator, 
cause the subject to be considered inappropriate for inclusion in the study.
34. History of lower limb amputation (including toe amputation), or if occurring between
Visit 1 and Visit 201 (randomization).


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5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Epoch 2 (placebo run-in)
The sponsor will provide the following single-blind study medication for Epoch 2:

LIK066 matching placebo tablets
All subjects will take 1 tablet in the morning. The medication will be prepared for the placebo 
run-in in kits.
Epoch 3 (treatment)
The sponsor will provide the following double-blind study medication for Epoch 3:

LIK066 2.5 mg tablets

LIK066 10 mg tablets

LIK066 25 mg tablets

LIK066 50 mg tablets

LIK066 matching placebo tablets
For each treatment arm (see Section 5.2), subjects will receive one of the tablets described 
above. All subjects will take 1 tablet in the morning.
5.1.2
Additional treatment
No additional treatment beyond investigational drug and placebo are included in this trial.
5.2
Treatment arms
All subjects entering Epoch 2 (run-in) will receive placebo.
At Visit 201 (randomization), subjects eligible for randomization will be assigned 2:2:3:3:3 to 
one of the following treatment arms in Epoch 3 (see Section 3.1.2):

2.5 mg qd LIK066 (approx. 20 subjects)

10 mg qd LIK066 (approx. 20 subjects)

25 mg qd LIK066 (approx. 30 subjects)

50 mg qd LIK066 (approx. 30 subjects)

Placebo (approx. 30 subjects)
5.3
Treatment assignment and randomization
At Visit 201, all eligible patients/subjects will be randomized via Novartis Interactive 
Response Technology (NIRT) to one of the treatment arms for Epoch 3. The investigator or 
his/her delegate will contact the NIRT after confirming that the patient fulfills all the 


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inclusion/exclusion criteria. The NIRT will assign a randomization number to the patient, 
which will be used to link the patient to a treatment arm and will specify a unique medication 
number for the first package of study drug to be dispensed to the patient. The randomization 
number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. 
A patient randomization list will be produced by a vendor using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
Randomization will be stratified into (see Section 3.1.2):

Dysglycemic

T2DM
Efforts will be made by close monitoring of the enrollment through the NIRT system to 
ensure each of the two stratification sub-groups with at least 45% of total subjects enrolled in 
the study.
The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Randomization Group.
5.4
Treatment blinding
Patient/subjects, investigator staff and persons performing the assessments will remain blind 
to the identity of the treatment from the time of randomization until database lock, using the 
following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone else involved in the study with the following 
exceptions: the randomization codes associated with patients/subjects from whom PK samples 
are taken will be disclosed to PK analysts who will keep PK results confidential until data 
base lock. (2) the identity of the treatments will be concealed by the use of study drug that are 
all identical in packaging, labeling, schedule of administration, appearance, taste and odor.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.


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Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the NIRT and provide the 
requested identifying information for the patient to register them into the NIRT. The site must 
select the CRF book with a matching Subject Number from the EDC system to enter data.
If for any reasons the patient fails to be treated with study medication after randomization, the 
NIRT must be notified within 2 days that the patient was not treated. The reason for not being 
treated will be entered on the Run-in epoch Study Disposition CRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.
At Visit 101, investigator staff will identify the study drug package(s) for run-in placebo to 
dispense to the patient by contacting the NIRT and obtaining the medication number(s).
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the five treatment arms (see Section 5.2). 
Immediately before dispensing the package to the patient, investigator staff will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient's unique subject number.
5.5.3
Handling of study and additional treatment
5.5.3.1
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 
designees 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 CPO 
Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient 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. Patients/subjects will 
be asked to return all unused study treatment and packaging at each study visit and where 
applicable, at the time of discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, 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.
5.5.3.2
Handling of additional treatment
Not applicable.


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5.5.4
Instructions for prescribing and taking study treatment
All kits of study treatment assigned by the NIRT will be recorded/databased in the NIRT.
The investigator should ensure that the subject clearly understands the dosing instructions 
outlined below.

At Visit 101 (Epoch 2), each subject will be dispensed study drug containing blisters with 
study medication. The blisters are constructed to easily deliver the daily required number 
of tablets for the morning dose. The kits contain sufficient medication for the run-in period 
of up to 4 weeks until Visit 199/201.

From Visit 201 till Visit 299 (Epoch 3), subjects will be dispensed study drug containing 
blisters with study medication. The blisters are constructed to easily deliver the daily 
required number of tablets for the morning dose. The kits contain sufficient medication for 
the time between each visit according to Table 6-1.
In Epoch 2 and Epoch 3, subjects will be instructed to take 1 tablet LIK066 (or matching 
placebo) in the morning, immediately before the meal. Study drug should be taken the same 
time throughout the study.
No study drug should be taken on the morning of a study visit; subjects with T2DM should 
not take their anti-diabetic treatment. Subjects should arrive in the fasting state; ie no food or 
drinks (except water) for a minimum of 8h before the scheduled visit. If the subject has not 
fasted for an adequate period of time, the collection of fasting laboratory evaluations must be 
rescheduled. The study drug regimen (and, if applicable, rescue medication as defined in 
Section 5.5.6) should not be taken prior to obtaining the fasting laboratory test samples.
If a dose is missed and the subject realizes this within 4h, the study drugs should be taken 
otherwise the subject should take the next scheduled dose.
Previously dispensed study medication blisters, including any remaining study medication, 
must be returned to the study center at each study visit.
All prescribed dosages and all dose changes during the study must be recorded on the 
appropriate study drug Dosage Administration Record eCRF(s). All kits of study treatment 
assigned by the NIRT will be recorded/databased in the NIRT. The investigator must promote 
compliance by instructing the patient to take the study treatment exactly as prescribed and by 
stating that compliance is necessary for the patient's safety and the validity of the study. The 
patient must also be instructed to contact the investigator if he/she is unable for any reason to 
take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments are not permitted. Dose interruptions are not permitted unless for 
safety reasons (see Section 7.1).
5.5.6
Rescue medication
During Epoch 3, rescue medication may be used in addition to ongoing study medication for 
those subjects with T2DM whose glycemic control is deteriorating. The subject must come in 
for an unscheduled visit to have a sample drawn for FPG measurement performed by the 
central laboratory if:


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
Self-measured FPG on two consecutive occasions exceeds the limits in Table 5-1.

The result from a blood sample analyzed by the central laboratory exceeds the limits 
described in Table 5-1.
Table 5-1
Rescue criteria for FPG (subjects with T2DM)
Timeframe
Parameter
Value
Action
Between V201 
(Randomization) 
and V204 (Week 8)
FPG
> 240 mg/dL 
(13.3 mM)
Unscheduled visit for central laboratory parameter 
measurement.
If elevation confirmed by central laboratory: 
background OAD may be escalated to the 
maximum approved dose, followed by addition of
another allowed OAD (eg a DPP-4 inhibitor used 
according to the label or insulin as per the 
investigator's discretion)
Between V204 
(Week 8) and V299
(Week 12)
FPG
> 220 mg/dL 
(12.2 mM)
If the results confirm that the limits have been exceeded, first the background OAD should be 
escalated to the maximal approved dose in steps if clinically indicated, followed by addition 
of rescue medication.
Rescue medication, a dipeptidyl peptidase-4 (DPP-4) inhibitor or insulin, should be used 
according to the local label. Rescue medication must be provided locally.
Rescued subjects will continue to participate in the study to allow for assessment of exposure 
and safety of LIK066.
Use of rescue medication must be recorded on the Rescue Medication eCRF.
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications/significant non-drug therapies eCRF.
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 patient or allowing a new medication to be started.
5.5.8
Prohibited medication
Use of following treatments is not allowed for entire study period:

St. John's wort (strong CYP3A inducer)

GLP-1 agonists

SGLT2 inhibitors other than study medication

Pharmacologically active weight-loss medication (including herbal medication)

Alpha glucosidase inhibitor
Some medications or products must be used with caution:


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
Use of grapefruit juice (strong inhibitor of CYP3A4) should be discouraged and its 
consumption must not happen within 2h of study medication intake.

Use of antibiotic or antifungal medications that are strong inhibitors of CYP3A4 should be 
limited to 10 days during the study. Examples of such medications are clarithromycin, 
telithromycin, itraconazole, ketoconazole, voriconazole or posaconazole.

Use of strong UGT inhibitors such as probenecid, valproic acid or mefenamic acid should 
be limited to 10 days during the study.
5.5.9
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the NIRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a communication 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 NIRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject 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.
Patients whose treatment has been unmasked must be discontinued from the study treatment 
(see Section 5.6.2).
5.6
Study completion and discontinuation
5.6.1
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
The study as a whole will be considered completed when all randomized subjects have 
completed the last visit planned in the protocol (see Table 6-1) or have discontinued the study 
prematurely.
For subjects who are loss to follow-up, see Section 5.6.4.
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.


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For all patients/subjects a safety follow-up should be contacted 30 days after last visit. The 
information to be collected at this follow up includes concomitant medications, adverse events, 
and survival status.
5.6.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator or 
the sponsor (see Section 5.6.5).
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances:

Patient wish

Pregnancy (see Section 6.5.5 and Section 7.6)

Use of prohibited treatment (see Section 5.5.8)

Any situation in which study participation might result in a safety risk to the patient

Emergence of the following AE: ketoacidosis (see also Section 7.8.1), or lower limb 
amputation (including toe amputation)

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject's overall status, prevents the subject from continuing 
participation in the study.

Subjects whose study treatment has been unmasked (see Section 5.5.9)

Withdrawal of consent (see Section 5.6.3)
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the study site as soon as possible, after 
discontinuation of study drug, for a study treatment discontinuation visit. Treatment 
discontinuation visit assessments detailed in the “unscheduled treatment discontinuation visit” 
(UNS) in Table 6-1 should be completed and recorded in the eCRF. The investigator must 
determine the primary reason for the patient's premature discontinuation of study treatment 
and record this information on the Dosage Administration eCRF.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits:

new and/or concomitant treatments

adverse events/Serious Adverse Events
If the patient cannot or is unwilling to attend any visit(s), the site staff should attempt
telephone contact with the patient, or with a person pre-designated by the patient. This 
telephone contact should preferably be done according to the study visit schedule.
The investigator must also contact the NIRT to register the patient's discontinuation from 
study treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.


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5.6.3
Withdrawal of informed consent
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason 
at any time. Withdrawal of consent from the study is defined as when a patient:

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 and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient's decision to withdraw his/her consent and record 
this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient's study withdrawal should be made as per Table 6-1.
5.6.4
Loss to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient's interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.


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6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Subjects must be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at 
which time all of the assessments listed for the final visit will be performed. At this final visit, 
all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF.
Subjects will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.


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Table 6-1
Assessment schedule
Epoch
1
Screening
2
Run-in
3
Treatment
Visit
1
101
102
199
201
RND
202
203
204
299* TD/ 
PSD/EOS
Week
−6
−4
−2 - −1
0
2
4
8
12
Screening assessments
Informed consent
X
Inclusion/exclusion (Section 4)
X
X
X
Subject demographics (Section 6.2)
X
Medical history
X
Medical history: protocol solicited events
X
Smoking & alcohol history (Section 6.2)
X
Efficacy
Height (Section 6.4.1)
X
Weight (Section 6.4.1)
X
X
X
X
X
X
X
X
Waist circumference (Section 6.4.2)
X
X
X
X
X
X
X
BP (SBP & DBP) (Section 6.4.5)
X
X
X
X
X
X
X
HbA1c (Section 6.4.3)
X
X
X
FPG (Section 6.4.4)
X
X
X
Fasting lipid profile (Section 6.4.6)
X‡
X
X
hsCRP (Section 6.4.6)
X
X
Uric acid (Section 6.4.7)
X
X
Urine albumin and Urine albumin to 
creatinine ratio (Section 6.4.8)
X
X
VFA and SFA by CT (Section 6.4.9)
X†
X


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Epoch
1
Screening
2
Run-in
3
Treatment
Visit
1
101
102
199
201
RND
202
203
204
299* TD/ 
PSD/EOS
Week
−6
−4
−2 - −1
0
2
4
8
12
Safety
Complete physical exam (Section 6.5.1)
S
S
Short physical exam (Section 6.5.1)
S
S
S
S
S
S
Vital signs (Section 6.5.2)
X
X
X
X
X
X
X
Hematology (Section 6.5.3.1)
X
X
X
X
Biochemistry (Section 6.5.3.2)
X
X
X
X
TSH (Section 6.5.3.2)
X
Pregnancy test (serum, Section 6.5.5)
X
Pregnancy (urine dipstick, Section 6.5.5)
X
X
X
Hematuria (urine dipstick, Section 6.5.3.3)
X
Urinalysis (Section 6.5.3.3)
X
X
PK trough (Section 6.6.3)
X
ECG (Section 6.5.4)
X
X
AEs (Section 7.1)
X
X
X
X
X
X
X
SAEs (Section 7.2)
X
X
X
X
X
X
X
Ketoacidosis AEs (Section 7.8.1)
X
X
X
X
X
X
X
Hypoglycemia AEs (Section 7.8.2)
X
X
X
X
X
X
X


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Epoch
1
Screening
2
Run-in
3
Treatment
Visit
1
101
102
199
201
RND
202
203
204
299* TD/ 
PSD/EOS
Week
−6
−4
−2 - −1
0
2
4
8
12
Medication records
Prior & concomitant medications
X
X
X
X
X
X
X
X
Surgical and medical procedures
X
X
X
X
X
X
X
Dose administration record
X
X
X
X
X
X
X
Administrative procedures
NIRT system
X
X
X
X
X
X
X
X
Lifestyle instructions (Section 3.1.1)
S
S
S
S
S
Dispense glucometer (T2DM subjects)
S
Glycemia diary (T2DM subjects)
S
S
S
S
S
S
Study drug accountability
S
S
S
S
S
S
Screening phase disposition
X
Run-in phase disposition
X
Study completion
X
TD = Study treatment discontinuation; PSD = Premature subject discontinuation; X = assessment to be recorded on clinical data base; S = assessment 
to be recorded on source documentation only; RND = Randomization visit; EOS = end of study; * These assessments are also to be conducted for 
subjects who prematurely withdraw from the study; † −14 ~ −8 days; ‡ TG only


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6.1
Information to be collected on screening failures
All subjects who have signed informed consent but not entered into the next epoch/period will 
have the study completion page for the screening epoch/period, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics
Demographic and BL characteristics data to be collected on all subjects include: year of birth, 
age, sex, race, ethnicity, source of subject referral, relevant medical history/current medical 
conditions present before signing informed consent including smoking and alcohol history. 
Where possible, diagnoses and notable symptoms will be recorded.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the ICF signature.
6.3
Treatment exposure and compliance
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the subject. This information should be captured in the 
source documents at each visit. All study treatment dispensed and returned must be recorded 
in the Drug Accountability Log. The site will also be required to complete the appropriate 
Dosage Administration Record eCRF to record any study drug regimen changes or 
interruptions.
On-treatment medication
For all medications (other than the study drug regimen) initiated after the start of study, the 
reason for prescribing the medication, and the start and, where applicable, end dates will be 
recorded on the Concomitant Medications/Significant Non-Drug Therapies eCRF.
Rescue medication
Information regarding the administration of rescue medication as per Section 5.5.6 will be 
recorded on the appropriate eCRF.
6.4
Efficacy
6.4.1
Weight
Body weight will be measured to the nearest 0.1 kg at visits indicated in Table 6-1 on a 
calibrated scale provided by the sponsor. The measurement will be performed with the study 
subject in underwear (or a hospital gown) and without shoes. Voiding before weight 
measurement is required.
Height will be measured at Visit 1 and will be used to calculate BMI.


