Clinical trial NCT03205150
Conditions: Obese Patients With Non-alcoholic Steatohepatitis (NASH)
Keywords: non-alcoholic steatohepatitis NASH Obese Type 2 diabetes mellitus non-alcoholic fatty liver disease
Sponsor: Novartis Pharmaceuticals
Start date: 2017-10-04; Completion date: 2019-11-14
Enrollment: 107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess the effects of LIK066 on a variety of metabolic and inflammation biomarkers in patients with non-alcoholic steatohepatitis (NASH)

Detailed description:
This was a a non-confirmatory, multicenter, patient and investigator blinded, randomized, placebo-controlled, parallel group study in patients with non-alcoholic steatohepatitis (NASH).

The study consisted of a 28 day screening period (Day -44 to Day -16), a baseline period of 14 days (Day -15 to Day -1), a treatment period of 12 weeks (Day 1 to Day 84), and a study completion evaluation approximately 28 days after the last drug administration. The patients were advised to maintain their recommended diet during the study.

Patients who met the inclusion/exclusion criteria at screening went to the study site for baseline assessments. All baseline safety evaluation results were available prior to the first dosing.

The study started by enrolling patients into the 150 mg and placebo arms with a randomization ratio of 2:1. After the enrollment of the first 33 patients, the 30 mg arm was added to the study and the randomization ratio changed to a 2:4:1 ratio (150 mg: 30 mg: placebo) to maintain the 2:2:1 ratio across the three groups (150 mg: 30 mg: placebo) at study completion.

Arms: arm 1: Film coated tablet of LIK066 30 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84. arm 2: Film coated tablet of LIK066 150 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84 arm 3: LIK066 0 mg film-coated tablet(Placebo matching tablets) was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84.
Interventions: intervention 1: LIK066 intervention 2: Placebo
Intervention descriptions: intervention 1: Film coated tablet of LIK066 either 30mg or 150 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84 intervention 2: LIK066 0 mg film-coated tablet(Placebo matching tablets) was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84.

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LIK066
Clinical Trial Protocol CLIK066X2204
A 12-week randomized, patient and investigator blinded, 
placebo-controlled, parallel group study to investigate the 
efficacy of LIK066 in obese patients with non-alcoholic 
steatohepatitis (NASH)
Document type:
Amended Protocol Version
EUDRACT number:
2017-002046-71
Version number:
v03 (Clean)
Clinical Trial Phase:
Phase II
Release date:
29-August-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................10
Glossary of terms...............................................................................................................11
Protocol Synopsis ..............................................................................................................18
1
Introduction .......................................................................................................................23
1.1
Background............................................................................................................23
1.2
Nonclinical data.....................................................................................................24
1.2.1
Teratogenicity and reproductive toxicity data.......................................25
1.3
Clinical data...........................................................................................................25
1.3.1
Human safety and tolerability data .......................................................25
1.3.2
Human pharmacokinetic data................................................................26
1.3.3
Human pharmacodynamic data.............................................................26
1.4
Study purpose ........................................................................................................26
2
Objectives and endpoints...................................................................................................27
2.1
Primary objective(s)...............................................................................................27
2.2
Secondary objective(s)...........................................................................................27
2.3
Exploratory objective(s) ........................................................................................28
3
Investigational plan ...........................................................................................................29
3.1
Study design...........................................................................................................29
3.2
Rationale of study design.......................................................................................30
3.3
Rationale for dose/regimen, route of administration and duration of treatment....31
3.4
Rationale for choice of comparator .......................................................................31
3.5
Purpose and timing of interim analyses/design adaptations..................................32
3.6
Risks and benefits..................................................................................................32
3.6.1
Blood sample volumes..........................................................................33
4
Population..........................................................................................................................33
4.1
Inclusion criteria ....................................................................................................34
4.2
Exclusion criteria...................................................................................................34
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5
Restrictions for Study Subjects .........................................................................................38
5.1
Contraception requirements...................................................................................38
5.2
Prohibited treatment...............................................................................................39
5.3
Dietary restrictions.................................................................................................40
5.4
Other restrictions ...................................................................................................40
6
Treatment...........................................................................................................................40
6.1
Study treatment......................................................................................................40
6.1.1
Investigational treatment and control drug(s) .......................................40
6.1.2
Additional study treatment....................................................................40
6.2
Treatment arms......................................................................................................41
6.3
Treatment assignment and randomization.............................................................41
6.4
Treatment blinding.................................................................................................42
6.5
Treating the subject................................................................................................43
6.6
Permitted dose adjustments and interruptions of study treatment.........................43
6.7
Emergency breaking of assigned treatment code ..................................................44
6.8
Treatment exposure and compliance .....................................................................44
6.9
Recommended treatment of adverse events ..........................................................44
6.10
Concomitant treatment...........................................................................................45
7
Study completion and discontinuation ..............................................................................45
7.1
Study completion and post-study treatment ..........................................................45
7.2
Discontinuation of study treatment........................................................................45
7.3
Withdrawal of informed consent ...........................................................................47
7.4
Lost to follow-up ...................................................................................................48
7.5
Study Stopping rules..............................................................................................48
7.6
Early study termination by the sponsor .................................................................48
8
Procedures and assessments ..............................................................................................49
8.1
Assessment schedule .............................................................................................49
8.2
Informed consent procedures.................................................................................53
8.3
Subject screening...................................................................................................53
8.4
Subject demographics/other baseline characteristics.............................................53
8.5
Efficacy / Pharmacodynamics ...............................................................................54
8.5.1
Clinical Outcome Assessments (COAs) ...............................................54
8.5.2
Body Weight .........................................................................................54
8.5.3
Body Height ..........................................................................................54
8.5.5
MRI .......................................................................................................54
8.5.6
Liver function tests................................................................................55
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8.5.7
Markers of Liver Fibrosis......................................................................55
8.5.8
Waist circumference, Hip circumference and waist:hip ratio...............55
8.6
Safety.....................................................................................................................55
8.6.1
Alcohol Test and Drug Screen ..............................................................55
8.6.2
Body Temperature.................................................................................55
8.6.3
Blood chemistry ....................................................................................56
8.6.4
Blood Pressure and Pulse Rate..............................................................56
8.6.5
Hepatitis and HIV Screen......................................................................56
8.6.6
Hematology...........................................................................................56
8.6.7
Pregnancy and assessments of fertility .................................................56
8.6.8
Physical Examination............................................................................57
8.6.9
Urinalysis ..............................................................................................57
8.6.10
ECG evaluation.....................................................................................57
8.7
Pharmacokinetics...................................................................................................57
8.8
Other assessments..................................................................................................58
9
Safety monitoring..............................................................................................................59
9.1
Adverse events.......................................................................................................59
9.2
Serious adverse event reporting.............................................................................61
9.2.1
Definition of SAE .................................................................................61
9.2.2
SAE reporting........................................................................................62
9.3
Liver safety monitoring .........................................................................................62
9.4
Renal safety monitoring.........................................................................................67
9.4.1
Renal safety monitoring........................................................................67
9.5
Reporting of study treatment errors including misuse/abuse ................................68
9.6
Pregnancy reporting...............................................................................................69
9.7
Early phase safety monitoring ...............................................................................69
9.8
AEs of special interest ...........................................................................................70
9.8.1
Ketoacidosis ..........................................................................................70
9.8.2
Hypoglycemia .......................................................................................70
9.8.3
Orthostatic hypotension ........................................................................71
9.8.4
Fournier’s gangrene ..............................................................................71
10 Data review and database management.............................................................................72
10.1
Site monitoring ......................................................................................................72
10.2
Data collection.......................................................................................................72
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10.3
Database management and quality control............................................................73
10.4
Data Monitoring Committee..................................................................................74
10.5
Adjudication Committee........................................................................................74
11 Data analysis......................................................................................................................74
11.1
Analysis sets ..........................................................................................................74
11.2
Subject demographics and other baseline characteristics......................................74
11.3
Treatments .............................................................................................................74
11.4
Analysis of the primary variable(s) .......................................................................74
11.4.1
Primary Variable(s)...............................................................................74
11.4.2
Statistical model, hypothesis, and method of analysis..........................75
11.4.3
Handling of missing values/censoring/discontinuations.......................75
11.4.4
Sensitivity analyses ...............................................................................75
11.5
Analysis of secondary variable(s)..........................................................................76
11.5.1
Efficacy / Pharmacodynamics...............................................................76
11.5.2
Safety.....................................................................................................76
11.5.3
Pharmacokinetics ..................................................................................77
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................78
11.5.5
Other assessments .................................................................................78
11.6
Analysis of exploratory variables (if applicable)...................................................78
11.7
Sample size calculation..........................................................................................79
11.8
Power for analysis of key secondary variables......................................................79
11.9
Interim analyses.....................................................................................................80
12 Ethical considerations........................................................................................................80
12.1
Regulatory and ethical compliance........................................................................80
12.2
Responsibilities of the investigator and IRB/IEC..................................................80
12.3
Publication of study protocol and results...............................................................81
12.4
Quality Control and Quality Assurance.................................................................81
13 Protocol adherence ............................................................................................................81
13.1
Protocol Amendments ...........................................................................................82
14 References .........................................................................................................................83
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List of tables
Table 5-1
Prohibited medication ...........................................................................39
Table 5-2
Permitted medications if dose is stable (within 25 percent of 
current dose) for at least 3 months prior to randomization...................39
Table 6-3
Blinding levels ......................................................................................43
Table 8-1
Assessment Schedule ............................................................................50
Table 9-1
Liver Event Definitions.........................................................................63
Table 9-2
Actions required for Liver Events.........................................................64
Table 9-3
Exclusion of underlying liver disease ...................................................66
Table 9-4
Specific Renal Alert Criteria and Actions.............................................67
Table 9-5
Follow-up of renal events......................................................................68
Table 9-6
Summary of reporting requirements for medication errors...................69
List of figures
Figure 3-1
Study Schematic....................................................................................29
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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
b.i.d
twice a day
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CPK
creatine kinase
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CV
coefficient of variation
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
IA
Interim Analysis
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL1b
Interleukin 1 beta
INR
International Normalized Ratio
IRB
Institutional Review Board
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IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LFT
Liver function test
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
ml
milliliter(s)
MRI
Magnetic Resonance Imaging
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
p.o.
oral
PD
pharmacodynamic(s)
PDFF
Proton Density Fat Fraction
PK
pharmacokinetic(s)
qd
once a day
RBC
red blood cell(s)
SAE
serious adverse event
SBP
Systolic Blood Pressure
sCR
serum creatinine
SD
standard deviation
SGLT
Sodium glucose co-transporter
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
t.i.d
thrice a day
T2DM
Type 2 Diabetes Mellitus
TBL
total bilirubin
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
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Pharmacokinetic definitions and symbols
AUClast
The area under the plasma (or serum or blood) concentration-time 
curve from time zero to the time of the last quantifiable concentration 
[mass x time / volume]
Cmax
The observed maximum plasma (or serum or blood) concentration 
following drug administration [mass / volume]
Tmax
The time to reach the maximum concentration after drug 
administration [time]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a 
placebo) which is used as a comparator to the investigational 
drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
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 subject entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch 
is associated with a purpose (e.g. screening, randomization, 
treatment, follow-up) which applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who 
volunteers to be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 
and Directive 2001/20/EC and is synonymous with 
“investigational new drug,” "Investigational Medicinal 
Product," or “test substance”
Medication pack number
A unique identifier on the label of each drug package in 
studies that dispense study treatment using an IRT system
Part
A single component of a study which contains different 
objectives or populations within that single study. Common 
parts within a study are: a single dose part and a multiple dose 
part, or a part in patients with established disease and in those 
with newly-diagnosed disease.
Patient
An individual with the condition of interest