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6.4.2
Waist circumference
Waist circumference will be measured to the nearest 0.1 cm at visits indicated in Table 6-1 in 
a standing position, at the end of a normal expiration, using a tape at the level of umbilicus.
6.4.3
HbA1c
HbA1c will be measured from a blood sample obtained at visits indicated in Table 6-1 and 
analyzed using a National Glycohemoglobin Standardization Program certified method at a 
central laboratory.
6.4.4
FPG
FPG will be measured from a blood sample obtained after an overnight fast (patients should
not eat or drink anything (except water) for at least 8h before each study visit) at visits 
indicated in Table 6-1 and analyzed at a central laboratory.
6.4.5
BP
Arterial BP, pulse rate readings and signs and symptoms of orthostasis will be assessed with 
an automated BP device. If an automated device cannot be used, the BP will be measured with
an alternative device.
Three sitting BP measurements and one standing BP measurement will be performed at visits 
indicated in Table 6-1. Every effort should be made to have the same staff member obtain BP 
measurements for a given subject, at the same time of day, using the same equipment, at each 
visit.
Sitting BP and standing measurements must be performed prior to any procedure (eg blood 
draw) or medication intake. At Visit 1 (screening) BP must be measured at both arms. The 
arm with the higher SBP reading must be used for the BP measurements at Visit 1 and the 
same arm must be used at all subsequent visits. The arm used at each visit must be 
documented in the source documentation.
The subject should be in a relaxed setting and measurements should not be taken immediately 
after exertion or the consumption of coffee. At each study visit, after the subject has been 
sitting for 5 minutes with the back supported and both feet placed on the floor, SBP and DBP 
will be measured three times using the BP device and an appropriate size cuff. The bladder of 
the cuff should be large enough to encircle 80% of the arm. The cuff should be placed so its 
bottom is 1 to 2 cm above the elbow and the arm should be supported so that the bottom of the 
cuff is at the level of the heart. The tube should run down the center of the arm, approximately 
in line with the middle finger. The subject should be asked to relax his/her arm and turn the 
palm upward. The subject should not speak or move their arm during the measurement 
deflation of the cuff. Three separate sitting BP should be obtained with a full two-minute 
interval between measurements and with the cuff fully deflated between measurements. The 
subject will then stand, and after standing for two minutes, one BP measurement will be taken 
(see also Section 6.5.2).
All 3 sitting BP measurements and the single standing measurement will be recorded and 
documented in the eCRF and in the subject's source documents. All 3 sitting BP readings will 
be used for evaluation of sitting BP.


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6.4.6
Fasting lipid profile & inflammation biomarkers
Fasting lipid profile, TG and hsCRP as described in Table 6-2 will be measured on blood 
samples obtained after an overnight fast at visits indicated in Table 6-1 and analyzed at a 
central laboratory.
Table 6-2
Fasting lipid profile, TG & inflammation biomarkers
Category
Parameter(s)
Fasting lipid profile & TGs
TG, total cholesterol, HDL cholesterol, LDL cholesterol (calculated, 
direct), lipoproteins (apolipoprotein A-I, apolipoprotein B), calculated 
VLDL cholesterol and non-HDL cholesterol.
Inflammation biomarkers
hsCRP
6.4.7
Uric acid
Uric acid will be measured from a blood sample at visits indicated in Table 6-1 and analyzed 
at a central laboratory.
6.4.8
Urine albumin and Urine albumin to creatinine ratio
Urine albumin and urine albumin to creatinine ratio will be measured from urine sample at 
visits indicated in Table 6-1 and analyzed at a central laboratory.
6.4.9
VFA and SFA
VFA and SFA by CT scan will be measured at visits indicated in Table 6-1 and evaluated 
centrally. VFA and SFA results will not be communicated to the study sites or the Novartis 
study team to avoid unmasking. Details on FA assessment by CT scan are explained in the 
separate manual.
6.4.10
Appropriateness of efficacy assessments
Measurements of weight, waist circumference, HbA1c, FPG, BP and fasting lipids are 
standard measures to assess the efficacy of a weight loss drug and its effect on 
cardio-metabolic parameters. Fat area measurement allows for evaluation of LIK066's
primary mode of action's contribution to weight loss.
6.5
Safety
6.5.1
Physical examination
A complete physical examination will be performed at visits indicated in Table 6-1 and 
includes the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities (including feet), vascular 
status, neurological status and volume status (see Section 3.1.1). If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic examinations will be 
performed.
A short physical exam will include the examination of general appearance (including feet) and 
assessments described in Section 6.4.5. They will be performed at all scheduled visits 
indicated in Table 6-1 and at unscheduled study visits.


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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 the ICF must be 
included in the medical history part of the eCRF. Significant findings made after first 
administration of investigational drug which meet the definition of an AE must be recorded on 
the AE section of the eCRF.
6.5.2
Vital signs
BP will be measured as described in Section 6.4.5 at visits indicated in Table 6-1. The pulse 
rate from the last sitting BP measurement will be recorded. Respiratory rate will also be 
measured. Clinically notable vital signs are defined in Appendix 1.
6.5.3
Laboratory evaluations
Laboratory evaluations for safety will be performed at visits indicated in Table 6-1 and all 
specimens collected will be analyzed at a central laboratory. Details on the collection, 
shipment of samples, reporting of results by the central laboratory as well as laboratory 
notable range deviations are provided in the laboratory manual.
6.5.3.1
Hematology
Samples for analysis of hematology (see Table 6-3) will be collected at visits indicated in 
Table 6-1.
Table 6-3
Hematology evaluations
Category
Parameter(s)
Hematology
RBC (total), WBC (total), platelet count (direct), hemoglobin, hematocrit, 
basophils (absolute, %), eosinophils (absolute, %), lymphocytes 
(absolute, %), monocytes (absolute, %), neutrophils (absolute, %)
6.5.3.2
Clinical chemistry
Samples for analysis of clinical chemistry (see Table 6-4) will be collected at visits indicated 
in Table 6-1.
Table 6-4
Clinical chemistry
Category
Parameter(s)
Biochemistry
ALT, albumin, alkaline phosphatase (ALP), AST, bicarbonates, bilirubin 
(direct, total), blood urea nitrogen (BUN), calcium (total), chloride, 
creatinine, cystatin C, eGFR (MDRD), magnesium, phosphates, 
potassium, protein (total), sodium, uric acid, γ-GT, amylase, lipase
Chemistry (TSH)
TSH
Chemistry (pregnancy)
Serum β-HCG
6.5.3.3
Urinalysis
Urine samples will be collected for analysis of parameters listed in Table 6-5 at visits 
indicated in Table 6-1. Urine will be used to assess pregnancy and hematuria (dipstick) at 
visits indicated in Table 6-1 as well. Glucosuria results will not be communicated to the study 
sites or the Novartis study team to avoid unmasking.


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Table 6-5
Urinalysis
Category
Parameter(s)
Urinalysis
pH, specific gravity, protein, glucose, ketones, nitrites, blood, leucocytes
Urinalysis
Urine albumin, urine albumin to creatinine ratio (spot urine)
Urine (dipstick)
Hematuria
Urine (dipstick)
Pregnancy test (β-hCG)
6.5.4
Electrocardiogram (ECG)
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable ECG 
baseline. The preferred sequence of cardiovascular data collection during study visits is ECG 
collection first, followed by vital signs, and blood sampling.
Single 12 lead ECGs are collected and interpreted by the principal investigator or their 
designee. The Fridericia QT correction formula should be used to assess the QT interval.
Each ECG tracing must be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs must be performed to confirm the safety.
Clinically significant abnormalities must be recorded on the relevant section of the Medical 
History/Current Medical Conditions/AE eCRF(s) as appropriate.
6.5.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing (see 
Section 6.5.3.2 & Section 6.5.3.3). Additional pregnancy testing might be performed if 
requested by local requirements.
A positive urine pregnancy test requires immediate interruption of study drug until serum 
β-human chorionic gonadotropin (β-hCG) is performed and found to be negative. If positive, 
the subject must be discontinued from the study treatment (see Section 5.6.2).
6.5.6
Appropriateness of safety measurements
The safety assessments are standard for this indication/subject population. The following 
additional assessments are included to document and evaluate risks identified with SGLT2 
inhibitors or during the LIK066 clinical program:


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6.6
Other assessments
6.6.2
Resource utilization
Not applicable
6.6.3
Pharmacokinetics
PK trough sampling will be performed in all subjects at time-points indicated in Table 6-1. At 
the morning of the visit, subjects must be in a fasting state (see Section 5.5.4). Details on PK 


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trough sample collection, numbering, processing and shipment is explained in the laboratory 
manual.
7
Safety monitoring
7.1
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 subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results 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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment

Yes

No

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.


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
whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE) 
and which seriousness criteria have been met.

action taken regarding [investigational] treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

patient hospitalized/patient's hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product 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 has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient's personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator's source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect


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
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient's
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30 day period after the last study visit should only be reported to Novartis safety if the 
investigator suspects a causal relationship to study treatment.
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.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study treatment, 
complete the SAE Report Form in English, and submit the completed form within 24 hours to 


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Novartis. Detailed instructions regarding the submission process and requirements for 
signature are to be found in the investigator folder provided to each site.
Follow-up information is submitted as instructed in the investigator folder. Each 
re-occurrence, complication, or progression of the original event must be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not, and whether the patient continued or withdrew from study 
participation.
If the SAE is not previously documented in the Investigator's Brochure (new occurrence) and 
is thought to be related to the study treatment a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.


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For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution.
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist's consultancy, based on investigator's discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 3.
7.5
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, patient or 
consumer (European Medicines Agency 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 collected in 
the Dose Administration Record eCRF 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.


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Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration eCRF
(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
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
7.7
Prospective suicidality assessment
Not applicable.
7.8
AEs of special interest
7.8.1
Ketoacidosis
In rare cases, SGLT-2 inhibitors can lead to ketoacidosis. Therefore, investigators must pay 
close attention for any signs of ketoacidosis. Signs and symptoms of ketoacidosis may include 
deep and rapid breathing, nausea, vomiting, severe abdominal pain, confusion, unusual fatigue 
or sleepiness, and coma. All signs and/or symptoms and results from relevant laboratory tests 
must be reported on the AE eCRF. If ketoacidosis is confirmed, the study treatment should be 
handled as per Section 5.6.2 and appropriate measures must be taken to correct the acidosis 
and monitor glucose levels.
Every case of ketoacidosis must be reported to the Ketoacidosis adjudication committee (see 
Section 8.5), and the Ketoacidosis Adjudication eCRF must be completed.
7.8.2
Hypoglycemia
Patients with T2DM treated with anti-diabetic agents may be at an increased risk of 
hypoglycemia due to the expected weight loss. All patients with diabetes must be educated 
regarding hypoglycemic symptoms and treatment. This education should include general 
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
Explanation of possible triggers of hypoglycemia (eg, strenuous exercise, delayed meals, 
changes in meal composition, illness, Ramadan-period, etc.).

Identification of the symptoms of hypoglycemia (eg, central symptoms such as dizziness, 
lightheadedness; adrenergic symptoms such as fast heart rate, palpitations, heart 
racing/pounding, shakiness; cholinergic symptoms such as sweating, hunger, blurred 
vision, impairment of motor function, confusion or inappropriate behavior).

Review of appropriate treatment for events (oral glucose intake).
A home glucose monitor will be provided with all appropriate supplies and its use will be 
explained to the subject. Blood glucose should be measured each time the subject experiences 
symptoms which may be suggestive of hypoglycemia, as well as other time points as 
recommended by the investigator to inform about the need for reducing or discontinuing anti-
diabetic treatment to prevent severe hypoglycemic events.
Any time the subject experiences symptoms which they suspect are related to hypoglycemia, 
the subject should treat the event as appropriate. Subjects should record the event in the 
glycemia study diary, including: 

The glucose value.

Precipitating factors (strenuous exercise, delayed or missed meals, changes in meal 
composition, illness, ramadan-period, etc.).

Time of occurrence in relation to the last medication and to the last meal intake.

The treatment used.

The response to the treatment used.

Need for assistance to treat the hypoglycemia event.

Additionally, if a subject performs routine self-monitoring of blood glucose, any 
asymptomatic plasma glucose < 70 mg/dL (< 3.9 mM) should be treated and recorded in 
the glycemia study diary.

The glycemia study diaries will be dispensed at run-in (Visit 101) and at following visits. 
The subject must return the completed study diary at each following visit.
Subjects without diabetes must have the symptoms of hypoglycemia explained and will be 
asked to report them at every study visit, if such occur. These subjects will not be provided 
with blood glucose meters or diaries.
Data entry
The glycemia study diary will be reviewed by the investigator at each visit and any 
hypoglycemia must be recorded on the Hypoglycemic Events eCRF.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator's meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource or eCRFs) 
with the investigators and their staff. During the study, Novartis employs several methods of 


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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 patient 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 patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the 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 patients/subjects will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the
investigational site.
8.3
Database management and quality control
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will 
make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.


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Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
Readings of VFA/SFA will be processed centrally and the results will be sent electronically to 
Novartis.
 
 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using the NIRT. The database will be sent electronically.
Each occurrence of a code break via NIRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
A Ketoacidosis adjudication committee will review cases suspected for ketoacidosis as 
defined in the adjudication charter (see also Section 7.8.1).
9
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
9.1
Analysis sets
The following analysis sets will be used for the statistical analyses:
Enrolled set (ENR): all subjects who signed the ICF.
Randomized set (RAN): all subjects who have received a randomization number, regardless 
of receiving trial medication.


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Full analysis set (FAS): the FAS comprises of all subjects to whom study treatment has been 
assigned, except those who are not qualified for randomization but were inadvertently 
randomized into the study and did not take any study drug. Following the intent-to-treat 
principle, subjects will be analyzed according to the treatment assigned to at randomization.
Safety set (SAF): the SAF includes all subjects who received at least one dose of study 
medication. Subjects will be analyzed according to treatment received. Note that the safety set 
allows the inclusion of non-randomized subjects who received the study drug in error.
The per-protocol set (PPS) is a subset of the FAS. It consists of all randomized subjects in 
the FAS who took at least one dose of study medication and have no major protocol 
deviations affecting the primary endpoint analysis.
Major protocol deviations will be pre-specified prior to un-blinding treatment codes for 
analyses.
9.2
Patient demographics and other baseline characteristics
The number of enrolled subjects, randomized subjects and screen failed subjects, as well as 
the number of subjects in each analysis set will be summarized.
Demographics, baseline characteristics, disease history and medical history will be 
summarized overall (total) and by treatment group for the FAS. Descriptive statistics (mean, 
Q1, median, Q3, standard deviation (SD), minimum and maximum) will be presented for 
continuous variables for each treatment group and for all subjects (total). The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects (total).
9.3
Treatments
The duration of double-blind treatment exposure (days) in Epoch 3 will be summarized by 
treatment group both descriptively (i.e. mean, standard deviation, median, Q1 (25th percentile), 
Q3 (75th percentile), minimum and maximum) and by duration category for the safety set.
The number and percentage of subjects receiving prior and concomitant medications will be 
summarized by treatment group and overall in SAF in separate tables according to the 
hierarchy levels of the WHO coding dictionary. Prior medications are defined as drugs taken 
and stopped prior to first dose of study medication. Any medication given at least once 
between the day of first dose of double-blind study medication and the end of Epoch 3 visit 
will be a concomitant medication, including those which were started pre-BL and continued 
into the treatment period. Subjects' background anti-diabetic medications at baseline will be 
summarized by treatment and medication type.
The number and percentage of subjects taking rescue medication, and duration of exposure to 
rescue medication during Epoch 3 will be summarized by treatment group.
The use of prohibited medication, if any, will also be summarized.


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9.4
Analysis of the primary variable(s)
9.4.1
Primary Variable(s)
The primary analysis variable is the percent change in body weight (kg) from BL at Week 12. 
BL is defined as the last body weight value measured prior to or at the randomization visit 
(Visit 201). This analysis will be carried out on the FAS, with missing Week 12 values 
imputed as described in Section 9.4.3.
9.4.2
Statistical model, hypothesis, and method of analysis
The primary objective will be evaluated by the methodology using an optimally weighted 
contrast test (Pinheiro et al 2006, Pinheiro et al 2014). To this end, a candidate model set is 
defined corresponding to the range of expected mean response. The candidate model set is 
used to generate a set of weights for the calculation of optimal contrasts between the 
responses in the studied dose groups and the placebo group. A statistical test comparing all 
doses to the control group is used, hence a multiplicity adjustment is applied that accounts for 
the multiple possible dose response behavior considered. A critical value is derived from a 
multivariate t-distribution using the correlation matrix induced by the correlations between the 
weights corresponding to the candidate sets.
Test of the dose response signal
The null hypothesis of a flat dose-response relationship for the percentage reduction in body 
weight compared to placebo will be tested at a one-sided significance level of 2.5% against 
the alternative hypothesis of a dose-response relationship leading to a significant decrease in 
percent body weight.
Hence, the following null and alternative hypotheses will be tested:

H0: There is no dose-response relationship for LIK066 (i.e. the dose response relationship 
is flat).

H1: There is a dose-response relationship for LIK066 (i.e. as dose increases, the percent 
weight decreases).
In order to preserve the family-wise error rate at one-sided significance level of 2.5%, the 
optimal contrasts derived from the model candidate set will be individually compared to the 
critical value derived using a multiplicity adjustment accounting for all tests comparing 
LIK066 doses to placebo. The rejection of the null hypothesis will be achieved using the 
maximum test statistic from each estimated contrast test in the candidate set.
The candidate models generating the contrast weights are described below and depicted in 
Figure 9-1:

Emax model: ED50 = 5 mg

Emax model: ED50 = 25 mg

Linear

Quadratic: δ = −0.014

Sigmoid Emax model: ED50 = 12.5 mg, h = 3

Linear on log dose, with offset value = 0.1


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Figure 9-1
Dose-response curve of candidate models
The analysis to derive the test statistics is based on an analysis of covariance (ANCOVA) 
model with the percent change in body weight from BL, to Week 12 as a response variable, 
treatment (placebo and all LIK066 doses), stratum indicator (dysglycemic /T2DM) as factors 
and BL weight as a covariate.
The response variable of percent change in body weight from BL to Week 12 used in the 
above ANCOVA is from an imputed dataset, where the missing Week 12 weight is imputed 
using the multiple imputation method as described in Section 9.4.3. In order to account for the 
imputation uncertainty, this ANCOVA model will be repeated for each imputed dataset, 
which results in a set of least squares (LS) mean estimates for all dose groups and the related 
covariance matrices. Rubin's rule will be used to combine the multiple sets of LS mean 
estimates and the related covariance matrices to a single set of LS mean estimates of percent 
changes of body weight at Week 12 for all dose groups and the related covariance matrix.
The optimal contrasts derived from the candidate model sets will be applied to the combined 
estimated dose means and covariance matrix to obtain the t statistics for each candidate model 
and the common critical value C0.025. C0.025 is the common critical value derived from the 
reference multivariate t-distribution with the 6x6 correlation matrix induced by testing the 
candidate dose response models with respect to comparing each LIK066 dose to the placebo 
group.
The hypothesis H0 will be rejected and the statistical significance of dose-response in body 
weight reduction is established if the max (t1, t2, t3, t4, t5, t6) ≥C0.025.


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Model averaging to obtain the dose responses
The response data in each imputed data set, including relevant covariates, will be used to fit 
the models in the candidate set. The estimated dose-response will be derived by using model 
averaging methods on a subset of candidate models, for which the associated contrast tests are 
statistically significant. Model averaging will be carried out for each imputed data set, and the 
resulting mean efficacy estimates and confidence intervals will be derived using the 
combination variance that accounts for the uncertainty of the imputed data using Rubin's
combination rules.
Target dose selection will be based on the model averaged dose response estimates of mean 
weight lowering efficacy of LIK066 over the dose range studied in this study.
9.4.3
Handling of missing values/censoring/discontinuations
Missing data for the primary endpoint will be imputed using a multiple imputation approach 
that assumes that the missingness mechanism can be retrieved from observed data (missing at 
random; MAR). The imputation model will include the longitudinal sequence of body weight 
data collected at each visit up to and including Week 12 visit as response variable, and 
treatment, visit and BL covariates (e.g. stratification factor, baseline body weight, height and 
gender) as independent variables.
The full detailed information about the multiple imputation algorithms will be specified in a 
separate statistical analysis plan.
9.4.4
Sensitivity analyses
The dose-response modeling as described in Section 9.4.2 will be conducted in the PPS as 
well.
Results based on the single best dose response model fit will also be reported.
Summary statistics for body weight will be presented by visit by treatment for observed and 
imputed values. The summary statistics n, mean, SD, median, minimum, maximum, Q1 and 
Q3 will be presented for the BL values and similarly for absolute values at and changes from 
BL to the post-BL visits. Figures will be produced to visually show the raw and the imputed 
mean changes by visit over 12 weeks of Epoch 3 for each treatment group, for all subjects and 
by strata separately.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
Variables

Responder rates based on percent decrease in body weight from BL at Week 12 ≥3%, 
≥5%, or ≥10%

Dose-response relationship in dysglycemic subjects and subjects with T2DM after 12
weeks of treatment.

Change from BL at Week 12 in waist circumference at umbilical level.

Change from BL at Week 12 in HbA1c


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
Change from BL at Week 12 in FPG

Change from BL at Week 12 in SBP and DBP

Changes from BL at Week 12 in the fasting lipid profile (TG, total cholesterol, HDL 
cholesterol, LDL cholesterol, lipoproteins, calculated VLDL cholesterol and non-HDL 
cholesterol) and hsCRP

Change from BL at Week 12 in uric acid

Change from BL at Week 12 in urine albumin

Change from BL at Week 12 in urine albumin to creatinine ratio

Change from BL at Week 12 in fat area parameters (VFA and SFA)
Analysis method: responder analysis
For the responder analysis, a logistic regression model will be performed using the percent 
decrease in body weight from BL at Week 12 ≥3%, ≥5% or ≥10% (yes/no) as a response 
variable, treatment, and glycemic stratification factor as fixed factors and BL body weight as a 
covariate, respectively. The Week 12 missing values will be imputed using the multiple 
imputation method as described in Section 9.4.3. In order to account for the imputation 
uncertainty, this logistic regression model will be repeated for each imputed dataset, which 
results in a set of estimated odds ratio and its 95% confidence interval of an LIK066 dose vs
placebo for all dose groups. Rubin's rule will be used to combine the multiple sets of odds 
ratios and 95% confidence intervals to a single set of odds ratio and its 95% confidence 
interval of an LIK066 dose vs placebo. Similar analysis by glycemic status stratification factor 
will be performed to assess the responder across each of the subgroups (subjects with 
dysglycemic and subjects with T2DM).
In addition, subjects meeting the pre-defined response criteria (percent decrease in body 
weight from BL at Week 12 ≥3%, ≥5% or ≥10%) will be summarized by treatment for all 
subjects and by glycemic stratification factor. A Cochran-Mantel-Haenszel-test will be 
performed to compare each dose to the placebo.
Analysis method: dose-response relationship by glycemic stratification factor 
For the dose-response relationship in subjects with dysglycemic and subjects with T2DM, the 
dose-response modeling with the same candidate model sets for the primary variable as 
described in Section 9.4.2 will be performed on percent change of body weight from BL at 
Week 12 for these two subsets of subjects separately.
Analysis for other secondary endpoints
For changes from BL at Week 12 in waist circumference, HbA1c, FPG, SBP, DBP, uric acid, 
urine albumin and urine albumin to creatinine ratio, a repeated measure ANCOVA model 
with treatment, visit, and treatment by visit interaction as fixed-effect factors and BL as a 
covariate, and a common unstructured covariance matrix among visits between treatments 
will be performed separately for each variable. The adjusted mean changes at Week 12 within 
each treatment, the differences in mean changes at Week 12 between the LIK066 and placebo 
treatments, and their 95% confidence intervals obtained from the above model will be 


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presented. The analysis is based on likelihood method with an assumption of MAR for 
missing data.
In addition, a repeated measure ANCOVA model with treatment, visit, stratification factor 
(dysglycemic, T2DM) and treatment by visit, treatment by stratification factor and treatment 
by visit by stratification factor interactions as fixed-effect factors and BL as a covariate, and a 
common unstructured covariance matrix among visits between treatments will be performed 
for the primary and secondary efficacy variables, respectively. The adjusted mean changes at 
Week 12 within each treatment, the differences in mean changes at Week 12 between the 
LIK066 and placebo treatments for each stratum, and their 95% confidence intervals obtained 
from the above models will be presented by strata for each efficacy endpoint.
Similar repeated measure ANCOVA models will be performed for percent changes of lipid 
parameters and fat area parameters, and log10-transformed hsCRP from BL to Week 12.
Summaries of absolute values and change from BL by treatment group and visit will be 
presented for all secondary efficacy variables for all subjects and by strata. Figures will be 
produced to visually show the raw mean changes by visit over 12 weeks of Epoch 3 for each 
treatment group, for overall and by strata separately. 
All analyses on secondary variables will be performed in the FAS.
9.5.2
Safety variables
All safety analyses will be performed in the SAF.
AEs
Treatment emergent AEs will be summarized. A treatment-emergent AE is defined as any AE 
that develops after initiation of the study treatments or any event already present that worsens 
following exposure to the study treatment. The number and percentage of subjects having AEs 
will be presented by treatment group and different hierarchy levels of the MedDRA coding 
dictionary. Summaries will also be presented by greatest severity, for AEs suspected to be 
related to study drug, serious AEs, AEs leading to discontinuation, to dosage adjustment, to 
death and other significant AEs. The hypoglycemic events will be similarly summarized. 
Further information related to hypoglycemic events (eg if third party assistance required, was 
medical assistance received, etc.) may be provided as well.
AEs related to identified and potential risks as specified in the development safety profiling 
plan will be summarized and presented separately.
The frequencies and percentages of the adjudication confirmed ketoacidosis events will be 
provided by treatment.
In addition, for selected AEs including hypotension, hypoglycemia, hyperkalemia, diarrhea, 
and genital and urinary tract infection, a by-stratification factor of BL glycemic status 
subgroup analysis will be provided.
Laboratory data, vital signs and ECG
Descriptive summary statistics including for the change from BL to each study visit up to and 
including Week 12 visit will be presented by treatment group for each laboratory parameter, 


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as well as for the maximum change from BL. In addition, shift tables will be provided for all 
parameters with available ranges to compare a subject's BL laboratory evaluation relative to 
the most extreme post-BL value. For the shift tables, normal ranges as well as specifically 
defined clinically notable/abnormality limits, if available – will be used.
The vital sign and ECG data collected during Epoch 3 will be descriptively summarized by 
treatment as appropriate.
9.5.3
Resource utilization
Not applicable.
9.5.4
Pharmacokinetics
Individual LIK066 plasma concentration data will be listed by treatment, subject, and visit. 
Concentrations below the lower limit of quantification will be treated as zero in summary 
statistics. A geometric mean will not be reported if the dataset includes zero values.
9.5.5
DNA
Not applicable.