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Personal data
Subject information collected by the Investigator that is 
transferred to Novartis for the purpose of the clinical trial. 
This data includes subject identifier information, study 
information and biological samples.
Randomization number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
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 treatment
Any drug or combination of drugs administered to the study 
participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment 
prior to the defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the 
informed consent. This number is the definitive, unique 
identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample 
labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to 
each dosed subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study occurs only when a 
subject does not want to participate in the study any longer 
and does not allow any further collection of personal data 


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Protocol No. CLIK066X2204
Protocol Synopsis
Protocol number
CLIK066X2204
Full Title
A 12-week randomized, patient and investigator blinded, placebo-
controlled, parallel group study to investigate the efficacy of LIK066 
in obese patients with non-alcoholic steatohepatitis (NASH)
Brief title
Study to assess efficacy of LIK066 in obese patients with 
non-alcoholic steatohepatitis (NASH)
Sponsor and Clinical Trial 
Phase
Novartis
Phase II
Intervention type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to assess the effects of LIK066 on liver 
function tests (LFT) and a variety of metabolic and inflammation 
biomarkers 
in 
patients 
with 
phenotypic 
non-alcoholic 
steatohepatitis (NASH) after 12 weeks of treatment. Data from this 
study will be used to support further development of LIK066 in the 
treatment of patients with NASH.
Primary Objective(s)

To determine the effect of LIK066 on Liver Function test
(circulating ALT) after 12 weeks of treatment
Secondary Objectives

To determine the effect of LIK066 on intrahepatic lipid as
measured by percent liver fat by MRI after 12 weeks of
treatment

To determine the effect of LIK066 on total body weight after
12 weeks of treatment

To determine the effect of LIK066 on non-invasive markers of
liver fibrosis after 12 weeks of treatment

To determine the safety and tolerability of LIK066 as
measured by adverse events and safety laboratory tests

To evaluate the pharmacokinetics (Cmax, Tmax and
AUClast) of LIK066 in NASH patients

To determine the effect of LIK066 on circulating aspartate
aminotransferase (AST) after 12 weeks of treatment.
Study design
This is a non-confirmatory, multicenter, patient and investigator 
blinded, randomized, placebo-controlled, parallel group study in 
patients with NASH. The study will consist of a screening period 
up to 28 days, baseline period up to 14 days, treatment period of 
12 weeks followed up by a study completion evaluation 
approximately 28 days after
the final drug administration.
Finally, there will be a safety follow up phone call 30 days after the 
last visit.


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Population
The study population will be comprised of male and female adult 
overweight or obese patients with EITHER histologic evidence of 
NASH on liver biopsy within 2 years prior to randomization and 
elevated ALT OR phenotypic diagnosis of NASH based on 
elevated ALT, elevated BMI and diagnosis of Type 2 diabetes 
(T2D) by HbA1c
Key Inclusion criteria
Presence of NASH as demonstrated by ONE of the following:
EITHER
Histologic confirmed NASH based on liver biopsy obtained 2 years 
or less before randomization with a , fibrosis level of F1, F2 or F3, 
in the absence of a histological diagnosis of alternative chronic liver 
diseases AND ALT ≥ 50 IU/L (males) or ≥ 35 IU/L (females) at 
screening
OR
Phenotypic diagnosis of NASH based on presence of ALL THREE 
of the following at screening:

ALT ≥ 50 IU/L (males) or ≥ 35 IU/L (females) AND

BMI ≥ 27 kg/m2 (in patients with a self-identified race other
than Asian)  or ≥23 kg/m2 (in patients with a self-identified
Asian race) AND

Diagnosis of Type 2 diabetes mellitus by HbA1C:   ≥ 6.5%
and ≤ 10%
Key Exclusion criteria

Use of GLP-1 agonists such as liraglutide, exenatide ,
lixisenatide, albiglutide or dulaglutide; SGLT-2 inhibitors such
as canagliflozin, empagliflozin or dapagliflozin;
Thiazolidinediones (TZDs) such as pioglitazone; FXR
agonists such as obeticholic acid (OCA) and any
pharmacologically active weight-loss medications such as
lorcaserin prior to 6 weeks of screening visit and up to end of
study visit

eGFR ≤ 45ml/min/1.73m2 based on MDRD equation

Patients on treatment with the following medicines unless
they are on a constant dose for ≥3 months before
randomization: anti-diabetic medications, insulin (if ≥25%
change in dose), beta-blockers, thiazide diuretics, fibrates,
statins, niacin, ezetimibe, vitamin E (if  doses > 400 IU/day;
doses > 800 IU/day are prohibited), thyroid hormone,
psychotropic medications, estrogen or estrogen containing
birth control

Current or history of significant alcohol consumption for a
period of more than 3 consecutive months within 1 year prior
to screening (significant alcohol consumption is defined as
more than 20 g/day in females and more than 30 g/day in
males, on average)

Presence of cirrhosis on liver biopsy or clinical diagnosis of
cirrhosis

Type I diabetes and uncontrolled diabetes defined as HbAlc
> 10 % within 60 days prior to enrollment.

Patients with contraindications to MRI imaging


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
For those patients that have had a previous liver biopsy:
Significant weight loss (>15%) or change in clinical status (in
the opinion of the investigator) since the diagnostic liver
biopsy to screening

History or presence of other concomitant liver diseases

Clinical evidence of hepatic decompensation or severe liver
impairment.

History of drug or alcohol abuse within the 12 months prior to
dosing, or evidence of such abuse as indicated by the
laboratory assays conducted during screening and baseline.

History of inflammatory bowel disease.

History or current diagnosis of ECG abnormalities indicating
significant risk of safety for patients participating in the study

History of ketoacidosis, lactic acidosis, or hyperosmolar coma
OR if occurring between Screening Visit and Randomization
Visit.

History of lower limb amputation (including toe amputation)
OR if occurring between Screening Visit and Randomization
Visit.

Any history of  and/or  suspected Fournier’s gangrene
Study treatment
Study treatments are defined as:

50 mg LIK066 tablets

10 mg LIK066 tablet

Matching placebo tablets
Initially, patients will be randomly assigned to one of the following 
two treatments in a ratio of 2:1:
A: LIK066 150 mg
B: Matching placebo
A third, 30 mg qd arm (C) will be initiated after 33 patients have 
been enrolled in the initial two arm portion of the study. 
The randomization will change to a 2:4:1 ratio (150 mg: 30 mg: 
placebo) to maintain a 2:2:1 ratio across the three arms 
(150 mg:30 mg: placebo) at study end. 
Pharmacokinetic 
assessments

Cmax

Tmax

AUClast
Efficacy/PD assessments

Circulating alanine aminotransferase (ALT)

Circulating aspartate aminotrasferase (AST)

Proton Density liver fat fraction (PDFF) by MRI

Anthropometric assessments

Markers of liver fibrosis
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Key safety assessments

Physical Examination

Vital Signs

Laboratory Evaluations

Electrocardiogram

Pregnancy assessments

Urinalysis
Other assessments
Data analysis
The change from baseline to week 12 in ALT is the primary efficacy 
variable
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Key words
SGLT inhibitors; Non-alcoholic steatohepatitis (NASH)