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9.7
Interim analyses
Not applicable.
9.8
Sample size calculation
The study planned to randomize approximately 130 subjects in total, allocated in the ratio of 
3:2:2:3:3 to the following Epoch 3 treatment groups:
1. placebo
2. LIK066 2.5 mg qd
3. LIK066 10 mg qd
4. LIK066 25 mg qd
5. LIK066 50 mg qd
This randomization scheme implies that the Epoch 3 treatment for a specific subject is 
determined simultaneously at randomization visit. The randomization will be stratified by 
subjects' glycemic status: T2DM and dysglycemic (see Section 3.1.2).
Sample sizes are considered from two viewpoints. One is that this study should be statistically 
powered to identify the dose-response relationship regarding the effect of LIK066 on weight 
loss. The other is that this is the first study to enroll Japanese patients, and that the highest 
dose arms, 25 mg and 50 mg qd arms, and the placebo arm as a control, should include more 
patients to obtain sufficient information on safety and/or tolerability of LIK066 in Japanese 
patients. The detail of the first viewpoint will follow.
Table 9-1 summarizes the average power and the lowest power across the candidate 
dose-response shapes in Figure 9-1, under different scenarios with the assumptions on effect 
size of body weight loss (percent change from BL) for the dose of maximum effect, and the 
related standard deviations. In power evaluation, it was also assumed that dose-response is 
assessed with controlling the overall family-wise type I error at a one-sided significance level 
of 2.5%.
It was assumed that the effect of losses to follow-up is equivalent to effectively having 10% 
fewer subjects than randomized, even if the multiple imputation approach used to handle 
missing values should be able to recover some information for such subjects.
Table 9-1
Power for detecting a significant dose response signal*
Effect size for best dose
Standard deviation
Average power
Minimum power**
3.5%
3%
99.70%
99.52%
3.5%
3.5%
98.11%
97.28%
4.0%
3%
99.97%
99.94%
4.0%
3.5%
99.59%
99.35%
* Assumes 130 subjects in total with effective sample size of 117 subjects due to an effect of missing 
data equivalent to 10% fewer subjects. Calculations were performed using R Dose Finding package.
** Power for a significant dose-response contrast test across all scenarios mentioned in
Section 9.4.2. The quadratic model has the lowest power.


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10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if applicable
after such consent has been provided by a legally acceptable representative(s) of the patient. 
In cases where the patient's representative gives consent, the patient must be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she must indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting 
any study-specific procedures (e.g. all of the procedures described in the protocol). The 
process of obtaining informed consent must be documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
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, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.


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10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management system that includes all activities involved 
in quality assurance and quality control, including the assignment of roles and responsibilities, 
the reporting of results, and the documentation of actions and escalation of issues identified 
during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Global 
Development Quality Audit, a group 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.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
11.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/subjects may be implemented immediately provided the health authorities
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.


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12
References
American association of clinical endocrinologists and American college of endocrinology
(2016) Clinical practice guidelines for comprehensive medical care of patients with obesity. 
Endocrine Practice; DOI: 10.4158/EP161365.GL.
Bailey CJ, Gross JL, Pieters A, et al. (2010) Effect of dapagliflozin in patients with type 2
diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind,
placebo-controlled trial. Lancet; 375:2223-33.
Japan Society for the Study of Obesity (2016) Guidelines for the management of obesity 
disease 2016. Tokyo, Life Science Publishing Co., Ltd.
Nauck MA, Del Prato S, Meier JJ, et al. (2011) Dapagliflozin versus glipizide as add-on 
therapy in patients with type 2 diabetes who have inadequate glycemic control with 
metformin. Diabetes Care; 34(9):2015-22.
Nyirjesy P, Zhao Y, Ways K, et al. (2012) Evaluation of vulvovaginal symptoms and Candida
colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium
glucose co-transporter 2 inhibitor. Curr Med Res Opin; 28(7):1173-8.
Pinheiro J, Bornkamp B, Bretz F (2006) Design and analysis of dose finding studies
combining multiple comparisons and modeling procedures. J Biopharm Stat; 16(5):639-56.
Pinheiro J, Bornkamp B, Glimm E, et al. (2014) Model-based dose finding under model
uncertainty using general parametric models. Stat Med; 33(10):1646-61.
Rosenstock J and Ferrannini E (2015) Euglycemic diabetic ketoacidosis: a predictable,
detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care; 38:1638-42.
References are available upon request.


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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Vital signs range deviations are defined as per Table 13-1.
Table 13-1
Vital signs notable range deviations
Vital sign
Notable abnormalities
Pulse (beats/min)
either ≥120 + increase ≥25* or > 130
either ≤50 + decrease ≥30* or < 40
BP (mmHg)
systolic
either ≥180 + increase ≥30* or > 200
either ≤90 + decrease ≥30* or < 75
diastolic
either ≥105 + increase ≥20* or > 115
either ≤50 + decrease ≥20* or < 40
* Refers to post-BL value as compared to BL value.


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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 × ULN < ALT / AST 5 × ULN

1.5 × ULN < TBL 2 × ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy's Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy's Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 5 to ≤8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 weeks, 
discontinue the study drug

Establish causality
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring

Complete liver CRF
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 to ≤5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study 
drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver 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.


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 - 49% compared to baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 
≥50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption
Consider patient hospitalization /specialized treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or 
≥3 mg/mmol;
Protein-creatinine ratio (PCR ) ≥150 mg/g 
or > 15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or discontinuation
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
Monitor patient regularly (frequency at investigator's discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ± 10% variability over last 6 months or protein-creatinine ratio stabilization at a 
new level with ±50% variability over last 6 months.

SAP_001.pdf: 
Clinical Development 
LIK066B 
CLIK066B1201 / NCT03320941
A randomized, double-blind, dose-finding study to evaluate 
the change in weight after 12 weeks treatment with 4 doses 
of LIK066 compared to placebo in Japanese patients with 
obesity disease 
Statistical Analysis Plan (SAP) 
Author: 
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Amendment 2 to Final 1.0 
Release date: 
13-Sep-2018
Number of pages: 
45 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Page 2 
SAP 
CLIK066B1201 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for 
update 
Section and title impacted 
(Current) 
09NOV2017 
Prior 
to 
FPFV 
 
First Final 
version 
 
20JUL2018 
Prior 
to 
DBL 
Alignment with 
B2201 on 
definition of 
baseline 
Any 
measurement, 
regardless of 
whether 
scheduled or 
not, could be 
handled as 
baseline if it 
occurs at or 
before visit 
201. 
2.1.1 General definition 
20JUL2018 
Prior 
to 
DBL 
Project-level 
update on the  
model-
averaging 
method 
The model-
averaging is 
implemented 
via a 
parametric 
bootstrap 
method.  
2.5.1 Primary endpoint 
20JUL2018 
Prior 
to 
DBL 
Project-level 
update on the 
method for 
multiple 
imputation 
The 
imputation 
model is 
updated. 
2.5.3 Handling of missing 
balues/consoring/discontinuations 
20JUL2018 
Prior 
to 
DBL 
Project-level 
update on the  
model-
averaging 
method 
The plan for 
dose-
response 
model based 
on the best-fit 
model is 
cancelled. 
2.5.4 Supportive analyses 
20JUL2018 
Prior 
to 
DBL 
Revision of 
display of 
summary 
statistics for 
BW 
BW is to be 
summarized 
using percent 
changes for 
overall 
population 
and 
subgroups. 
For subgroup 
summaries, 
only observed 
values are to 
be included. 
2.5.4 Supportive analyses 


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Page 3 
SAP 
CLIK066B1201 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for 
update 
Section and title impacted 
(Current) 
20JUL2018 
Prior 
to 
DBL 
Clarification 
on CMH test 
It is clarified to 
use observed 
values for 
CMH test for 
BW responder 
analysis. 
2.7.2 Statistical hypothesis, 
model, and method of analysis 
20JUL2018 
Prior 
to 
DBL 
Update of  
ANCOVA 
models for 
efficacy 
analysis 
The baseline 
glycemic 
status is 
added to 
ANCOVA 
models for 
secondary 
efficacy 
endpoints. 
2.7.2 Statistical hypothesis, 
model, and method of analysis 
20JUL2018 
Prior 
to 
DBL 
Simplification 
of subgroup 
analysis by 
stratum 
ANCOVA 
models are 
applied by 
stratum. 
2.7.2 Statistical hypothesis, 
model, and method of analysis 
20JUL2018 
Prior 
to 
DBL 
Change of 
cut-off value 
for AE 
frequecies 
Summary of 
the most 
frequent AEs 
includes AEs 
whose 
frequencies 
are >= 5% in 
50mg qd arm.  
2.8.1.1 Adverse events of special 
interest / grouping of AEs 
20JUL2018 
Prior 
to 
DBL 
Clarification of 
diarrhea event 
for analysis of 
event periods 
The number 
of days with 
“on-treatment” 
diarrhea is 
used for 
negative 
binomial 
regression 
analysis.  
2.8.1.1 Adverse events of special 
interest / grouping of AEs 
20JUL2018 
Prior 
to 
DBL 
Project-level 
update on 
analysis plan 
for 
hypoglycemic 
events 
It is clarified to 
summarize 
“clinically 
significant” 
hypoglycemic 
events. 
Also it is 
updated how 
to use 
hypoglycemic 
events in AE 
summary. 
2.8.1.1 Adverse events of special 
interest / grouping of AEs 


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Page 4 
SAP 
CLIK066B1201 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for 
update 
Section and title impacted 
(Current) 
20JUL2018 
Prior 
to 
DBL 
Project-level 
update on the 
AE of special 
interest 
“Pre-
amputation 
events” is 
additionally 
listed as AE of 
special 
interest. 
2.8.1.1 Adverse events of special 
interest / grouping of AEs 
20JUL2018 
Prior 
to 
DBL 
Clarification of 
cut-off values 
for shift tables 
Cut-off values 
are specified 
for selected 
ECG 
parameters. 
2.8.4.1 ECG and cardiac imaging 
data 
20JUL2018 
Prior 
to 
DBL 
Documentaton 
of the change 
in analysis 
plan from the 
protocol 
It is clarified 
which 
analysis to be 
changed from 
the study 
protocol. 
4 Change to protocol specified 
analysis 
20JUL2018 
Pror 
to 
DBL 
To remove 
confusing 
information 
about 
handling of  
hypoglycemic 
event data 
No impact 
5.2 AEs coding/grading 


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Date 
Time 
point 
Reason for 
update 
Outcome for 
update 
Section and title impacted 
(Current) 
20JUL2018 
Prior 
to 
DBL 
To add PD 
OTH01 to 
handle 
erroneous 
randomization 
Any patient 
would be 
excluded from 
PPS if 
randomised 
under a 
CRC’s 
erroneous 
operation at 
the site. 
5.5 Rule of exclusion criteria of 
analysis sets 
13SEP2018 
Prior 
to 
DBL 
To update the 
units for eGFR 
and FPG to SI 
units 
The units in 
TFLs are 
updated. 
2.3 Patient disposition, 
demographics and other baseline 
characteristics 
13SEP2018 
Prior 
to 
DBL 
To clarify at 
which time 
point for BW 
to be 
summarized 
as baseline 
data 
It becomes 
clear that 
screening BW 
is to be 
sumamrized.  
2.3 Patient disposition, 
demographics and other baseline 
characteristics 
13SEP2018 
Prior 
to 
DBL 
To add 
categorized 
summary on 
BL eGFR with 
Japanese 
coefficients 
The plan for 
BL summary 
is updated. 
2.3 Patient disposition, 
demographics and other baseline 
characteristics 
13SEP2018 
Prior 
to 
DBL 
To revise 
ANCOVA 
models for 
efficacy 
variables 
assessed only 
at BL and 
Week 12. 
The factors 
incuded in the 
ANCOVA 
models are 
revised. 
2.7.2 Statistical hypothesis, 
model, and method of analysis 
 
4 Change to the protocol 
specified analyses 
13SEP2018 
Prior 
to 
DBL 
To specify in 
the footnote 
for Table 2-4 
that by-visit 
summary will 
be provided 
as only 
efficacy 
analysis. 
For uric acid, 
urine albumin, 
and urine 
alubmin to 
creatinine 
ratio by-visit 
summary 
statistics will 
be displayed 
as efficacy 
analyses. 
2.8.3 Laboratory data 


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Date 
Time 
point 
Reason for 
update 
Outcome for 
update 
Section and title impacted 
(Current) 
 


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Table of contents 
Table of contents ................................................................................................................. 7 
List of abbreviations ............................................................................................................ 9 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design........................................................................................................... 10 
1.1.1 
Epoch 2 (run-in) .................................................................................... 10 
1.1.2 
Epoch 3 (treatment) ............................................................................... 11 
1.2 
Study objectives and endpoints ............................................................................. 12 
2 
Statistical methods ............................................................................................................. 14 
2.1 
Data analysis general information ......................................................................... 14 
2.1.1 
General definitions ................................................................................ 14 
2.2 
Analysis sets .......................................................................................................... 14 
2.2.1 
Subgroup of interest .............................................................................. 15 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.3.1 
Patient disposition ................................................................................. 17 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 18 
2.5 
Analysis of the primary objective .......................................................................... 19 
2.5.1 
Primary endpoint ................................................................................... 19 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 22 
2.5.4 
Supportive analyses ............................................................................... 22 
2.6 
Analysis of the key secondary objective ............................................................... 23 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 23 
2.7.1 
Secondary endpoints ............................................................................. 23 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 25 
2.8 
Safety analyses ....................................................................................................... 25 
2.8.1 
Adverse events (AEs) ............................................................................ 25 
2.8.2 
Deaths .................................................................................................... 30 
2.8.3 
Laboratory data ..................................................................................... 30 
2.8.4 
Other safety data ................................................................................... 31 
2.8.5 
Liver events ........................................................................................... 33 
2.8.6 
Renal events .......................................................................................... 34 


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2.9 
Pharmacokinetic endpoints .................................................................................... 34 
2.10 
PD and PK/PD analyses......................................................................................... 35 
 
 35 
 
 36 
2.13 
Other Exploratory analyses .................................................................................... 36 
2.14 
Interim analysis ...................................................................................................... 36 
3 
Sample size calculation ..................................................................................................... 37 
4 
Change to protocol specified analyses .............................................................................. 38 
5 
Appendix ........................................................................................................................... 39 
5.1 
Imputation rules ..................................................................................................... 39 
5.1.1 
Study drug ............................................................................................. 39 
5.1.2 
AE date imputation ............................................................................... 39 
5.1.3 
Concomitant medication date imputation ............................................. 40 
5.2 
AEs coding/grading ............................................................................................... 41 
5.3 
Laboratory parameters derivations ........................................................................ 41 
5.3.1 
Japanese coefficient for eGFR .............................................................. 41 
5.4 
Statistical models ................................................................................................... 42 
5.4.1 
Primary analysis .................................................................................... 42 
5.4.2 
Key secondary analysis ......................................................................... 42 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 42 
5.6 
Anti-diabetic medications search criteria .............................................................. 43 
6 
Reference ........................................................................................................................... 45 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
BL 
Baseline 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
 