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1
Introduction
1.1
Background
Obesity has become a major global health problem that contributes causally to and exacerbates 
many serious co-morbidities including hypertension, dyslipidemia, type 2 diabetes (T2DM) and 
importantly non-alcoholic fatty liver disease (NAFLD). While there are as yet no medications 
approved for treatment of NAFLD, numerous medicines are available to treat other 
obesity-related diseases. Interestingly, relatively few agents that are effective, safe or scalable 
to the size of the affected population are available for the treatment of obesity itself 
(Morgen and Sorensen 2014). A novel mechanism to lower body weight is via inhibition of the 
sodium glucose co-transporters 1 and 2 (SGLTs) resulting in inhibition of the glucose 
absorption in the gut and reabsorption in the kidney (Chao and Henry 2010).
The presence of obesity and insulin resistance, often with clinical features of the metabolic 
syndrome, leads to a high-risk profile for the development of NAFLD. NAFLD is one of the 
most common liver diseases worldwide with a global prevalence estimated at 25% 
(Younossi et al 2016). Estimates of obesity among patients diagnosed with NAFLD by imaging 
show that more than 50% are obese albeit with regional variations; 64% for Asians, 37% for 
Europeans and 57% for North Americans (Younossi et al 2016). NAFLD encompasses a broad 
spectrum of disease severity, ranging from isolated steatosis to its more severe form with 
variable degrees of hepatocyte inflammation, necrosis and liver fibrosis, known as nonalcoholic 
steatohepatitis (NASH), which can progress to cirrhosis and end stage liver disease 
(Musso et al 2016; Calzadilla and Adams 2016). In support of the link between obesity and fatty 
liver linked hepatic injury, weight loss either through bariatric surgery, diet or exercise leads to 
improvement in histologic NASH. This suggests that targeting obesity in NASH patients is 
likely to limit or reverse liver disease progression (Lassailly et al 2015, Vilar-Gomez et al 2015)
LIK066 is a potent inhibitor of the sodium glucose co-transporters 1 and 2 (SGLTs) that 
decreases absorption of 
glucose in the gut and reabsorption in the kidney 
(Chao and Henry 2010). In the normal state, 90% of the filtered glucose is reabsorbed by 
SGLT2 in the proximal convoluted tubule cells of the kidney, with the remaining 10% 
reabsorbed by the SGLT1. Inhibition of SGLT2 results in benign glucosuria, decreased blood 
glucose and modestly lower body weight in healthy subjects and patients with T2DM 
(Bays 2013). In addition to expression in the kidney, SGLT1 is also expressed in the small 
intestine where it is required for glucose and galactose absorption. Inhibition of enteric SGLT1 
results in glucose and galactose malabsorption (Turk et al 1991) which results in calorie wasting 
and other potential endocrine-based weight loss mechanisms. Combined SGLT1 and SGLT2 
inhibition therefore offers the potential for improved efficacy over SGLT2 selective inhibitors 
in both lowering blood glucose and body weight.
LIK066 is an investigational dual SGLT1/2 inhibitor which is being developed as a novel 
treatment for obesity. Single and multiple doses of LIK066 induced glucosuria in healthy 
volunteers (HVs) and patients with T2DM, and significantly lowered glucose area under the 
time-concentration curve (AUC) after an oral glucose tolerance test (OGTT) in patients with 
T2DM. LIK066 was found to be safe and tolerated, had a favorable pharmacokinetic profile, 
and resulted in up to 3% placebo-adjusted weight loss over just 2 weeks in both healthy subjects 
and patients with T2DM. LIK066 at 150 mg daily dose (as qd, bid or tid) results in a significant 


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weight loss in obese patients (~ 6%) after 12 week treatment. Furthermore, twelve week 
treatment with LIK066 at 150 mg qd in normoglycemic and dysglycemic subjects was generally 
safe and well tolerated with diarrhea observed as a dose-limiting toxicity.
This study is a non-confirmatory, proof of concept study and is planned to assess the safety, 
tolerability and effect of LIK066 on serum ALT levels after 12 weeks of treatment with either 
LIK066 (150 mg OR 30 mg once daily) or placebo in either overweight or obese patients with 
type II diabetes mellitus (T2DM) OR patients with histologic evidence of NASH based on liver 
biopsy and elevated ALT levels.
1.2
Nonclinical data
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1.2.1
Teratogenicity and reproductive toxicity data
1.3
Clinical data
Four clinical studies have been completed for LIK066: a safety/tolerability/efficacy study in 
healthy subjects and patients with T2DM, a mechanistic study in patients with T2DM, and a 
proof-of-concept study in obese patients with normoglycemia or dysglycemia in the US, and an 
ethnic sensitivity study in healthy Japanese subjects. 
1.3.1
Human safety and tolerability data
LIK066 was administered to 72 healthy subjects in the US, 36 healthy subjects in Japan and 
41 patients with T2DM and 127 obese patients in the US. 
 Treatment with LIK066 at 150 mg qd for 12 weeks was also shown to be safe and 
tolerated. AEs were predominantly diarrhea, GI related and were observed after single or 
multiple doses in the higher daily dose groups (≥150 mg as qd, bid or tid). No SAEs, 
withdrawals from treatment for AEs or significant clinical, laboratory, or ECG abnormalities 
were related to LIK066 administration.
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With the exception of a small increase in urinary specific gravity, BUN and expected glucosuria, 
there were no consistent differences between LIK066 and placebo treated subjects in the 
prevalence or magniture of any specific laboratory abnormality or in the number of subjects 
observed to have an abnormality. In the most recently completed clinical trial (CLIK066X2201) 
in obese patients, 12 week treatment with LIK066 at 150 mg qd appeared to lead to a minor 
increase in subjects with urine ketones (urine dipstick) and anion gap, although there were no 
episodes of clinically meaningful ketoacidosis.
1.3.2
Human pharmacokinetic data
1.3.3
Human pharmacodynamic data
Administration of LIK066 to healthy subjects or obese patients lowered body weight, consistent 
with a potentially significant anti-obesity effect, and in patients with T2DM, LIK066 lowered 
average and postprandial glucose levels, thus also demonstrating a significant antidiabetic effect. 
In obese patients with BMI ≥ 35 kg/m2, treatment with LIK066 150 mg qd for 12 weeks 
significant lowered body weight (5.70% reduction). Two weeks of treatment with 75 mg bid or 
50 mg tid led to similar effects on body weight loss (2.39 % and 2.38%, respectively). In healthy 
volunteers, administration of LIK066 dose dependently increased urinary glucose excretion 
(UGE) to a maximal level of approximately 80 g/24 hr in HVs after single and multiple oral 
daily (14 days) dosing. In patients with T2DM, administration of LIK066 (multiple daily doses 
of 15 mg and single doses of 30, 300 mg) also increased urinary glucose excretion, leading to a 
placebo-adjusted UGE24 of 90-100 g over 24-hours. A single dose administration of LIK066 at 
15, 30 and 300 mg was associated with 30%, 31% and 48% reduction in the postprandial 
glucose levels during an oral glucose tolerance test (OGTT), respectively. In addition, two week 
average blood glucose levels measured using continuous glucose monitoring (CGM) decreased 
by 41 mg/dL following treatment with LIK066 15 mg once daily for 2 weeks. 
1.4
Study purpose
The purpose of this study is to assess the effects of LIK066 on a variety of metabolic and 
inflammation biomarkers in patients with NASH.
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2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To determine the effect of LIK066 on
Liver Function Test after 12 weeks of
treatment

Circulating alanine aminotransferase
(ALT) levels
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To determine the effect of LIK066 on
intrahepatic lipid after 12 weeks of
treatment.

Percent (%) Liver fat as measured by
Magnetic Resonance Imaging (MRI-
PDFF)

To determine the effect of LIK066 on
total body weight after 12 weeks of
treatment

Percent change in total body weight

To determine the effect of LIK066 on
non-invasive markers of liver fibrosis
after 12 weeks of treatment

Enhanced liver fibrosis panel (ELF:
PIIINP, TIMP-1, and Hyaluronic acid)

To determine the safety and tolerability
of LIK066

Adverse events, safety laboratory tests
including basic chemistry profile and
liver biochemical tests

To evaluate the pharmacokinetics (PK)
of LIK066 in NASH patients

Cmax, Tmax, AUClast

To determine the effect of LIK066 on
aspartate aminotransferase (AST) after
12 weeks of treatment