 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
The purpose of this Statistical Analysis Plan, SAP, is to document the analysis plan for reporting 
in the clinical study report from CLIK066B1201. 
1.1 
Study design 
This is a multi-center, randomized, double-blind, parallel-group dose-finding study evaluating 
the effect on weight, tolerability and safety of 4 doses of LIK066 vs placebo (see Figure 1-1). 
Following a screening visit (Visit 1) and a screening period of up to 2 weeks (Epoch 1), subjects 
meeting all eligibility criteria will enter the run-in Epoch 2 at Visit 101. 
1.1.1 
Epoch 2 (run-in) 
Subjects meeting the eligibility criteria will enter the placebo run-in (Epoch 2). During the 4 
weeks duration of Epoch 2, subjects will receive the placebo run-in medication. 
At Visit 101, the subject’s volume status must be assessed and hypovolemia must be corrected 
during the run-in in the elderly, in subjects with low SBP, or if on diuretics, angiotensin-
converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). 
At the start of Visit 101, all subjects will receive the following advice for lifestyle intervention 
(Japan Society for the Study of Obesity 2016): 
• Subjects with BMI ranging from ≥25 to <35 kg/m2 will be advised to follow a ‘25 × 
standard body weight (SBW)’ kcal/day; subjects with BMI ≥ 35 kg/m2 will be advised to 
follow a ‘20×SBW’ to ‘25×SBW’ kcal/day diet. Consumption of 50 to 60 % kcal from 
carbohydrate, 15 to 20% kcal from protein and 20 to 25% kcal from fat will be 
recommended.  
Standard body weight (kg) = height (m)2 ×22 
• Subjects will be advised to gradually increase their physical activity to reach a goal of 
more than 150 min of moderate intensity physical activity per week, preferably distributed 
over a week. 
Compliance with the lifestyle intervention shall be reviewed and re-enforced at every study visit. 
Subjects with T2DM 
Subjects with T2DM will continue their usual treatment, except for subjects taking sulfonylurea 
(SU) or insulin. These subjects may be at an increased risk of hypoglycemia due to the 
combination of the SU or insulin and weight loss, with or without consequent treatment with 
LIK066 in Epoch 3. Therefore: 
• The dose of SUs for subjects with T2DM using such medication (either as monotherapy or 
in combination with other oral anti-diabetic drugs (OADs)) may be reduced by up to 
50 %, or as close to 50 % as possible based on dose options available locally, along with 
following thresholds; glimepiride >2 mg/day to ≤2 mg/day, glibenclamide >1.25 mg/day 
to ≤1.25 mg/day and gliclazide >40 mg/day to ≤40 mg/day. In case of persistent 
deterioration in glycemic control, the concomitant background OAD should be initially 
escalated to the maximal approved dose, followed by addition of rescue medication when 


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required. To limit the number of subjects with early deterioration of glycemic control who 
would meet the FPG rescue criteria early after randomization, an FPG randomization 
criterion is included as an exclusion criteria.  
• For subjects on insulin, initial dose reduction of the total daily insulin dose by 10 % or 
more may be considered at investigator’s discretion based on subject’s total daily dose and 
glycemic control. In case of deterioration in glycemic control, insulin can be up-titrated. 
1.1.2 
Epoch 3 (treatment) 
After the run-in Epoch 2, eligible subjects will be randomized in the ratio of 2:2:3:3:3 to one of 
the following regimes at Visit 201 (randomization): 
• 2.5 mg qd LIK066 
• 10 mg qd LIK066 
• 25 mg qd LIK066 
• 50 mg qd LIK066 
• Placebo. 
At Visit 201, subjects will be randomized simultaneously to one of the five Epoch 3 treatment 
schedules. 
At randomization, subjects will be stratified according to their glycemic status at screening 
using the following criteria: 
• Dysglycemic: no prior clinical diagnosis of T2DM, FPG ≥110 mg/dL and/or HbA1c 
≥5.6% , except for HbA1c ≥ 6.5 % and FPG ≥ 126 mg/dL at Visit 1 (screening). 
• T2DM: prior diagnosis of T2DM, or subjects without prior diagnosis of T2DM with 
HbA1c ≥ 6.5 % and FPG ≥ 126 mg/dL at Visit 1 (screening). 
Following randomization, subjects will attend study visits in Epoch 3 (12 weeks) for assessment 
of efficacy, tolerability and safety parameters. During Epoch 3, subjects will take the study 
medication. 
The doses of antidiabetic and antihypertensive medications should be adjusted in patients who, 
according to the investigator, could be at a safety risk (e.g. repetitive or severe hypoglycemia, 
symptoms and signs of volume depletion, etc.). 


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Figure 1-1 
Study design 
 
The primary analysis time point is Week 12 (Visit 299). There is no interim analysis planned. 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
To examine the dose-response relationship of 
LIK066 (2.5 mg qd, 10 mg qd, 25 mg qd and 
50 mg qd) as measured by percent change from 
baseline (BL) in body weight relative to placebo 
after 12 weeks of treatment 
Endpoint(s) for primary objective(s)  
Percent change from BL in body weight  at 
Week 12 
Secondary Objective(s) 
To assess the responder rates according to 
percent decrease in body weight either ≥ 3 %, ≥ 
5 % or ≥ 10 %, from BL at Week 12, for the 
overall population and each of the subgroups 
(dysglycemic subjects and subjects with T2DM). 
Endpoint(s) for secondary objective(s) 
Responder rates according to percent change 
in body weight ≥3%, ≥5%, ≥10% from BL at 
Week 12 
To assess the dose-response relationship for 
weight loss in dysglycemic subjects and subjects 
with T2DM after 12 weeks of treatment. 
Dose response relationship for weight loss 
among subgroups (dysglycemic, T2DM) at 
Week 12 
To evaluate the effect of all LIK066 doses vs 
placebo for the overall population and by 
subgroups (dysglycemic subjects and subjects 
with T2DM) after 12 weeks of treatment. 
Change from baseline at Week 12 on: 
Waist circumference at umbilical level 
Hemoglobin A1c (HbA1c) 
Fasting plasma glucose (FPG) 


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Objective(s) 
Endpoint(s) 
Systolic blood pressure (SBP) and diastolic 
blood pressure (DBP). 
Fasting lipid profile and high sensitivity C-
reactive protein (hsCRP) 
Uric acid 
Urine albumin and urine albumin creatinine 
ratio 
Visceral fat area (VFA) and subcutaneous fat 
area (SFA) by CT 
To evaluate safety (adverse events (AEs) and 
laboratory parameters) and tolerability of LIK066 
over 12 weeks of treatment. 
AEs including events of special interest,  
Laboratory parameters, 
Vital sign, 
ECG 
To evaluate the pharmacokinetics (PK) of 
LIK066 
PK (trough). 


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2 
Statistical methods 
2.1 
Data analysis general information 
Novartis will perform the analysis for the study. SAS Version 9.4 or higher will be used to 
perform all the statistical analyses in the report. 
In general, for continuous data, mean, standard deviation, median, lower quartile, upper quartile, 
minimum, and maximum will be presented. Categorical data will be presented as frequencies 
and percentages of patients in each category. For categorical variable summaries, an additional 
category ‘Missing’ will be presented if there are missing values for that variable. If not 
otherwise specified, p-values will be presented for two-sided hypothesis testing and two-sided 
confidence intervals will be displayed; the level of significance will be 5% unless otherwise 
stated. 
There is no analysis cut-off date for the study. 
The strattification factor, glycemic status, will be included as a factor in an ANCOVA model 
for each analysis wherever applicable and feasible.  
Details in key statisical methodology will be reported in CSR Appendix 16.1.9. 
2.1.1 
General definitions  
Baseline (Week 0) for the randomized treatment period will be defined as the last measurement 
before or at the randomization visit.  
The first day of administration of randomized study treatment (first dose) is defined as Day 1 
for the study. If the date of first administration is missing, then randomization date will be used 
as Day 1.  
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, study 
day for a particular event date is calculated as [Date of event] – [Date of first dose] + 1. For the 
dates before Day 1, study day for an event date is calculated as [Date of event] – [Date of first 
dose]. Duration of an event will be calculated as [Event end date] – [Event start date] + 1. The 
descriptor “Day 0” will not be used.   
The treatment groups presented are: 
• LIK066 2.5 mg qd 
• LIK066 10 mg qd 
• LIK066 25 mg qd 
• LIK066 50 mg qd 
• Placebo 
• Total (if applicable) 
2.2 
Analysis sets 
The following analysis sets will be used for the statistical analyses: 


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Enrolled set (ENR): all subjects who signed the ICF. 
Randomized set (RAN): all subjects who have received a randomization number, regardless 
of receiving trial medication. 
Run-in set (RUN): All subjects who enter the run-in epoch.  
Full analysis set (FAS): the FAS comprises all subjects to whom study treatment has been 
assigned, except those who are not qualified for randomization but were inadvertently 
randomized into the study and did not take any study drug. Following the intent-to-treat 
principle, subjects will be analyzed according to the treatment assigned to at randomization.  
Safety set (SAF): the SAF includes all subjects who received at least one dose of study 
medication. Subjects will be analyzed according to treatment received. Note that the safety set 
allows the inclusion of non-randomized subjects who received the study drug in error. 
The per-protocol set (PPS) is a subset of the FAS. It consists of all randomized subjects in the 
FAS who have been exposed to study medication for at least 11 weeks, and have no major 
protocol deviations affecting the primary endpoint analysis. 
Exposure to study medication for at least 11 weeks means that the overall duration of exposure 
is equal to or longer than 77 days, counted from start of randomized medication to the last intake. 
Major protocol deviations will be pre-specified prior to un-blinding treatment codes for 
analyses. 
2.2.1 
Subgroup of interest 
Subgroups of interest include: 
• Baseline glycemic status (dysglycemic, and T2DM) 
• Age (<65, ≥65) 
• Sex (Male, Female) 
• BMI (<27, ≥27; <30, ≥30; <35, ≥35) 
Table 2-1 
Specification of subgroups 
Subgroup 
Method of derivation 
Disposition/ 
Background & 
Demographics / 
Exposure 
Efficacy 
Safety 
Baseline glycemic status 
(dysglycemic, and T2DM) 
Screening  
X 
X 
X 
Age groups:  
(<65, ≥65 years) 
Screening (derived) 
 
X 
X 
Sex (Male/Female) 
Screening 
X 
X 
X 
BMI (<27, ≥27; <30, ≥30; <35, 
≥35) 
Baseline for body 
weight, and screening 
for height 
 
X 
 


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Table 2-1 provides an overview of how subgroups are defined/derived and what type of analyses 
may be performed. Details are specified in relevant sections below. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographics, baseline characteristics, disease history and medical history will be summarized 
in total and by treatment group for the FAS. Descriptive statistics (mean, Q1, median, Q3, 
standard deviation, minimum and maximum) will be presented for continuous variables for each 
treatment group and for all subjects in total. The number and percentage of subjects in each 
category will be presented for categorical variables for each treatment group and in total. 
Demographics and baseline characteristics will be similarly summarized by gender and baseline 
glycemic status as well. 
Continuous variables: 
• Age  
• Height 
• Weight at screening 
• Body mass index (BMI) 
• Waist circumference (cm) 
• Baseline VFA (cm2) 
• Baseline SFA (cm2) 
• Smoking pack years 
• Baseline pulse (bpm) 
• Baseline systolic blood pressure (mmHg) 
• Baseline diastolic blood pressure (mmHg) 
• Baseline HbA1c (%) 
• Baseline FPG (mmol/L) 
• Baseline eGFR MDRD (mL/min) 
• Baseline eGFR MDRD with a Japanese coefficient (mL/min) 
Categorical variables 
• Age category (< 65, ≥ 65) 
• Gender 
• Subjects of child bearing status (females only) 
• Race 
• Smoking status at baseline 
• Alcohol history (0, 1, 2, >=3 drinks/day) 
• BMI (<27, ≥27; <30, ≥30; <35, ≥35) 
• Baseline glycemic status (dysglycemic, and T2DM) 
• Baseline VFA category (<150 cm2, ≥150 cm2) 


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• Baseline HbA1c category (<6.5, ≥6.5 - < 8%, ≥8%) 
• Baseline eGFR MDRD category (<60, ≥60 mL/min) 
Baseline eGFR MDRD category with a Japanese coefficient (<60, ≥60 mL/min) 
BMI will be calculated using the following formula: 
 
BMI = (body weight in kilograms) / (height in meters)2 
For BMI, the last value of height and body weight prior to randomization will be used.  
Medical history will be coded with the medical dictionary for regulatory activities terminology 
(MedDRA) using the most recent version at the time of database lock. The number and 
percentage of subjects with each medical condition will be provided by treatment group, 
primary system organ class, and preferred term. 
The protocol solicited medical history events will be summarized by event type, event status 
(yes, no, unknown), and treatment.  
2.3.1 
Patient disposition 
ENR or RAN will be used for the summary and listing of patient disposition.  
Based on the ENR, the number and percentage of patients successfully screened will be 
presented. In addition, the primary reasons for screen failures will be summarized by presenting 
number and percentage of screen failed patients by category. The number and percentage of 
subjects entered, completed, and failed in run-in will be summarized using the RUN. The 
reasons for run-in failures will be provided. The number and percentage of randomized subjects 
who completed the Epoch 3, who discontinued the Epoch 3 and the reasons for discontinuation 
will be presented for each treatment group using the RAN.  
The number of randomized subjects included in each analysis set (FAS, SAF, and PPS) will be 
presented by treatment group. The number and percentage of subjects with protocol deviations 
as well as the criteria leading to exclusion from analysis sets will be presented in separate tables 
for the RAN. Subject exclusion from analysis sets will be listed with reasons for exclusion.  
The number of randomized subjects included in each analysis set (FAS, SAF, and PPS) will 
also be presented by treatment group and baseline glycemic status.  
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The duration of double-blind treatment exposure in Epoch 3 will be summarized by treatment 
group both descriptively in days (mean, standard deviation, minimum, Q1, median, Q3, and 
maximum) and by duration category in weeks (≤2, >2-4, >4-8, >8-12, and >12) for the SAF.  
• Duration of exposure (days) = last dose date of Epoch 3 – first dose date + 1 
• Duration of exposure (weeks) = (last dose date of Epoch 3 – first dose date + 1)/7 


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Overall subject-years on-treatment in Epoch 3 will be reported by each treatment group. 
• Overall subject-years on-treatment = sum of duration of treatment exposure (in days) 
from all subjects / 365.25 
The duration of double-blind treatment exposure excluding treatment interruptions in Epoch 3 
will also be summarized descriptively and by duration categories as above.  
• Duration of exposure excluding treatment interruptions (days) = last dose date of Epoch 
3 – first dose date + 1– number of days of treatment interruption 
Number and percentage of subjects with treatment interruption and permanent treatment 
discontinuations in Epoch 3 will be provided by reason for treatment interruption or 
discontinuation. 
Duration of treatment interruption will also be summarized as appropriate.  
2.4.2 
Prior, concomitant and post therapies 
Prior medications are defined as any drugs taken and stopped prior to the first dose of study 
medication. Concomitant medications for Epoch 3 are any medications given at least once 
between the day of first dose of double-blind study medication and the end of Epoch 3, 
including those which started pre-BL and continued into the treatment period.  
The number and percentage of subjects receiving prior and concomitant medications will be 
summarized by treatment group and overall in the SAF in separate tables by therapeutic class 
and preferred term.  
The number and percentage of subjects taking rescue medication, and duration of exposure to 
rescue medication during Epoch 3 will be summarized by treatment group. 
The number and percentage of subjects on anti-diabetic medications at BL (randomization visit) 
will be summarized by treatment, baseline glycemic status, and medication types: 
• Any anti-diabetic medication (insulin or OADs) 
• Insulin 
• OADs (used as single pills) 
• Metformin 
• SU - Sulfonylureas (including Sulfonamides) 
• AGIs 
• TZDs 
• DPP-4 inhibitors 
• Combination of OADs 
• Phenformin + SU 
• Metformin + SU 
• Metformin + TZD 
• SU + TZD 
• Metformin + DPP-4i 


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• Metformin + AGI 
• DPP-4i + TZD 
• Other 
The search criteria for the anti-diabetic medications by type are included in the appendix. 
The use of prohibited medications, defined in Table 2-2 below, will also be summarized.  
Table 2-2 
Prohibited medication for reporting 
Prohibited Medication  
Drug code 
Empagliflozin 
07271601 
Clarithromycin 
00984601 
Telithromycin 
01548701 
Itraconazole 
00780701 
Ketoconazole 
00532501 
Voriconazole 
01510101 
Posaconazole 
01762801 
Probenecid 
00045101 
Valproic Acid 
00228501 
Mefenamic Acid 
00044201 
 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary analysis variable is the percent change in body weight (kg) from BL at Week 12. 
BL is defined as the last body weight value measured prior to or at the randomization visit (Visit 
201). This analysis will be carried out on the FAS, with missing Week 12 values imputed as 
described in Section 2.5.3. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary objective will be evaluated by the methodology using an optimally weighted 
contrast test (Pinheiro et al. 2006, Pinheiro et al. 2014). To this end, a candidate model set is 
defined corresponding to the range of expected mean response. The candidate model set is used 
to generate a set of weights for the calculation of optimal contrasts between the responses in the 
studied dose groups and the placebo group. A statistical test comparing all doses to the control 
group is used, hence a multiplicity adjustment is applied that accounts for the multiple possible 
dose response behavior considered. A critical value is derived from a multivariate t-distribution 
using the correlation matrix induced by the correlations between the weights corresponding to 
the candidate sets. 


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Test of the dose response signal 
The null hypothesis of a flat dose-response relationship for the percentage reduction in body 
weight compared to placebo will be tested at a one-sided significance level of 2.5% against the 
alternative hypothesis of a dose-response relationship leading to a significant decrease in 
percent body weight.  
Hence, the following null and alternative hypotheses will be tested: 
• H0: There is no dose-response relationship for LIK066 (i.e. the dose response relationship 
is flat). 
• H1: There is a dose-response relationship for LIK066 (i.e. as dose increases, the percent 
weight decreases). 
In order to preserve the family-wise error rate at one-sided significance level of 2.5%, the 
optimal contrasts derived from the model candidate set will be individually compared to the 
critical value derived using a multiplicity adjustment accounting for all tests comparing LIK066 
doses to placebo. The rejection of the null hypothesis will be achieved using the maximum test 
statistic from each estimated contrast test in the candidate set. 
The candidate models generating the contrast weights are described below and depicted in 
Figure 2-1: 
• Emax model: ED50 = 5 mg 
• Emax model: ED50 = 25 mg 
• Linear 
• Quadratic: δ = -0.014 
• Sigmoid Emax model: ED50 = 12.5 mg, h = 3 
• Linear on log dose, with offset value = 0.1 


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Figure 2-1 
Dose-response curve of candidate models 
 
The analysis to derive the test statistics is based on an analysis of covariance (ANCOVA) model 
with the percent change in body weight from BL, to Week 12 as a response variable, treatment 
(placebo and all LIK066 doses), stratum indicator (dysglycemic /T2DM) as factors and BL 
weight as a covariate. 
The response variable of percent change in body weight from BL to Week 12 used in the above 
ANCOVA is from an imputed dataset, where the missing Week 12 weight is imputed using the 
multiple imputation method as described in Section 2.5.3. In order to account for the imputation 
uncertainty, this ANCOVA model will be repeated for each imputed dataset, which results in a 
set of least squares (LS) mean estimates for all dose groups and the related covariance matrices. 
Rubin’s rule will be used to combine the multiple sets of LS mean estimates and the related 
covariance matrices to a single set of LS mean estimates of percent changes of body weight at 
Week 12 for all dose groups and the related covariance matrix. 
The optimal contrasts derived from the candidate model sets will be applied to the combined 
estimated dose means and covariance matrix to obtain the t statistics for each candidate model 
and the common critical value C0.025. C0.025 is the common critical value derived from the 
reference multivariate t-distribution with the 6x6 correlation matrix induced by testing the 
candidate dose response models with respect to comparing each LIK066 dose to the placebo 
group. 
The hypothesis H01 will be rejected and the statistical significance of dose-response in body 
weight reduction is established if the max (t1, t2, t3, t4, t5, t6) ≥ C0.025. 


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Model averaging to obtain the dose responses 
A parametric bootstrap-based model averaging approach will be implemented to obtain the dose 
response estimates for qd and bid dosing regimens according to the following steps: 
1. The parametric bootstrap procedure will draw a sample  of mean percent changes in 
body weight from baseline to Week 12 for all doses (including placebo) from a 
multivariate normal distribution, with mean and covariance matrix was determined 
using Rubin’s rule, as described earlier. This sample corresponds to the mean 
response for each dose (including placebo). 
2. Model selection will be performed as follows: dose-response models as depicted in 
Figure 2-1 will be fit to this bootstrap sample. The best model will be selected on 
basis of the gAIC criterion. 
3. The dose response estimate will be calculated for each dose group, including placebo, 
using this model. The difference in estimated dose response between each dose and 
placebo will also be calculated. The target doses of interest in each dosing regimen 
will be calculated based on this model as well. 
4. The above procedure  (steps 1-3) will be repeated 5,000 times. The mean dose-
response estimates by dose group and mean differences of dose-response estimates 
between each LIK dose and placebo, the target doses of interest, as well as their 95% 
confidence intervals will be calculated based on the quantiles (median, 2.5th and 97.5th 
percentiles) of these multiple sets of dose-response and target dose estimates 
generated in step 3. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing data for the primary endpoint will be imputed using a multiple imputation approach 
that assumes that the missingness mechanism can be retrieved from observed data (missing at 
random; MAR). The imputation model will be fitted within each treatment and stratum, using 
MCMC method, based on the longitudinal sequence of body weight data collected at each visit 
up to and including Week 12. . 
2.5.4 
Supportive analyses 
As a sensitivity analysis, the dose-response modeling as described in Section 2.5.2 will be 
conducted in the PPS as well. In addition, the same dose-response modeling will be conducted 
in the FAS using on-treatment weight data only. On-treatment data refer to those collected 
during the double-blind period, and prior to or within 7 days of the final study medication intake 
date. 
Summary statistics for body weight will be presented by visit by treatment for observed and 
imputed values. The summary statistics n, mean, SD, median, minimum, maximum, Q1 and Q3 
will be presented for the BL values and similarly for absolute values at and percent changes 
from BL to the post-BL visits. Also summary statistics will be presented using observed values 
only by visit, treatment, and subgroup of interest: baseline glycemic status, age group, gender, 
and BMI category. 


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Figures will be produced to visually show the raw and the imputed mean percent changes by 
visit over 12 weeks of Epoch 3 for each treatment group, for all subjects and by strata separately. 
2.6 
Analysis of the key secondary objective 
There is no key secondary objective for the study. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
• Responder rates based on percent decrease in body weight from BL at Week 12 ≥ 3%, 
≥ 5%, or ≥ 10% 
• Dose-response relationship in dysglycemic subjects and subjects with T2DM after 12 weeks 
of treatment. 
• Change from BL at Week 12 in waist circumference at umbilical level. 
• Change from BL at Week 12 in HbA1c 
• Change from BL at Week 12 in FPG 
• Change from BL at Week 12 in SBP and DBP 
• Percent changes from BL at Week 12 in the fasting lipid profile (TG, total cholesterol, HDL 
cholesterol, LDL cholesterol, lipoproteins, calculated VLDL cholesterol and non-HDL 
cholesterol)  
• Change from BL at Week 12 in log10-transformed hsCRP 
• Change from BL at Week 12 in uric acid 
• Change from BL at Week 12 in urine albumin 
• Change from BL at Week 12 in urine albumin to creatinine ratio 
• Change from BL at Week 12 in fat area parameters (VFA and SFA) 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Analysis method: responder analysis 
For the responder analysis, a logistic regression model will be performed using the percent 
decrease in body weight from BL at Week 12 ≥ 3%, ≥ 5% or ≥ 10% (yes/no) as a response 
variable, treatment, and glycemic stratification factor as fixed factors and BL body weight as a 
covariate, respectively. The Week 12 missing values will be imputed using the multiple 
imputation method as described in Section 2.5.3. In order to account for the imputation 
uncertainty, this logistic regression model will be repeated for each imputed dataset, which 
results in a set of estimated odds ratio and its 95% confidence interval of an LIK066 dose vs 
placebo for all dose groups. Rubin's rule will be used to combine the multiple sets of odds ratios 
and 95% confidence intervals to a single set of odds ratio and its 95% confidence interval of an 


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LIK066 dose vs placebo. Similar analysis by glycemic status stratification factor will be 
performed to assess the responder across each of the subgroups (subjects with dysglycemic and 
subjects with T2DM). 
In addition, subjects meeting the pre-defined response criteria (percent decrease in body weight 
from BL at Week 12 ≥ 3%, ≥ 5% or ≥ 10%) will be summarized by treatment for all subjects 
and by glycemic stratification factor. Cochran-Mantel-Haenszel-test will be performed to 
compare each dose to the placebo using observed values. 
Analysis method: dose-response relationship by glycemic stratification factor  
For the dose-response relationship in subjects with dysglycemic and subjects with T2DM, the 
dose-response modeling with the same candidate model sets for the primary variable as 
described in Section 2.5.2 will be performed on percent change of body weight from BL at 
Week 12 for these two subsets of subjects separately. 
Analysis for other secondary endpoints 
Other efficacy secondary endpoints are analyzed using ANCOVA models. 
• For changes from BL at Week 12 in HbA1c, FPG, lipid parameters,  fat area 
parameters, uric acid, urine albumin, urine albumin to creatinine  ratio, and log10-
transformed hsCRP,  an ANCOVA model will be applied for individual variables, 
including treatment and baseline glycemic status as fixed effect factors, and baseline 
as a covariate. 
• For changes from BL at Week 12 in other variables, a repeated measure ANCOVA 
model will be applied  with treatment, visit, baseline glycemic status, and treatment 
by visit interaction as fixed-effect factors and baseline as a covariate, and an 
unstructured covariance matrix among visits common between treatments. 
The adjusted mean changes at Week 12 within each treatment, the differences in mean changes 
at Week 12 between the LIK066 and placebo treatments, and their 95% confidence intervals 
obtained from the above model will be presented. 
In addition, ANCOVA analyses will be applied by baseline glycemic status. 
• For changes from BL at Week 12 in HbA1c, FPG, lipid parameters,  fat area 
parameters, urine albumin, urine albumin to creatinine  ratio, and log10-transformed 
hsCRP,  an ANCOVA model will be applied for individual variables, including 
treatment as a fixed effect factor, and baseline as a covariate. 
• For changes from BL at Week 12 in other variables, a repeated measure ANCOVA 
model will be applied  with treatment, visit, and treatment by visit interaction as 
fixed-effect factors and baseline as a covariate, and an unstructured covariance matrix 
among visits common between treatments. 
The adjusted mean changes at Week 12 within each treatment, the differences in mean changes 
at Week 12 between the LIK066 and placebo treatments for each stratum, and their 95% 
confidence intervals obtained from the above models will be presented by strata for each 
efficacy endpoint. 


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Summaries of absolute values and change from BL by treatment group and visit will be 
presented for all secondary efficacy variables for all subjects and by strata. Figures will be 
produced to visually show the raw mean changes by visit over 12 weeks of Epoch 3 for each 
treatment group, for overall and by strata separately.  
All analyses on secondary variables will be performed in the FAS. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing body weight at Week 12 will be imputed using the multiple imputation method as 
described in Section 2.5.3.  
Repeated measure ANCOVA models, which use all available data, will be used to analyze other 
secondary variables. The approach yields valid results, i.e. confidence intervals with correct 
coverage and tests with the correct size under a missing at random (MAR) process (Siddiqui 
et.al. 2009).   
2.8 
Safety analyses 
All safety analyses will be based on SAF. 
2.8.1 
Adverse events (AEs) 
A treatment-emergent AE is defined as any AE that develops after initiation of the study 
treatments or any event already present that worsens following exposure to the study treatment. 
Treatment emergent AEs will be summarized. The number and percentage of subjects having 
AEs will be summarized by system organ class, preferred term, and treatment group.  Unless 
otherwise specified, primary system organ will be sorted alphabetically and, within each 
primary system organ class, the preferred terms will be sorted in descending order of frequency 
in the LIK066 50 mg qd arm. If a patient reported more than one AE with the same preferred 
term, the AE will be counted only once. If a patient reported more than one AE within the same 
primary system organ class, the patient will be counted only once at the system organ class level. 
The number and percentage of subjects having AEs will be summarized by system organ class, 
preferred term, treatment group, and subgroups of interest (baseline glycemic status, age group 
and sex) as well.  
The most frequent AEs (>=5% in  LIK066 50mg qd arm group) will be presented by preferred 
term in descending order of frequency in the LIK066 50 mg qd arm.   
AEs will also be presented by greatest severity. If a patient reported more than one AE with the 
same preferred term, the highest severity will be presented. All AEs will be summarized by 
highest severity, primary system organ class, preferred term, and treatment. If a patient reported 
more than one AE within the same primary system organ class, only one AE will be counted 
for that patient at the highest severity level in the total row for each primary system organ class. 
Missing severity will be assumed to be severe in the summary table.   
AEs suspected to be related to study drug, serious AEs, fatal AEs, and AEs leading to study 
drug discontinuation, study drug interruption will be summarized by presenting number and 