Circulating aspartate aminotransferase
(AST) levels


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2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is a non-confirmatory, multicenter, patient and investigator blinded, randomized, placebo-
controlled, parallel group study in patients with NASH. The sponsor will remain unblinded to 
the treatment assignment of all patients to allow for continuous unblinded safety monitoring. 
The study will consist of a 28 day screening period (Day -44 to Day -16), a baseline period of 
14 days (Day -15 to Day -1), a treatment period of 12 weeks (Day 1 to Day 84), and a study 
completion evaluation approximately 28 days after the last drug administration. Finally, there 
will be a safety follow up phone call 30 days after the last visit. The patients will be advised to 
maintain their recommended diet during the study. The study design scheme is shown below.
Patients will be required to fast overnight for at least 8 hours before each clinic visit for blood 
collection and at least 3-4 hours before MRI procedure where applicable. Patients who meet the 
inclusion/exclusion criteria at screening will present to the study site for baseline assessments, 
including determination of the percent liver fat content
All baseline safety evaluation results must be available prior to the 
first dosing. At the beginning of the study after eligibility has been confirmed, patients will be 
randomized in a 2:1 ratio to receive either LIK066 at 150 mg qd  OR matching placebo qd, by 
oral administration. A third, 30 mg qd arm will be initiated  after 33 patients have been enrolled 
in the initial two arm portion of the study. For the entire study, patients will be randomized to 
either LIK066 at 150 mg qd, 30 mg qd or matching placebo at a ratio of 2:2:1. The placebo 
group will be supplemented by an equal number of historic controls from trials such as the 
FLINT study (Neuschwander-Tetri et al 2015) 
 As reflected in the inclusion criteria, Asians tend to have NASH at much lower BMI. 
Therefore, patients with Asian race will be stratified by BMI of <30 kg/m2 or ≥30 kg/m2 at 
baseline, all other patients will be stratified by BMI of<35 kg/m2 or ≥35 kg/m2 at baseline. 
The Asian race will be based on the patient self-report captured on the demography eCRF. Finally, 
patients identifying themselves as Pacific Islanders will be grouped with the non-Asian group.
Figure 3-1
Study Schematic
*30 mg dose arm  to start after 33 patients have enrolled into initial two arms of 150mg and placebo
cohorts at a 2:1 randomization ratio.  After the enrollment of these 33 patients, the randomization will
change to a 2:4:1 ratio (150 mg: 30 mg: placebo) to maintain a 2:2:1 ratio across the three arms
(150 mg:30 mg: placebo) at study end.  Total of approximately 110 subjects will enroll in the study.
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The first dose of study medication will be administered to patients under study site personnel 
supervision with meal on Day 1.  Patients will be provided with a supply of study medication 
and allowed to leave the site to continue the study as outpatients. Detailed instructions for taking 
study treatment will be provided in the Site Operations Manual (SOM). Patient compliance will 
be tracked by pill counts at each visit, patient diaries and PK sampling as indicated in the 
assessment Table 8-1. Patients will continue to take study medication once daily for twelve 
weeks (Day 2 to Day 84), as instructed by the investigator. Patients will return to the clinical 
site once weekly for the first 2 weeks (Days 7 and 14) and then return to the clinical site every 
2 weeks (days 28, 42 and 56). On day 56, the patients will take the study medication at the site 
prior to breakfast, following which pharmacokinetic sampling will occur for up to 6 hours post 
dose.  Patients will return to the clinic on  Day 84 for study assessments including MRI 
evaluation at the end of treatment. Finally, there will be an end of study (EOS) evaluation visit 
approximately 28 days after the last drug administration.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, urinalysis,) adverse event and serious 
adverse event monitoring.
Refer to the Assessment Schedule for details of safety, PK, and PD assessments
3.2
Rationale of study design
This randomized, multi-center, patient and investigator blinded, placebo-controlled study is 
designed to assess the efficacy of LIK066 relative to placebo in patients with NASH.
The completed study will enroll 110 patients who will be randomized in a 2:2:1 ratio to 150 mg 
daily, 30 mg daily and placebo. However, at the beginning of the study, patients will be enrolled 
into only two arms: 150 mg daily dose and placebo, randomized at 2:1.  
In order to maintain the scientific integrity of the study, the investigators and patients will 
remain blinded to their treatment allocation. 
the Novartis Clinical Trial Team (CTT) will be unblinded throughout 
the study.
To ensure that no bias is introduced by imbalance of severity of disease across different arms 
of the study, patients will be stratified to active or placebo arms on the basis of BMI.
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Currently there is no approved pharmacotherapy for patients with NASH. All patients will be 
encouraged to adhere to local advice regarding diet and exercise regimens. To keep the dietary 
intake as constant as possible during the study, patients participating in this study will be 
advised to adhere to American Heart Association (AHA) diet or equivalent if there is a country 
specific recommended diet.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The primary efficacy endpoint for dose/exposure-response analysis for LIK066, from 
previously completed clinical studies, was body weight loss, and other pharmacodynamic 
endpoints such as urinary and plasma glucose.  
 Of note, in the 12 week study in obese patients, the 
150 mg daily dose was generally safe and well tolerated. The primary AE was diarrhea, which 
did not lead to any discontinuation of treatment or patient withdrawals from the study. 
Body weight loss is an important factor in therapeutic 
development for NASH as weight loss through either bariatric surgery or life style modification 
deters progression of the disease (Lassailly et al 2015, Vilar-Gomez et al 2015).
 Furthermore, exposure of LIK066 in non-cirrhotic NASH patients 
(patient population in this study) is anticipated to be in the range of that observed  in previous 
studies since these patients are not expected to have hepatic dysfunction.
The duration of the study is based on findings in  published literature relating to Obeticholic 
acid and elafibranor (Mudaliar et al 2013; Neuschwander-Tetri et al 2015; Ratziu et al 2016), 
which demonstrate that 12 weeks will provide an ample time frame to test biochemical changes 
likely to result from improvement to the NASH phenotype. In addition observations from other 
studies with surgical, diet and pharmacotherapy including Novartis' diacylglycerol 
acytransferase 1 inhibitor(LCQ908; pradigastat) suggest that 12 weeks is also an adequate 
timeframe to test an effect on liver fat.
3.4
Rationale for choice of comparator
A placebo will be used as a comparator to provide estimates of net drug effects for efficacy and 
safety/tolerability assessments.
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3.5
Purpose and timing of interim analyses/design adaptations
3.6
Risks and benefits
There is no anticipated therapeutic benefit expected for patients participating in this study 
although a small amount of weight loss may be anticipated. The risk to patients in this trial will 
be minimized by adherence to the inclusion/exclusion criteria, close clinical monitoring during 
the treatment periods, and stopping rules outlined in Section 7.1.
Risks of LIK066 administration in human subjects may include the development of 
gastrointestinal adverse reactions, urinary tract infection, , postural hypotension due to volume 
depletion, ketoacidosis,  renal and hepatic toxicity, changes in calcium homeostasis with 
subsequent effects on bones, hypoglycemia and genitourinary infections (including necrotizing 
fasciitis of the genitalia and perineum commonly referred to as Fournier’s gangrene 
(see Section 9.8.4). 
Doses of LIK066 proposed in this study have been tested and deemed safe in healthy subjects. 
Patients should be monitored closely and treated according to the standard of care if deemed 
necessary by the principal investigator.
In long-term clinical studies in patients with T2DM with CVD or at high risk for CVD, an 
increase in cases of lower limb amputation (primarily of the toe) has been observed with the 
SGLT-2 inhibitor canagliflozin (Neal et al 2017). No increased risk of lower limb amputations 
has been reported for other SGLT2 inhibitors. In addition, no lower limb amputations have been 
seen in LIK066 studies to date, but since this risk may constitute a possible class affect, patients
with a higher risk for amputation events should be instructed on routine preventative foot care 
and maintaining adequate hydration.
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LIK066 is considered an aneugen at extremely high doses. With the doses and treatment 
duration proposed in this study, at least 20-fold exposure multiple is maintained relative to the 
threshold NOEL exposure for aneugenicity. LIK066 is not anticipated to increase the risk of 
adverse developmental or reproductive outcomes in humans when administered at the highest 
planned clinical dose of 150 mg. Women of child bearing potential should be informed that 
taking the study drug may involve unknown risks to the fetus if pregnancy were to occur during 
the study and must agree that in order to participate in the study they must adhere to the 
contraception requirement for the duration of the study (Section 4.2). If there is any question 
that the subject will not reliably comply, they should not be entered in the study.
Blood samples will be collected frequently during the study either via venipuncture or cannula. 
Risks associated with blood collection include pain, swelling and/or bruising at the insertion 
site of the needle. Although rare, localized clot formation, infections and nerve damage may 
occur. Lightheadedness and/or fainting may also occur during or shortly after the blood draw.
MRI makes use of powerful magnetic fields and radio waves, which are believed to cause no 
direct adverse consequences when used within FDA-approved specifications. No MRI contrast 
will be administered in this study. Thus in principle, MRI scans can be repeated in the same 
patient as often as necessary. The MRI scanning equipment may cause a feeling of 
claustrophobia in susceptible persons; therefore, sensitivity to enclosed spaces should be 
queried at screening. Refer to eligibility criteria (Section 4.2) to exclude patients who are not 
suitable candidates for MRI scanning.
3.6.1
Blood sample volumes
Approximately 325 mL of blood is planned to be collected over a period of approximately 
22 weeks, from each patient as part of the study. Additional samples required for monitoring of 
any safety findings would be in addition to this volume. This is not considered to be a risk for 
this population.
Timings of blood sample collection are outlined in the Table 8-1 Assessment Schedule.
A summary blood log is provided in the Site Operations Manual. Instructions for all sample 
collection, processing, storage and shipment information will be contained in the Central 
Laboratory Manual
4
Population
Patients with a phenotype consistent with NASH
The study population will be comprised of male and female adult overweight or obese patients 
with EITHER histologic evidence of NASH on liver biopsy within 2 years prior to 
randomization and elevated ALT OR phenotypic diagnosis of NASH based on elevated ALT, 
Type 2 diabetes mellitus by elevated HbA1c and increased BMI; full details are outlined in 
Section 4.1 (Inclusion criteria).  Approximately 110 patients will be randomized in the study.  
At least 88 subjects are expected to complete the study.
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4.1
Inclusion criteria
Patients with a phenotype consistent with NASH, 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. Presence of NASH as demonstrated by ONE of the following:
EITHER
Histologic confirmed NASH based on liver biopsy obtained 2 years or less before
randomization with a fibrosis level of F1, F2 or F3, in the absence of a histological
diagnosis of alternative chronic liver diseases AND ALT ≥ 50 IU/L (males) or ≥ 35 IU/L
(females) at screening.
OR
Phenotypic diagnosis of NASH based on presence of ALL THREE of the following at
screening:

ALT ≥ 50 IU/L (males) or ≥ 35 IU/L (females) AND

BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian) or
≥23 kg/m2 (in patients with a self-identified Asian race) AND

Diagnosis of Type 2 diabetes mellitus by HbA1C:   ≥ 6.5% and ≤ 10%
3. Patients must weigh no more than 150 kg (330 lbs.) to participate in the study. Inclusion
of subjects with higher weights up to 200 kg (440 lbs.) may occur if a MRI scanner with a
table weight of 200kg (440 lbs.) is available.
4. Male and female patients 18 years or older (at the time of the screening visit)
5. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
4.2
Exclusion criteria
Patients with a phenotype consistent with NASH, fulfilling any of the following criteria are not
eligible for inclusion in this study:
1. History or presence of other concomitant liver diseases including:

Hepatitis B or C virus (HCV, HBV) infection. Patients with history of HCV who
attained sustained virologic response more than 3 years prior to screening are not excluded.