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percentage of patients with an event by primary system organ class, preferred term, and 
treatment.  
All AEs in the database will be listed. The listings will include those AEs reported during the 
run-in epoch, and AEs reported after study discontinuation for those who discontinue the study 
prior to Week 12.   
Legal requirement for AE reporting 
For the legal requirements of ClinicalTrials.gov, two required tables on treatment emergent AEs 
which are not SAEs with an incidence greater than 2% and on treatment emergent SAEs and 
SAEs suspected to be related to study treatment will be provided by system organ class, 
preferred term, and 5 randomized treatment arms on the SAF for overall study duration. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
AEs of special interest, such as risks defined in the development safety profiling plan (DSPP), 
or topics of interest regarding signal detection or routine analysis, are defined in the electronic 
case retrieval sheet (eCRS) that is stored in GPS. 
The pre-defined issues of special interest for LIK066 including identified risks, potential risks, 
and special assessments are listed below: 
• Bone fractures 
• Cardiotoxicity 
• Diarrhea  
• Electrolyte disturbances 
• Genital  infections 
• Hepatotoxicity 
• Hypersensitivity 
• Hypoglycemia 
• Impaired renal function 
• Increased LDL 


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• Intravascular volume depletion 
• Ketoacidosis 
• Malignancy 
• Pancreatitis 
• Urinary tract infections 
• Venothrombotic and embolic events 
• Lower limb amputation 
• Pre-amputation events 
Treatment-emergent AEs of special interest which occur during Epoch 3 will be summarized 
by risk category and preferred term, by treatment. The AEs of special interest will be 
summarized by risk category, preferred term, treatment, and subgroups of interest (baseline 
glycemic status, age group, and sex) as well. 
In addition, exposure-adjusted incidence rates per 100 patient years regardless of study drug 
relationship, by treatment will be provided by risk category and preferred term. The 95% 
confidence interval for the overall exposure-adjusted incidence rates per 100 patients will also 
be presented for each risk category, along with relative risk and 95% confidence interval. 
Additional analyses for the pre-defined risks of diarrhea, ketoacidosis and hypoglycemia will 
be performed as described below: 
Diarrhea events of special interest 
Number of days with diarrhea events will be calculated for all patients with at least one 
incidence of diarrhea and will be summarized descriptively by treatment. 
• Number of days for one diarrhea incidence = AE end date – AE start date +1.  
• Number of days with diarrhea events for a patient = sum of days on diarrhea over all 
incidences that occurred in Epoch 3. 
The number and percentage of patients with diarrhea events during the double-blind treatment 
period (while patients on study medication) will also be summarized by treatment over time in 
the following time window: 0 - <2, 2 - <4, 4 - <8, and 8 - <12 weeks. 
In addition, the number of days with diarrhea while on-treatment will be analyzed via a negative 
binomial regression model. The model will include the number of days with diarrhea as a 
response variable, treatment, baseline glycemic status as factors, and log(duration of exposure 
in days) as an offset variable.  
Ketoacidosis events of special interest 
All cases of ketoacidosis will be adjudicated by an independent committee. The frequencies and 
percentages of the adjudication confirmed ketoacidosis events will be provided by treatment.  
The site-reported ketoacidosis events will also be summarized by treatment. In addition, the 
ketoacidosis events will be listed at individual patient level, with the site-reported event profile 
and symptoms and the adjudication outcome displayed as well. 


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Hypoglycemic events of special interest 
There are two categories of clinically significant hypoglycemic events: 


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Table 2-3 
Criteria for hypoglycaemia events 
Category 
Criteria 
Severe hypoglycaemia 
An event, requiring assistance of another person (third 
party assistance) to actively administer carbohydrate, 
glucagon, or other corrective actions, confirmed or not by a 
blood glucose measurement 
Other clinically significant 
hypoglycaemia 
Plasma glucose < 3.0 mmol/l (54 mg/dl) with or without 
typical symptoms of hypoglycaemia, and which is handled 
by the subject himself/herself. 
Hypoglycemic events entered into the study Hypoglycemic event eCRF will be included in all 
of the AE summaries in Section 2.8.1. Hypoglycemia classification is included in the Appendix 
Table 5-1.  
In addition, patients reporting at least one clinically significant hypoglycemic event, and the 
subgroup of patients reporting >2 such events, patients discontinued study medication or 
withdrew from the study due to clinically significant hypoglycemic events, patients reporting 
severe hypoglycemic events, and patients reporting other clinically significant hypoglycemic 
events will be summarized by numbers and percentages in each  treatment group.  The exposure-
adjusted incidence rates, relative risks and the related 95% confidence intervals of LIK groups 
versus placebo for the overall, severe and other clinically significant hypoglycemic incidences 
will be calculated respectively, and presented along with other safety risks/events of interest. 
The clinically significant hypoglycemic events will also be summarized by event profile as 
follows: 
• Severity (Mild, Moderate, Severe) 
• Meeting the definition of an SAE (Yes, No) 
• Seriousness (Death, Requires or prolongs hospitalization, Life threatening, Congenital 
anomaly or birth defect, Significant disability, Other medically importance serious 
event) 
• Discontinuation due to hypoglycemic events (Yes, No) 
• Relationship to the study treatment (No, Investigational treatment, Other study 
treatment, Both and/or indistinguishable) 
• Action taken with study treatment (Dose increased, Dose not changed, Dose reduced, 
Drug interrupted, Drug withdrawn, Unknown, Not applicable)  
• Medication or therapy taken (Yes, No) 
• Outcome (Not recovered/not resolved, Recovered/resolved, Recovered/Resolved with 
sequelae, Fatal, Unknown) 
• Time of the day in 24-hour clock (>00:00–06:00, >06:00–12:00, >12:00–18:00, 
or >18:00–24:00) 
• Time between last meal and event 
• Time between last dose and event 
• Precipitating factors (None, Missed/delayed meal, Strenuous exercise, Alcohol 
consumption, Other) 


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• Third party assistance recieved (Yes, No) 
• Medical assistance received (Yes, No) 
In addition, for pre-defined risk and selected AEs including hypotension, hypoglycemia, 
hyperkalemia, diarrhea, genital infections and UTIs, a by-stratification factor of BL glycemic 
status subgroup analysis will be provided. 
A listing of AEs of special interest will be presented by treatment group and patient number.  
2.8.2 
Deaths 
Any deaths up to and including Week 12 will be included in a separate able by treatment group 
summarizing fatal events. 
Deaths will also be listed by treatment groups. 
2.8.3 
Laboratory data 
Table 2-4 displays laboratory parameters analyzed for reporting. 
Table 2-4 
Laboratory data 
Category 
Parameter(s) 
Hematology 
RBC (total), WBC (total), platelet count (direct), hemoglobin, hematocrit, 
basophils (absolute, %), eosinophils (absolute, %), lymphocytes 
(absolute, %), monocytes (absolute, %), neutrophils (absolute, %) 
Biochemistry 
ALT, albumin, alkaline phosphatase (ALP), AST, bicarbonates, bilirubin 
(direct, total), blood urea nitrogen (BUN), calcium (total), chloride, 
creatinine, cystatin C, eGFR (MDRD, MDRD with the Japanese 
coefficient), magnesium, phosphates, potassium, protein (total), sodium, 
uric acid*, γ-GT, amylase, lipase 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, nitrites, blood, leucocytes, 
urine albumin*, urine albumin to creatinine ratio (spot urine)* 
*: By-visit summary statistics for the parameter is provided only as efficacy analysis.  
Descriptive summary statistics including for the change from BL to each study visit up to and 
including Week 12 visit will be presented by treatment group for each laboratory parameter, as 
well as for the maximum change from BL. In addition, shift tables will be provided for all 
parameters with available ranges to compare a subject’s BL laboratory evaluation relative to 
the most extreme post-BL value. For the shift tables, normal ranges as well as specifically 
defined clinically notable/abnormality limits, if available – will be used. 
A listing of all patients with notable laboratory values will be provided.  
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline are shown in Table 2-5. 


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Table 2-5 
Clinically notable laboratory abnormalities for selected tests 
Parameter 
Criteria (based on a percent change from baseline or change 
from baseline) 
Hematology 
  
RBC (total) 
>50% increase, >20% decrease 
WBC (total) 
>50% increase, >50% decrease 
Platelet count  
>75% increase, >50% decrease 
Hemoglobin  
>50% increase, >20% decrease 
Hematocrit 
>50% increase, >20% decrease 
Clinical chemistry 
  
ALT 
>150% increase  
AST 
>150% increase 
BUN 
>50% increase 
Creatinine 
>50% increase 
Total bilirubin 
>100% increase 
ALP 
>100% increase  
Sodium 
>5% increase, >150 mmol/L, <130 mmol/L  
Potassium 
absolute values < 3.0 mmol/L, > 5.9 mmol/L 
Chloride 
>10% increase, >10% decrease 
Calcium 
>10% increase, >10% decrease, hyper > 2.6 mmol/L 
Uric acid 
>50% increase 
Plasma glucose 
>50% increase  
Plasma glucose 
< 3.0 mmol/L (54 mg/dL) 
 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
The following quantitative variables will be summarized:  
• QTcF duration (msec) 
• Heart rate (beats/min) 
• PR duration (msec) 
• RR duration (msec) 
• QRS duration (msec) 
Changes from baseline for ECG variables will be provided; for QTcF and heart rate, inferential 
statistics will be generated as well.  
The number and percentage of subjects with the following criterion will be presented.  
• QTcF > 500 msec 
• QTcF > 480 msec 
• QTcF > 450 msec 


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• QTcF increases from baseline ≥ 30 msec 
• QTcF increases from baseline ≥ 60 msec 
• PR > 200 and ≤ 220 msec 
• PR > 220 msec 
• PR increases from baseline > 25%  and to a value > 200 msec 
• QRS > 110 and ≤ 120 msec 
• QRS > 120 msec 
• QRS changes from baseline > 25 % and to a value > 110 msec 
• Heart rate > 100 beats/min 
Heart rate < 50 beats/min 
In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, total) 
with the maximum on-study result (normal, abnormal, not available, total) will be provided for 
each variable. The cut-off values are :  
• QTcF: 450 msec for male, or 460 for female 
• QRS: 120 msec 
• PR: 200 msec 
• HR: 100 beats/min 
 
A listing of ECG parameters together with newly occurring or worsening abnormalities will be 
provided.  
2.8.4.2 
Vital signs 
For vital sign data collected during Epoch 3, descriptive statistics will be provided for absolute 
values and change from baseline at each assessment time point by treatment group as 
appropriate. 
The number and percentage of patients with newly occurring or worsening notable values, 
including notable change from baseline will be summarized by vital sign parameter at each 
assessment time point by treatment group. Notable absolute values and notable changes from 
baseline for each vital sign parameter are defined in Table 2-6. 
Table 2-6 
Vital signs notable range deviations 
Vital signs 
 
Notable abnormalities 
Pulse (beats/min) 
 
either ≥ 120 + increase ≥ 25* or > 130 
 
 
either ≤ 50 + decrease ≥ 30* or < 40 
BP (mmHg) 
systolic 
either ≥ 180 + increase ≥ 30* or > 200 
 
 
either ≤ 90 + decrease ≥ 30* or < 75 
 
diastolic 
either ≥ 105 + increase ≥ 20* or > 115 
 
 
either ≤ 50 + decrease ≥ 20* or < 40 


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* Refers to post-BL value as compared to BL value. 
  
A listing of all patients with notable vital sign values and changes will be provided. 
2.8.5 
Liver events 
Liver events and laboratory trigger definitions and follow-up requirements are defined in 
Appendix 2 of the protocol.  
The laboratory parameters for liver function will be shown in the laboratory standard tables as 
discussed in Section 2.8.3. In addition, summary tables will be provided on the number and 
percentage of subjects who meet the liver toxicity criteria post baseline by Week 12 displayed 
in Table 2-7.  
Listings of patients with clinically notable LFT values will be provided.   
Table 2-7 
Criteria for evaluating liver toxicity 
Parameter 
Criterion 
ALT or AST 
ALT or AST > 3xULN 
 
ALT or AST > 5xULN 
 
ALT or AST > 8xULN 
 
ALT or AST > 10xULN 
 
 
Hy’s category 
ALT or AST >3x ULN and TBL >1.5x ULN 
 
ALT or AST > 3xULN & TBL > 2xULN 
 
ALT or AST > 5xULN & TBL > 2xULN  
 
ALT or AST > 8xULN & TBL > 2xULN  
 
ALT or AST > 10xULN & TBL > 2xULN 
 
ALT or AST > 3xULN & TBL > 2xULN & ALP ≤ 2xULN 
 
 
TBL&ALP 
TBL >1.5x ULN and ALP >2x ULN 
 
TBL >2x ULN and ALP >2x ULN 
 
 
Isolated TBL 
TBL >1.5x ULN & ALT and AST <3x ULN and ALP <2x ULN 
 
TBL >2x ULN & ALT and AST <3x ULN and ALP <2x ULN 
 
TBL >3x ULN & ALT and AST <3x ULN and ALP <2x ULN 
 
 
Isolated ALP 
ALP >1.5x ULN &  ALT and AST <3x ULN and TBL <1.5x ULN 
 
ALP >2x ULN &  ALT and AST <3x ULN and TBL <1.5x ULN 
 
ALP >3x ULN & ALT and AST <3x ULN and TBL <1.5x ULN 
 
ALP >5x ULN & ALT and AST <3x ULN and TBL <1.5x ULN 
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: 
total bilirubin; ULN: upper limit of normal.  


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2.8.6 
Renal events 
The overall frequency of events and percentage of patients with renal events during the 
treatment period will be provided for the Week 12 analysis. Furthermore, the frequency and 
percentage of patients with renal events during Epoch 3 will be provided by treatment and the 
first identified criterion. The frequency of patients with renal events and percentage will be 
provided for clinical signs and symptoms by the treatment. The criteria for renal events are 
displayed in Table 2-8. 
Renal event overview data, pathology data, and imaging data will be provided in listings.  
The renal function lab data will be analyzed in Section 2.8.3 Laboratory data.  
Table 2-8 
Specific renal alert criteria  
Criteria 
Action required 
Serum event 
Serum creatinine increase 
25 – 49 % compared to BL 
Confirm 25 % increase after 24-48h  
Follow up within 2-5 days 
Acute kidney injury: serum creatinine increase 
≥50 % compared to BL 
Follow up within 24-48h if possible 
Consider study treatment interruption  
Consider subject hospitalization /specialized 
treatment 
Urine event 
New dipstick proteinuria ≥ 1+ 
Albumin- or protein-creatinine ratio increase 
≥2-fold 
Albumin-creatinine ratio (ACR) ≥30 mg/g or 
≥3 mg/mmol; 
Protein-creatinine ratio (PCR)≥150 mg/g 
or >15 mg/mmol 
Confirm value after 24 to 48h 
Perform urine microscopy 
Consider study treatment interruption / or 
discontinuation  
New dipstick hematuria ≥ 1+ not due to trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR  
 
2.9 
Pharmacokinetic endpoints   
PK trough sampling will be performed in all subjects at visit 299. 
Plasma concentration of LIK066 will be summarized by treatment. Descriptive statistics 
includes n, mean, standard deviation, minimum, median, maximum, coefficient of variation (%) 
for arithmetic mean, geometric mean, and coefficient of variation (%) for geometric mean.  
Concentrations below the lower limit of quantification (LLOQ) will be treated as zero in 
summary statistics. A geometric mean will not be reported if the dataset includes zero values.  
Individual LIK066 plasma concentration data will be listed by treatment, subject, and visit.  