Primary biliary cholangitis (PBC)

Primary sclerosing cholangitis (PSC)

Alcoholic liver disease

Definite autoimmune liver disease or overlap hepatitis

Suspected or confirmed Gilbert's syndrome

Known bile duct obstruction

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2. History or current diagnosis of ECG abnormalities indicating significant risk of safety for
patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
in a first degree relative.
3. Use of GLP-1 agonists such as liraglutide, exenatide , lixisenatide, albiglutide or
dulaglutide; SGLT-2 inhibitors such as canagliflozin, empagliflozin or dapagliflozin;
Thiazolidinediones (TZDs) such as pioglitazone; FXR agonists such as obeticholic acid
(OCA) and any pharmacologically active weight-loss medications such as lorcaserin prior
to 6 weeks of screening visit and up to end of study visit.
6. Patients with contraindications to MRI imaging, including:

Brain aneurysm clip

Implanted neural stimulator

Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires

Prosthetic heart valves

Cochlear implant

Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)

Other implanted medical devices (e.g., insulin pumps)

Metal shrapnel or bullets still in the body

Severe claustrophobia despite use of anxiolytics

Tattoos (as determined by the Investigator and Imager)

Weight in excess of MRI machine capacity

Joint replacements
7. Inability to reliably quantify alcohol consumption based upon local study physician
judgment.
8. Current or history of significant alcohol consumption for a period of more than 3
consecutive months within 1 year prior to screening (significant alcohol consumption is
defined as more than 20 g/day in females and more than 30 g/day in males, on average).
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10. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the
presence of any of the following abnormalities:

Serum albumin < 32 g/L

INR > 1.3

Direct bilirubin > 13 mg/L

ALT or AST > 8× ULN

Alkaline Phosphatase > 3 × ULN

History of esophageal varices, ascites or hepatic encephalopathy

Splenomegaly
12. Presence of cirrhosis on liver biopsy or clinical diagnosis of cirrhosis.
16. Patients taking medications prohibited by the protocol. See Section 5.2 for further details.
17. For those patients that have had a previous liver biopsy: Significant weight loss (>15%) or
change in clinical status (in the opinion of the investigator) since the diagnostic liver
biopsy to screening (refer to Section 4.1 #3).
22. History of non-alcohol drug abuse within the 12 months prior to dosing, or evidence of
such abuse as indicated by the laboratory assays conducted during screening and baseline.
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23. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using basic methods of contraception during dosing
and for 5 days (approximately 5 times the terminal half life) after stopping study
medication. 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

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment.
In case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the
study the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap.

Use of oral (estrogen and progesterone), injected or implanted combined hormonal
methods of contraception or placement of an intrauterine device (IUD) or intrauterine
system (IUS), or other forms of hormonal contraception that have comparable
efficacy (failure rate <1%), for example hormone vaginal ring or transdermal
hormone contraception. In case of use of oral contraception women should have been
stable on the same pill for a minimum of 3 months before taking study treatment.
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.
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The investigator must ensure that all patients being considered for the study meet the above 
eligibility criteria.
Patient selection is to be established by checking through all eligibility criteria at screening and 
baseline. A relevant record (e.g. checklist) of the eligibility criteria must be stored with the 
source documentation at the study site.
Provided patients meet all other eligibility criteria, patients with a single lab value outside of 
the allowable range may be considered eligible for enrolment, as long as the abnormal lab value 
is within 10% of the allowable value. Platelets and eGFR values must always fall inside the 
allowable range as listed in the inclusion and exclusion criteria.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
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 must agree that in 
order to participate in the study they must adhere to the contraception requirements specified in 
Section 4.2 (Exclusion criteria). If there were any question that the patient would not comply 
reliably, they should not be entered or continue in the study.
Male patients should be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. Please refer to exclusion criteria (Section 4.2) for details of 
contraception requirements for the study.
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5.2
Prohibited treatment
Use of the treatments displayed in Table 5-1 is NOT allowed after screening.
Table 5-1
Prohibited medication
Medication
Prohibited period
GLP-1 agonists such as liraglutide, exenatide, 
lixisenatide, albiglutide or dulaglutide  
See Exclusion criteria (Section 4.2)
SGLT2 inhibitors such as empagliflozin, 
canagliflozin, dapagliflozin OR ertugliflozin
See Exclusion criteria (Section 4.2)
Pharmacologically active weight-loss medications 
(eg. lorcaserin, phentermine/topiramate, bupropion-
naltrexone HCL, orlistat)
See Exclusion criteria (Section 4.2)
Treatment with drugs that alter intestinal motility 
(e.g. erythromycin, metoclopramide, tegaserod, 
methylnaltrexone, alvimopan, loperamide, 
diphenoxylate and atropine (Lomotil) and difenoxin 
and atropine (Motofen))
From 7 days prior to screening to EOS visit
Treatment with drugs that have a high incidence of 
diarrhea (e.g. Orlistat, Acarbose).
From 7 days prior to screening to EOS visit
Chronic systemic steroid treatment or systemic 
steroids for > 7 consecutive days for worsening of 
an underlying condition.
From 4 weeks prior to screening to EOS visit
Treatment with or use of strong inhibitors of 
CYP3A4/5 including boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir, fazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole.  Strong CYP3A 
inducers including avasimibe, carbamazepine, 
phenytoin, rifampin, St. John’s wort. 
See Exclusion criteria (Section 4.2)
General UGT inhibitors including probenecid and 
valproic acid.
See Exclusion criteria (Section 4.2)
Table 5-2
Permitted medications if dose is stable (within 25 percent of current
dose) for at least 3 months prior to randomization
Medications
Oral anti-diabetic medications such as metformin, sulfonylureas or DPP-4 inhibitors
Insulin*
Beta-blockers and thiazide diuretics 
Fibrates, statins, niacin, ezetimibe** 
Vitamin E (400-800 mg)*** 
Thyroid hormone 
Psychotropic medications (phenothiazines or second generation antipsychotics) 
Estrogen or estrogen containing birth control
*unless adjustment is required due to intercurrent illness; **unless adjustment is required to treat
medically significant increases in LDL that have been confirmed upon repeat testing; ***Only
applicable for patients taking ≥400 IU/day


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5.3
Dietary restrictions

Subjects will be asked to fast for approximately 8 hours overnight on certain days where
blood samples will be collected to measure various biomarkers and will be asked to fast at
least 3-4 hours before MRI procedures as described in the SOM.

Patients should maintain their usual physical activity and dietary habit and can drink water
ad libitum to ensure adequate hydration during the study.

Patients may reduce their carbohydrate intake in order to alleviate diarrhea, the primary
adverse events associated with LIK066 administration with meals that contain high
percentage of carbohydrate.

To keep the dietary intake as consistent as possible, patients participating in this study will
be counseled regarding appropriate exercise and diet per local standards, e.g. instruction to
carefully adhere to American Heart Association (AHA) diet or equivalent if there is a
country specific recommended diet.
5.4
Other restrictions
No initiation of strenuous physical exercise (e.g. weight training, aerobics, football) until after 
Study Completion evaluation.
6
Treatment
6.1
Study treatment
The study treatment includes once a day administration of either LIK066 (150mg) OR LIK066 
(30mg) OR placebo for 12 weeks. Details on the requirements for storage and management of 
study treatment, and instructions to be followed for subject numbering, prescribing/dispensing 
and taking study treatment are outlined in the Site Operations Manual.
6.1.1
Investigational treatment and control drug(s)
The investigational drug, LIK066 and matching placebo, will be prepared by Novartis and 
supplied to the Investigator site as double blinded patient packs and will be dispensed based on 
the IVRS. Study treatments are defined as:

50 mg LIK066 tablets

10 mg LIK066 tablets

Matching placebo tablets
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.


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6.2
Treatment arms
Initially patients will be assigned to one of the following two treatments (A or B) in a ratio of 
2:1. Study treatments are defined as:
A: LIK066 150 mg
B: Matching placebo
  A third, 30 mg qd arm (C) will be initiated after 33 patients have been enrolled in the initial 
two arm portion of the study. The randomization will change to a 2:4:1 ratio (150 mg: 30 mg: 
placebo) to maintain a 2:2:1 ratio across the three arms (150 mg:30 mg: placebo) at study end.
6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual patients by way of a randomization 
number. Randomization numbers will be assigned in ascending, sequential order to eligible 
patients via an IRT system (see Site Operations Manual for details).
The randomization number is only used to identify which treatment the patient has been 
randomized to receive. The Patient number assigned to a patient at screening remains the unique 
identifier for the patient throughout the study.  For information on patient numbering, please 
see ‘Patient numbering’ section in the Site Operations Manual.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject 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.
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6.4
Treatment blinding
This is a patient and investigator-blinded study. Patients and investigators will remain blinded 
to study treatment throughout the study, except where indicated below.
Drug product will be supplied as a double blinded patient packs and the identity of the 
treatments will be concealed by the use of study drugs that are all identical in packaging, 
labeling, schedule of administration, appearance, and odor.
Site staff
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study.
Unblinding a single patient at site for safety reasons (necessary for patient management) will 
occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff
The sponsor will remain unblinded to the treatment assignment of all patients to allow for 
continuous unblinded safety monitoring throughout the study.
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly but may be 
unblinded through communication of drug re-supply needs via the IRT system.
The clinical trial team is allowed to share unblinded results with other sponsor staff (e.g. 
decision boards) as required for internal decision making on the study or the project while the 
study is ongoing.
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Table 6-3
Blinding levels
6.5
Treating the subject
LIK066 will be administered to the subject via the oral route.  Patients will  be provided with a 
supply of study medication to self administer once daily for 12 weeks (Day 2 to Day 84) before 
lunch. See the Site Operations Manual for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Investigational treatment dose adjustments and/or interruptions are not permitted.
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6.7
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 IRT. 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 fax or email confirming this information. The system will 
automatically inform the study monitor for the site and the Study Team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will need to provide:

protocol number

study drug name (if available)

patient number.
In addition, the investigator must inform the patient on how to contact his/her backup in cases 
of emergency when he/she is unavailable to ensure that un-blinding can be performed at any 
time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given patient 
and whether the patient can continue in the study.
6.8
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all patients 
treated with LIK066, as detailed in Section 8.7.
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.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log.
6.9
Recommended treatment of adverse events
Treatment of AEs may be considered at the discretion of the Investigator. Medication used to 
treat AEs must be recorded on the Concomitant medications/Significant non-drug therapies 
CRF. In case of intolerable diarrhea, see SOM for guidelines on management of diarrhea.


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6.10
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation in 
the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
Study completion is defined as when the last patient completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
All patients should have a safety follow-up call conducted 30 days after last visit. 
The information collected is kept as source documentation.  All SAEs reported during this time 
period must be reported as described in Section 9.2 and the Site Operations Manual.  
Documentation of attempts to contact the patient should be recorded in the source 
documentation.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the subject or the investigator.
Study treatment must be discontinued under the following circumstances:

Patient decision - patients may choose to discontinue study treatment for any reason at any time.

The investigator believes that continuation would negatively impact the safety of the
patient or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the patient's safety

Pregnancy (see Section 8.6 (Safety) and Section 9.6 (Pregnancy reporting)

Discontinuation may be considered when patients have to be treated by prohibited
medications on a case by case basis.


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
Use of prohibited treatment as per recommendations in Table 5-1

Hypersensitivity (CTCAE grade 2 or higher) reaction to LIK066 requiring intervention.

Clinically significant diarrhea, suspected to be related to the study drug and not responsive
to recommended management per SOM that may put the patient at risk (identified by
investigator after consultation with the sponsor)

Symptomatic orthostasis confirmed by repeated orthostatic blood pressure changes
(more than a 20 mmHg drop in systolic or 10 mmHg drop in diastolic blood pressure and
increase in heart rate >20 bpm (compared to sitting results) when blood pressure and pulse
are taken after at least 3 minutes (standing)

Clinically significant urinary tract or genitourinary infections, at the discretion of the
investigator and consultation with the sponsor

Clinically symptomatic hypoglycemia confirmed by repeated blood glucose levels
(<56 mg/dL)

Ketoacidosis (symptoms of ketoacidosis include nausea, vomiting, abdominal pain,
unusual tiredness and trouble breathing) confirmed by blood pH and ketones.

For ALT, AST, total bilirubin and/or alkaline phosphatase elevations mandating study
treatment discontinuations, please refer to Section 9.3 and Table 9-1 and Table 9-2 for
further instructions and monitoring. Of note, ALT and AST are abnormal at baseline in
this study. Thus only elevation to >2X of the baseline value will trigger events listed in
Section 9.3.

Adverse events, abnormal laboratory values or abnormal test result that indicate a safety
risk to the patient, in the opinion of the investigator
Discontinuation of study treatment and patient withdrawal may occur, under the 
following circumstances:

Any protocol deviation that results in a significant risk to the patient’s safety in the
opinion of the investigator.

If continuation in the study is deemed detrimental to the patient’s well-being in the
opinion of the investigator.
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The appropriate personnel from the study site and Novartis (including the CTT, medically 
qualified representatives of the Sponsor, and the investigator) will assess whether study 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, investigator must determine the primary reason for 
the patient's premature discontinuation of study treatment and record this information on the 
Dosage Administration CRF.
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3, Withdrawal of Informed Consent). Where possible, they should 
return for the assessments as indicated in the assessment table. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the patient/pre-designated contact as specified in Section 7.4 (Lost to follow-up). 
This contact should preferably be done according to the study visit schedule.  The investigator 
must also contact the IRT to register the subject’s discontinuation from study treatment.
The investigator must also contact the IRT to register the patients's discontinuation from study 
treatment.
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
Assessment Schedule (Table 8-1).
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a subject’s samples until the time of withdrawal) according to applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.


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7.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A patient cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
7.5
Study Stopping rules
The severity of adverse events will be graded by the study site Investigator (or designee) based 
on clinical judgment and captured in the CRF AE page. This information will be used to 
quantify events that may lead to patient’s discontinuation or stopping dose arms or the study.
The study will be placed on hold pending full review of all available clinical safety data and 
discussion with the Investigator if any of the following occur and may be stopped or amended 
based on the outcome of the full safety review.

One patient on study drug experiences any adverse event that is CTCAE Grade 4 or higher
that is classified as related to study drug.

Two or more patients on study drug experience a similar adverse event that is a CTCAE
Grade 3 or higher other than ALT elevation.

The Principal Investigator and the Sponsor consider that the number and/or severity of
adverse events justify discontinuation of the study.

The Sponsor unilaterally requests it.
Safety reviews for study stopping will be conducted jointly between medically qualified 
representatives of the Sponsor and Investigator and a joint decision will be made.
7.6
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 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
patient must be seen as soon as possible and treated as a prematurely discontinued patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient's interests. The investigator 
will be responsible for informing IRBs/IECs of the early termination of the trial.


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8
Procedures and assessments
8.1
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects 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 recorded on the CRF.


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Table 8-1
Assessment Schedule
Epoch SCREENING Baseline
Treatment
EOS2
Follow 
up 
Phone 
call 
Visit Name
Screening
Baseline
Treatment
EOS
Visit Numbers1
1
101
2013
2023
2033
2043
2053
206
2073
399
Days
-44 to -16
-15 to -1
1
7
14
28
42
56
84
112
142
Time (post-dose)
-
-
0h
-
-
-
0h
0h3
1h
2h
4h
6h
0h
-
Informed consent4
X
Inclusion / Exclusion criteria
X
X
Medical history/current medical 
conditions
X
Demography
X
Alcohol Test and Drug Screen 
X
X
Hepatitis and HIV Screen
X
Pregnancy and assessments of 
fertility6
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
Body Temperature
X
X
X
X
X
X
X
X
X
X
Body Height
X
Body Weight
X
X
X
X
X
X
X
X
X
X
Waist and hip circumference
X
X
X
X
X
BMI
X
X
X
X
X
X
X
X
X
X
waist:hip ratio
X
X
X
X
X
Blood Pressure and Pulse Rate7
X
X8
X
X
X
X8
X
X8
X8
X
ECG evaluation
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
X
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Epoch SCREENING Baseline
Treatment
EOS2
Follow 
up 
Phone 
call 
Visit Name
Screening
Baseline
Treatment
EOS
Visit Numbers1
1
101
2013
2023
2033
2043
2053
206
2073
399
Days
-44 to -16
-15 to -1
1
7
14
28
42
56
84
112
142
Time (post-dose)
-
-
0h
-
-
-
0h
0h3
1h
2h
4h
6h
0h
-
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Coagulation Panel10
X
X
X
PK blood collection
X
X
X
X
X
X
X
X
X
Dose administration
X14
MRI16
X
X
X17
Comments
As required
Concomitant therapies
X18
Study completion information
X
Adverse Events
As required
X
Serious Adverse Events
As required
X
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1 Visit structure given for internal programming purpose only
2 If a patient withdraws from the study, or if study medication is discontinued for any reason, the patient should be scheduled for a subsequent visit at which time all 
assessments at the EOS visit should be performed.
3 All assessments to be performed pre-dose
4 Informed consent must be provided by all patients before any screening procedures are performed.
6 Serum pregnancy tests will be performed at Screening and end of study; urine tests may be used at other timepoints.  
7 Blood pressure and pulse rate will be measured in a sitting position unless otherwise noted. 
8 Measured in sitting and standing positions to assess orthostatic hypotension.
10 Coagulation panel includes PT/INR and aPTT
14 Patients will  be provided with a supply of study medication to self administer once daily for 12 weeks (Day 2 to Day 84). Patients should bring all used and unused 
medications, and diaries, to each visit.
16 MRI of abdomen and liver in all subjects. Quantification of liver fat will be performed on all subjects;
17 Assessment is only to be performed at EOS if a patient withdraws from the study, or discontinues study treatment early for any reason. 
18 A thorough review of any concomitant medications (including medication name, dose, unit, frequency, and route) should be performed at every visit.
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8.2
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this study. 
The informed consent form will also include a section related to optional future research which 
will require a separate signature if the patient agrees to future research.  Any changes to the 
proposed consent form suggested by the investigator must be agreed to by Novartis before 
submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and then must be discussed with the patient.
Ensure patients are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Subject screening
It is permissible to re-screen a patient if s/he fails the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis.
Information on what data should be collected for screening failures is outlined in the Site 
Operations Manual.
8.4
Subject demographics/other baseline characteristics
Pertinent demographic and baseline characteristic data will be collected on all patients.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
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8.5
Efficacy / Pharmacodynamics
Efficacy of LIK066 will be assessed based on the following assessments:

Liver function tests (ALT and AST)

Proton Density Liver Fat Fraction (PDFF) by Magnetic Resonance Imaging (MRI)

Anthropometric assessments (Height, Body Weight, BMI and waist:hip ratio)

Markers of liver fibrosis
Pharmacodynamic samples will be collected at the time points defined in the 
Assessment schedule. Follow instructions outlined in the central laboratory manual regarding 
sample collection, numbering, processing and shipment. In order to better define the PD profile, 
the timing of the sample collection may be altered based on emergent data. The number of 
samples/blood draws and total blood volume collected will not exceed those stated in the 
protocol. Pharmacodynamic (PD) samples will be obtained and evaluated in all patients at all 
dose levels.
8.5.1
Clinical Outcome Assessments (COAs)
Not applicable.
8.5.2
Body Weight

Body weight (to the nearest 0.1 kilogram [kg] will be measured on a calibrated scale.
The measurement can be performed with the study subject in underwear and without
shoes; or  while wearing minimal indoor clothing as indicated in Section 8.1 (Assessment
schedule). However, body weight measurements must be performed in a consistent
manner across all visits for a given patient. Voiding before weight measurement is
required. Details of these assessments will be provided in the site operations manual.