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2.10 
PD and PK/PD analyses 
Not applicable. 


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2.13 
Other Exploratory analyses 
Not applicable. 
2.14 
Interim analysis 
Not applicable. 


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3 
Sample size calculation 
The study planned to randomize approximately 130 subjects in total, allocated in the ratio of 
3:2:2:3:3 to the following Epoch 3 treatment groups: 
1. placebo 
2. LIK066 2.5 mg qd 
3. LIK066 10 mg qd 
4. LIK066 25 mg qd 
5. LIK066 50 mg qd 
This randomization scheme implies that the Epoch 3 treatment for a specific subject is 
determined simultaneously at randomization visit. The randomization will be stratified by 
subjects' glycemic status: T2DM and dysglycemic. 
Sample sizes are considered from two viewpoints. One is that this study should be statistically 
powered to identify the dose-response relationship regarding the effect of LIK066 on weight 
loss. The other is that this is the first study to enroll Japanese patients, and that the highest dose 
arms, 25 mg and 50 mg qd arms, and the placebo arm as a control, should include more patients 
to obtain sufficient information on safety and/or tolerability of LIK066 in Japanese patients. 
The detail of the first viewpoint will follow. 
Table 3-2 summarizes the average power and the lowest power across the candidate 
dose-response shapes in Figure 2-1, under different scenarios with the assumptions on effect 
size of body weight loss (percent change from BL) for the dose of maximum effect, and the 
related standard deviations. In power evaluation, it was also assumed that dose-response is 
assessed with controlling the overall family-wise type I error at a one-sided significance level 
of 2.5%. 
It was assumed that the effect of losses to follow-up is equivalent to effectively having 10% 
fewer subjects than randomized, even if the multiple imputation approach used to handle 
missing values should be able to recover some information for such subjects. 
 
Table 3-1 
Power for detecting a significant dose response signal* 
Effect size for best dose 
Standard deviation 
Average power 
Minimum power** 
3.5% 
3% 
99.70% 
99.52% 
3.5% 
3.5% 
98.11% 
97.28% 
4.0% 
3% 
99.97% 
99.94% 
4.0% 
3.5% 
99.59% 
99.35% 
* Assumes 130 subjects in total with effective sample size of 117 subjects due to an effect of missing 
data equivalent to 10% fewer subjects. Calculations were performed using R Dose Finding package. 
** Power for a significant dose-response contrast test across all scenarios mentioned in 
Section 2.5.2. The quadratic model has the lowest power. 
 


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4 
Change to protocol specified analyses 
 
Per project-level change, the summary on baseline anti-diabetic medications is changed to be 
provided by baseline glycemic status. 
Per project-level change, the procedures for modeling dose-response relationship are changed 
as follows: 
• Modeling via the best-fit model is cancelled. 
• The model-averaging method is changed. 
For efficacy secondary endpoints other than responder in body weight, ANCOVA models are 
changed depending on their scheduled post-baseline measurement time points 
• For endpoints measured only at Week 12,  the ANCOVA model is changed to the one 
including treatment and baseline glycemic status as fixed effect factors, and baseline 
as a covariate. Such endpoints include HbA1c, FPG, lipid parameters,  fat area 
parameters, urine albumin, urine albumin to creatinine  ratio, and log10-transformed 
hsCRP. 
• For other endpoints, baseline status is added to the repeated measure ANCOVA 
model. 
In addition, the models for subgroup analysis are changed to apply the same model by baseline 
glycemic status. 
• For endpoints measured only at Week 12,  the ANCOVA model for subgroup analysis 
is changed to the one including treatment as a fixed effect factor, and baseline as a 
covariate. 
• For other endpoints, the repeated measure ANCOVA model is changed to the one 
including treatment, visit, and treatment by visit interaction as fixed-effect factors and 
baseline as a covariate. 
 
 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Any partial dates will be imputed as the earlier day of  
• The last day in the month and  
• The end day of the corresponding epoch 
5.1.2 
AE date imputation 
AE end date imputation 
1. If ‘month’ is missing, the end date will be set to the earliest of the (min (last visit date, 
last dose date), 31DECYYYY, and date of death).  
2. If ‘day’ is missing, the end date will be set to the earliest of the (min (last visit date, 
last dose date), 31MONYYYY, and date of death). 
3. If ‘year’ is missing or AE is ongoing, the end date will not be imputed.  
AE start date imputation 
Before imputing AE start date, find the AE start reference date.  
• If the (imputed) AE end date is complete and the (imputed) AE end date < treatment 
start date then AE start reference date = min (informed consent date, earliest visit 
date). 
• Else AE start reference date = treatment start date 
After finding the AE start reference date: 
1. If ‘year’ is missing, the date uncertainty is too high; therefore the imputed AE start 
date will be set to NULL. 
2. If ‘year’ is less than the treatment start date ‘year’, the AE started before treatment; 
therefore:  
a. If ‘month’ is missing, the AE start date will be set to 01JULYYYY. 
b. If ‘day’ is missing, the AE start date will be set to 15 MONYYYY.  
3. If ‘year’ is greater than the treatment start date ‘year’, the AE started after treatment; 
therefore: 
a. If ‘month’ is missing, the AE start date will be set to 01JANYYYY.  
b. IF ‘month’ is not missing, the AE start date will be set to the later of 
(01MONYYYY, AE start reference date + 1). 
4. If ‘year’ is equal to the treatment start date ‘year’ 
a. If ‘month’ is missing, the AE start date will be set to the AE reference start date 
+1. 
b. If ‘month’ is less than the treatment start ‘month’, the AE start date will be set to 
15MONYYYY. 


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c. If ‘month’ is equal to or greater than the treatment start ‘month’, the AE start date 
will be set to the later of (01MONYYYY, AE start reference date+1). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, imputed AE start date will be set to the (imputed) AE end date.  
5.1.3 
Concomitant medication date imputation 
CM end date imputation  
1. If ‘day’ is missing and ‘month/year’ are non-missing then impute date as the earlier of 
(treatment end date, and 31MONYYYY).   
2. If ‘day/month’ are missing and ‘year’ is non-missing then impute date as the earlier of 
(treatment end date, and 31DECYYYY). 
3. If imputed end date is less than the start date, use the start date as the imputed end 
date.  
CM start date imputation  
1. If ‘year’ is missing, the start date will be set to one day prior to treatment start date.  
2. If ‘year’ is less than treatment start ‘year’, the CM started before treatment. Therefore: 
a. If ‘month’ is missing, the start date will be set to 01JULYYYY. 
b. If ‘month’ is non-missing, the start date will be set to 15MONYYYY. 
3. If ‘year’ is greater than treatment start ‘year’, the CM started after treatment. 
Therefore 
a. If ‘month’ is missing, the start date will be set to 01JANYYYY. 
b. If ‘month’ is non-missing, the start date will be set to 01MONYYYY. 
4. If ‘year’ is equal to the treatment start date ‘year’ 
a. If ‘month’ is missing or equal to the treatment start ‘month’, then the start date 
will be set to one day prior treatment start date. 
b. If ‘month’ is less than the treatment start ‘month’, the start date will be set to 
15MONYYYY.  
c. If ‘month’ is greater than the treatment start ‘month’, the start date will be set to 
01MONYYYY. 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date will be set to the (imputed) end date.  
5.1.3.1 
Prior therapies date imputation 
See Section 5.1.3. 
5.1.3.2 
Post therapies date imputation 
See Section 5.1.3. 


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5.1.3.3 
Other imputations 
Not applicable. 
5.2 
AEs coding/grading 
AEs will be coded according to MedDRA dictionary. The MedDRA version used for reporting 
will be described in the footnotes. Missing severity will be assumed to be severe in the summary 
table. 
Hypoglycemia classification is presented in Table 5-1. 
Table 5-1 
Hypoglycemia classification 
Category 
Definition 
Criteria as specified in the 
Hypo eCRF 
Severe 
hypoglycemia 
An event, requiring 
assistance of another 
person (third party 
assistance) to actively 
administer 
carbohydrate, glucagon, 
or other corrective 
actions, confirmed or not 
by a BG measurement 
An event with answer = ‘YES’ 
for any one of the two 
questions: 
Was third party assistance 
required? 
Was medical assistance 
received? 
 
Other clinically 
significant 
hypoglycemia 
Plasma glucose < 3.0 
mmol/l (54 mg/dl)* with 
or without typical 
symptoms of 
hypoglycaemia, and 
which is handled by the 
subject himself/herself. 
An event with answer = ‘YES’ 
to the question ‘Glucose 
measurement taken’ and the 
plasma glucose < 3.0 mmol/l 
(54 mg/dl), and answer = NO 
to both questions: 
Was third party assistance 
required? 
Was medical assistance 
received? 
*Blood glucose values need to be converted to plasma glucose values. 
A plasma glucose of 3.0 mmol/L (54 mg/dL) corresponds to a whole blood glucose of 2.7 mmol/L (48 
mg/dL) 
Plasma glucose = blood glucose * 1.12. 
 
5.3 
Laboratory parameters derivations 
5.3.1 
Japanese coefficient for eGFR 
The Japanese coefficient for the MDRD equation is 0.808. Thererfore, eGFR with Japanese 
coefficient, say eGFR-J, is defined as: 
eGFR-J = (source eGFR) × 0.808,  
where “source” eGFR is the one calculated by the central laboratory. 


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5.4 
Statistical models 
5.4.1 
Primary analysis 
See Section 2.5.2. 
5.4.2 
Key secondary analysis 
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets  
Table 5-2 
Protocol deviations that cause subjects to be excluded 
Deviation ID 
Description of Deviation 
Exclusion in Analyses 
INCL01 
No written informed consent obtained 
Excluded from ENR, RUN, RAN, 
FAS, SAF, and PPS 
TRT19 
Withdrawal of the consent without 
discontinuation of study drug 
Data collected after withdrawal 
of IC, excluded from FAS and 
SAF  
TRT34 
Mis-randomization 
Excluded from FAS and PPS 
INCL03 
BMI outside range or missing 
Excluded from PPS 
INCL04 
FPG and HbA1c not within range or 
missing 
Excluded from PPS 
INCL05 
Waist circumference outside range or 
missing 
Excluded from PPS 
INCL06 
VFA outside range or missing 
Excluded from PPS 
EXCL04 
Use of prohibited medications 
Excluded from PPS 
EXCL05 
History of malignancy 
Excluded from PPS 
EXCL06 
Pregnant or nursing 
Excluded from PPS 
EXCL08 
Use of pharmacologically active weight-
loss medications 
Excluded from PPS 
EXCL10 
Bariatric surgery 
Excluded from PPS 
EXCL20 
Substances or alcohol abuse 
Excluded from PPS 
TRT06 
Study treatment adjusted 
Excluded from PPS 
TRT11 
Study treatment unmasked and subject 
not discontinued from the study 
Excluded from PPS 
TRT15 
Use of prohibited medication and not 
discontinued from the study 
Excluded from PPS 
TRT22 
Use of another investigational drug 
Excluded from PPS 
TRT35 
Study medication taken after the 
morning meal 
Excluded from PPS 
TRT28 
Misdispensed medication and taken by 
subject 
Excluded from PPS 
OTH01 
Mis-randomization 
Excluded from PPS 


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Table 5-3 
Subject Classification 
Analysis Set 
PD ID that 
    
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
ENR 
INCL01 
Not having informed consent; 
Not having screening epoch disposition page 
RUN 
INCL01 
Not in ENR; 
Not having run-in epoch disposition page 
RAN 
INCL01 
Not randomized 
FAS 
INCL01, TRT19, TRT34 
Not in RAN; 
PPS 
INCL01, INCL03, INCL04, 
INCL05, INCL06, EXCL04, 
EXCL05, EXCL06, EXCL08, 
EXCL10, EXCL20, TRT06, 
TRT11, TRT15, TRT22, TRT35, 
TRT 28, TRT34, and OTH01 
Not in FAS; 
Overall exposure on DB medication < 10 weeks 
unless premature discontinuation due to 
adverse events 
SAF 
INCL01, TRT19 
No double-blind study drug taken 
5.6 
Anti-diabetic medications search criteria 
The documents attached below contain the search criteria of anti-diabetic medications for 
reporting. 
Table 5-4 
Search criteria for anti-diabetic medications by type 
Category 
Type 
ATC code or drug code 
Insulin 
All insulin A10A 
A10A (all insulin), and within this 
group: 
A10AB, A10AC, A10AD, A10AE 
and A10AF 
OADs – used as single pills 
Metformin 
A10BA Biguanides 
 
SU 
A10BB Sulfonylureas 
A10BC Sulfonamides 
(heterocyclic) 
 
AGIs 
A10BF Alpha glucosidase 
inhibitors 
 
TZDs 
A10BG Thiazolidinediones 
 
DPP-4i 
A10BH Dipeptidyl peptidase 4 
(DPP-4) inhibitors 
 
GLP-1 analogues 
A10BJ Glucagon-like peptide-1 
(GLP-1) analogues 
 
SGLT2i 
A10BK Sodium-glucose co-
transporter 2 (SGLT2) inhibitors 
Combinations of OADs 
 
See the slide attached below. 
 
 
 
Other 
 
A10BX Other 
Category 
Type 
ATC code or drug code 


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Classification of 
non-insulin drugs  
 


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6 
Reference 
Matsuo S, et al. (2009) Revised equations for estimated GFR from serum creatinine in Japan. 
American Journal of Kidney Disease; 53(6):982-92 
Pinheiro J, Bornkamp B, Bretz F (2006) Design and analysis of dose finding studies 
combining multiple comparisons and modeling procedures. Journal of Biopharmaceutical 
Statistics; 16(5): 639-56. 
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Statistics in Medicine; 33(10): 1646-661. 
Siddiqui O, Hung J HM, and O’Neill R (2009) MMRM vs. LOCF: a comprehensive 
comparison based on simulation study and 25 NDA datasets. Journal of Biopharmaceutical 
Statistics; 19(2):227-246