Body mass index (BMI) will be calculated as (Body weight (kg) / [Height (m)]2)
8.5.3
Body Height
Height will be measured at screening visit and will be used to calculate BMI.
8.5.5
MRI
Patients will undergo magnetic resonance imaging twice during the course of the study 
(Baseline and End of Treatment) to quantitate liver fat, 
as outlined in Section 8.1 (Assessment schedule). End of Treatment assessment is not to be 
performed if the patient prematurely discontinues treatment prior to Week 8.
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8.5.6
Liver function tests
ALT, AST, GGT, ALP (total), total bilirubin, and albumin will be assessed as indicated in the
Assessment schedule. The effect on circulating ALT levels will be the primary efficacy variable 
for this study.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reactive bilirubin will be quantified.
ALP isoenzymes and 5’NT will also be measured but will not form part of the screening 
requirements or safety data set.
The methods for assessment and recording are specified in the laboratory manual. Some of the 
liver function tests may be completed as part of the blood chemistry panel.
8.5.7
Markers of Liver Fibrosis

Enhanced liver fibrosis Test (ELF) panel: the following will be assessed: hyaluronic acid
(HA), tissue inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of
procollagen type III (PIIINP).
Additional information is provided in the site operations manual and central laboratory manual. 
These markers will be assessed as indicated in Section 8.1 Assessment schedule.
8.5.8
Waist circumference, Hip circumference and waist:hip ratio
Waist and hip circumference will be measured to the nearest 0.1 cm at visits indicated in
Table 8-1. Waist:hip ratio will be measured as described in SOM
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed.
8.6.1
Alcohol Test and Drug Screen 
All patients will be screened for alcohol and substances of abuse. See the Site Operations 
Manual for details.
8.6.2
Body Temperature
Body temperature will be measured as stated in the SOM.
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8.6.3
Blood chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, chloride, 
creatinine, CRP, γGT, glucose, LDH, CPK, inorganic phosphorus, lipase, amylase, magnesium, 
potassium, total protein, AST, ALT, sodium, triglycerides, urea/BUN and uric acid. If the total 
bilirubin concentration is increased above 1.5 times the upper limit of normal, direct and indirect 
reacting bilirubin should be differentiated.
8.6.4
Blood Pressure and Pulse Rate

Blood pressure (BP)

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

Pulse
8.6.5
Hepatitis and HIV Screen
All patients will be screened for HIV, Hepatitis B and C. See the Site Operations Manual for details.
8.6.6
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (e.g., 
neutrophils, basophils, eosinophils, monocytes, lymphocytes), erythrocyte sedimentation rate, 
and platelet count will be measured.
Coagulation parameters including aPTT, PT and INR will also be assessed; methods for 
assessment and recording are provided in the central laboratory manual.
8.6.7
Pregnancy and assessments of fertility
Pregnancy Testing
All pre-menopausal women who are not surgically sterile will have pregnancy testing.  See the
Assessment schedule (Section 8.1), for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements*.   A positive urine 
pregnancy test requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative.
*Additional pregnancy testing might be performed if requested per local requirements.
Refer to Section 9.6 for details on Reporting Pregnancy.


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Assessments of Fertility
Refer to Section 4.2 for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source. Subsequent hormone level assessment to confirm the woman is not of child bearing 
potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
In the absence of the above medical documentation, FSH testing will be required.  
8.6.8
Physical Examination
See Site Operations Manual for details. 
8.6.9
Urinalysis
Urine test by dipstick: Leukocytes, Nitrite, pH, Specific gravity, Protein, Glucose, Ketones, 
Urobilinogen, Bilirubin, Blood/hemoglobin.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
8.6.10
ECG evaluation
Details of assessment of ECG are provided in SOM. Measurement parameters: PR interval, 
QRS duration, heart rate, RR, QT, QTc. The Fridericia QT correction formula (QTcF) should 
be used for clinical decisions.
8.7
Pharmacokinetics
 
a 
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8.8
Other assessments
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.5 for an overview 
of the reporting requirements.
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 finding, laboratory test 
finding, 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 should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Section 9.3 and Section 9.4, respectively. 
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Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. The Common Toxicity Criteria (CTC) AE grade (version 4.0 or higher) for the adverse event.
If CTC-AE grading does not exist for an adverse event, use:
1 = mild
2 = moderate
3 = severe
4 = life threatening* (see Section 9.2 for definition of a serious adverse event (SAE))*Note: 
There may be cases where a CTCAE with a grade of 4 (life-threatening) may not necessarily
be an SAE (e.g. certain laboratory abnormalities in the absence of meeting other seriousness 
criteria).
CTC-AE grade 5 (death) is not used, but is collected as a seriousness criteria and also collected 
in other CRFs (e.g. Study Completion, Death/Survival).
2. Its relationship to the study treatment

Yes or

No
3. its duration (start and end dates) or if the event is ongoing an outcome of not recovered/not
resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness
criteria have been met
5. 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

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB).  Once an adverse event is detected, it must be followed
until its resolution or until it is judged to be permanent, and assessment should be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the subject, 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.


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9.2
Serious adverse event reporting
9.2.1
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

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

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the
indication under study  and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s general
condition

is medically significant, e.g. defined as an event that jeopardizes the 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 (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline)).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2.


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9.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days [after the last study visit] must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.
Note: SAEs reported by patients deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the Site 
Operations Manual.
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.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.   Note:  SAEs must be reported to 
Novartis within 24 hours of the investigator learning of its occurrence/receiving follow-up 
information.
9.3
Liver safety monitoring
To ensure 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 laboratory abnormalities and 
AEs have to be considered during the course of the study 1) Liver laboratory triggers which 
will require repeated assessments of the abnormal laboratory parameter and 2) Liver events 
which will require close observation, follow up monitoring,and the completion of the standard 
base liver eCRF pages.


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Please refer to Table 9-1 for complete definitions of liver events.
Table 9-1
Liver Event Definitions
Definition/ threshold
Liver laboratory triggers

ALT or AST ≥ 2× baseline value

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 ULN

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
Follow-up of liver events
Every liver event defined in Table 9-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below Additional details on actions required in case 
of liver events are outlined in Table 9-2.
For liver laboratory triggers

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and GGT) to confirm
elevation within the next 7 days. If any of the lab tests described in Table 9-1 are
abnormal, all tests should be repeated. These liver chemistry repeats should preferentially
be performed using the central laboratory, with the results provided via the standard
electronic transfer.  If results will not be available from the central laboratory within
24 hours, then the repeats can also be performed at a local laboratory to monitor the safety
of the patient. If a liver event is subsequently reported, any local liver chemistry tests
previously conducted that are associated with this event should have results reported on
the unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the patient will be initiated,
including consideration of treatment interruption if deemed appropriate.


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For Liver Events

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study
treatment), if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event
Thorough follow-up of the liver event should include:

Repeating liver chemistry tests to confirm elevation as appropriate. Testing should include
PT/INR ALT, AST, ALP, and GGT. If total bilirubin is elevated > 2 x ULN, fractionation
into direct and indirect bilirubin is required. To rule out muscular origin of transaminase
elevations, CPK should be measured along with liver chemistry tests. Frequency of
retesting should be done once a week if abnormalities stabilize or the study drug has been
discontinued and the subject is asymptomatic. Retesting should be continued up to
resolution or stabilization as described above.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and
special diets.

Exclusion of underlying liver disease, as specified in Table 9-3.

Imaging such as abdominal US, CT or MRI, as deemed appropriate by the investigator

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultation.
All follow-up information, and the procedures performed must be recorded as appropriate in
the CRF.
Table 9-2
Actions required for Liver Events
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study drug
immediately

Hospitalize, if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 10 × ULN

Repeat within 48 hr

If elevation persists,
discontinue drug

Hospitalize if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN AND INR > 1.5

Discontinue the study drug
immediately

Hospitalize, if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 10 × ULN

Repeat LFT within 1 week

If elevation persists continue
follow up,

If elevation persists for more
than 3 weeks discontinue drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN AND accompanied by
symptomsb

Discontinue the study drug
immediately

Hospitalize if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN if normal baseline
or
>2 x baseline if elevated before
drug exposure
(patient is asymptomatic)

Repeat LFT within 1 week

If elevation is confirmed,
initiate close observation of
the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks
ALP (isolated)
> 2 × ULN if normal baseline (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 if normal baseline  (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 GGT 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 from baseline is
confirmed, initiate close
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit


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Criteria
Actions required
Follow-up monitoring
Jaundice

Discontinue the study drug
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of a 
liver toxicity*

Consider study drug
interruption or discontinuation

Hospitalization if clinically
appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
c Resolution 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.
Table 9-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA;
anti-HCV, HCV RNA, IgM & IgG anti-HEV, HEV
RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM &
IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, gGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF,
hypotension, hypoxia, hepatic venous occlusion.
Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin
Primary biliary cholangitis

Anti-mitochondrial antibody


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9.4
Renal safety monitoring
9.4.1
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended actions and follow-up assessments are 
listed in Table 9-4 and Table 9-5, respectively. 
Table 9-4
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Serum creatinine increase > 50 % compared to 
baseline
Confirm > 50 % within 24-48 hours after receipt 
of the abnormal value
If confirmation of abnormal value is not possible 
in this timeframe study drug must be withheld 
until further evaluation is possible
Consider drug interruption
Consider patient hospitalization / specialized 
treatment
Albumin- or Protein-creatinine ratio increase ≥ 2-
fold compared toscreening or baseline levels 
whichever is higher
New onset dipstick proteinuria ≥ 3+
Protein-creatinine ratio (PCR) ≥ 1000 mg/g or ≥ 
100 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation
New onset dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR
New onset dipstick hematuria not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify, document and potentially eliminate risk factors that may have initiated or contributed 
to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain,
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic
failure, contrast media or other known nephrotoxin administration, or other potential
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis


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Table 9-5
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case 
Report Form (CRF) or via electronic data load. 
Review and record possible contributing factors 
to the renal event (co-medications, other co-
morbid conditions) and additional diagnostic 
procedures (MRI etc) in the CRF.

Urine dipstick and sediment microscopy

Blood pressure and body weight

Serum creatinine, electrolytes (sodium,
potassium, phosphate, calcium),
bicarbonate and uric acid

Urine output
Monitor patient regularly (frequency at 
investigator’s discretion) until:

Event resolution: (sCr within 10% of baseline
or protein-creatinine ratio within 50% of
baseline)
or

Event stabilization: sCr level with ±10%
variability over last 6 months or protein-
creatinine ratio stabilization at a new level
with ±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive
metric for integrated kidney function that requires excellent tubular function. A high urinary osmolality
in the setting of an increase in sCr will point toward a "pre-renal" cause rather than tubular toxicity.
9.5
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 (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF.  Study treatment errors are only to be reported 
to Novartis Drug Safety and Epidemiology department if the treatment error is associated with 
an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Drug Safety and Epidemiology. As such, instances 
of misuse or abuse are also to be reported using the SAE form/CRF. Table 9-6 summarizes the 
reporting requirements.


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Table 9-6
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose 
Administration (DAR) 
CRF
Document in AE CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
9.6
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.
The study drug must be discontinued, though the patient may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The patient may continue all other protocol assessments.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (email) 
and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (email) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.


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9.8
AEs of special interest
9.8.1
Ketoacidosis
In rare cases, SGLT-2 inibitors 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 7.2 and appropriate measures must be taken to correct the acidosis and monitor 
glucose levels according to standard of care.
Every case of ketoacidosis must be reported to the Ketoacidosis adjudication committee and the 
ketoacidosis adjudicaton eCRF must be completed.
9.8.2
Hypoglycemia
Stopping rule for hypoglycemia:
Because hypoglycemia is a potential risk of LIK066 treatment, glucose levels will be measured 
when a subject experiences a clinically symptomatic hypoglycemia. If a confirmed glucose 
level is <56 mg/dL by repeated measurement, study treatment may be discontinued and the 
patient will be treated according to standard of care for hypoglycemia.
During the course of the study, if any patient experiences symptoms of hypoglycemia (shaking, 
nervousness, hunger, nausea, palpitations, dizziness, or confusion), they will be instructed to 
seek immediate medical evaluation and treatment.
Education and reporting of hypoglycemia:
Patients with T2DM, treated with antidiabetic medications, especially with sulphonyurea or 
insulin, may be at increased risk of hypoglycemia. The doses of antidiabetic medications should 
be adjusted in patients, who, according to the investigator, could be at a safety risk of developing 
severe hypoglycemia. Every patient (all diabetic patients) must be educated regarding 
hypoglycemic symptoms and treatment. This education should include general review of 
hypoglycemia and use of glucometer as follows:

Explain of possible triggers of hypoglycemia (eg, strenuous exercise, delayed meals,
changes in meal composition, illness, etc.).

Explain the symptoms of hypoglycemia such as dizziness, lightheadedness; palpitations,
heart racing/pounding, shaking; sweating, hunger, blurred vision, impairment of motor
function, confusion.

Review of appropriate treatment for hypoglycemic events (oral glucose intake).


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Each patient will receive a home glucose monitor with all appropriate supplies.  When a subject 
experiences symptoms of hypoglycemia, blood glucose should be measured. At any time when 
the subject experiences symptoms of hypoglycemia, the subject should treat the event as 
appropriate.  Information related to the event should be recorded in the glycemia study diary as 
follows:

The glucose value.

Circumstances (strenuous exercise, delayed or missed meals, alcohol consumption etc.)
under which the hypoglycemic event occurred.

Time of occurrence in relation to the last medication and to the last meal intake.

Time when the event starts and ends.

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 subject must return the study diary at the next scheduled visit.
9.8.3
Orthostatic hypotension
Because orthostatic hypotension is a potential risk of LIK066 treatment, orthostatic blood 
pressure readings will be recorded throughout the study as shown in the Assessment schedule.
Any patient with clinically significant symptomatic orthostasis (more than 20 mmHg drop in 
systolic or 10 mmHg drop in diastolic blood pressure and increase in heart rate >20 bpm) will 
have the study treatment placed on hold. In addition, individuals with orthostasis will be treated 
with volume replacement according to standard of care (refer to Section 7.2 (Discontinuation 
of study treatment).
9.8.4
Fournier’s gangrene
FDA recently issued a safety warning about reported occurrences of a rare but serious and life-
threatening infection of the genitals and area around the genitals, necrotizing fasciitis of the 
genitalia and perineum, commonly referred to as Fournier’s gangrene (FG), associated with the 
SGLT2 inhibitor class of drugs for the treatment of type 2 diabetes.  Outcomes have included 
hospitalizations, multiple surgeries, and death. This serious medical condition requires urgent 
antibiotics and surgical intervention.  While no such cases have been reported with clinical trials
of LIK066, patients who present with pain, tenderness, erythema or swelling of the genitals and 
the perineum along with fever or malaise, should be evaluated for necrotizing fasciitis of the 
genitals and perineum. If FG is suspected, LIK066 treatment should be discontinued and 
appropriate medical (including broad-spectrum antibiotics) and surgical treatment initiated as 
appropriate. 
In general, subjects receiving LIK066 should be instructed to pay attention to genital hygiene 
and have appropriate hydration to reduce the risk of development of genitourinary infections 
including Fournier’s gangrene.


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10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource or eCRFs) 
with the investigators and their staff. During the study Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The monitor 
will visit the site to check the completeness of subject records, the accuracy of data capture / 
data entry, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and ensure that study drug is being stored, dispensed, and accounted for according 
to specifications. Key study personnel must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the 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 the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of the 
data to the CRO working on behalf of Novartis. The Investigator must certify that the data 
entered into the Electronic Case Report Forms are complete and accurate. After database lock, 
the investigator will receive copies of the subject data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and
Assessment schedule (Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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10.3
Database management and quality control
Novartis (or a designated CRO) will 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 
(or designated CRO) who will make the correction to the database. The signed copy of the Data 
Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
MRI data will be collected by the sites and will be transferred to imaging CRO for analysis. 
The data will then be electronically sent to Novartis.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of 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 management.
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10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
An Adjudication Committee will be established to assess suspected cases of ketoacidosis as 
described in the SOM.
11
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. 
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment received. 
The safety analysis set will include all patients who received any study drug.
The PK analysis set will include all patients with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all patients with available PD data and no protocol deviations 
with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
11.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment group 
and patient.
11.4
Analysis of the primary variable(s)
The primary objective of this study is to assess the efficacy of LIK066 on ALT in NASH 
patients during 12 weeks of treatment. 
11.4.1
Primary Variable(s)
Change from baseline to Week 12 in ALT is the primary efficacy variable. ‘Baseline’ is defined 
as the mean of ALT levels at baseline (V101) and pre-dose (V201) visits.


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11.4.2
Statistical model, hypothesis, and method of analysis
11.4.3
Handling of missing values/censoring/discontinuations
11.4.4
Sensitivity analyses
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11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
The secondary PD variables of this study are:

Intrahepatic lipid: Percent (%) Liver fat as measured by Magnetic Resonance Imaging
(MRI).

Anthropometric assessments: Weight, BMI, waist-to-hip (WTH) ratio

AST: Change from baseline to week 12

Non-invasive markers of liver fibrosis:

Enhanced liver fibrosis panel (ELF)
Baseline for all secondary parameters is defined as the last measurement prior to the first dose 
except for AST where baseline is the mean at baseline (V101) and pre-dose (V201) visits.
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time. 
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ECG evaluations
All ECG data will be listed by treatment group, patient and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, patient, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time. Selected lab markers such as AST, bilirubin, ALP, GGT, creatinine and BUN 
will be analyzed using the repeated measures ANCOVA as described in Section 11.4.2.
Adverse events
All information obtained on adverse events will be displayed by treatment group and patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A patient with multiple adverse events 
within a body system is only counted once towards the total of this body system.
11.5.3
Pharmacokinetics
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11.5.4
Pharmacokinetic / pharmacodynamic interactions
11.5.5
Other assessments
Not Applicable.
11.6
Analysis of exploratory variables (if applicable)
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11.6.1
Exploratory biomarkers
11.7
Sample size calculation
11.8
Power for analysis of key secondary variables
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11.9
Interim analyses
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the 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.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
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12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) 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 or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), 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.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of 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.


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13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to 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 subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
References are available upon request.
Bays H (2013). Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the 
Kidney to Improve Glycemic Control in Diabetes Mellitus. Diabetes Ther p. 195-220.
Calzadilla Bertot L, Adams LA (2016). The Natural Course of Non-Alcoholic Fatty Liver 
Disease. Int J Mol Sci.
Chao EC, Henry RR (2010). SGLT2 inhibition--a novel strategy for diabetes treatment. Nat 
Rev Drug Discov p. 551-9.
Lassailly G, Caiazzo R, Buob D, et al (2015). Bariatric Surgery Reduces Features of 
Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology p. 379-88; quiz 
e15-6.
Morgen CS, Sørensen TI (2014). Obesity: global trends in the prevalence of overweight and 
obesity. Nat Rev Endocrinol p. 513-4.
Mudaliar S, Henry RR, Sanyal AJ, et al (2013). Efficacy and safety of the farnesoid X 
receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver 
disease. Gastroenterology p. 574-82.e1.
Musso G, Cassader M, Gambino R (2016) Non-alcoholic steatohepatitis: emerging molecular 
targets and therapeutic strategies. Nat Rev Drug Discov p. 249-74.
Neal B, Perkovic V, Mahaffey KW, et.al. (2017) Canagliflozin and cardiovascular and renal 
events in Type 2 Diabetes. The New England Journal of Medicine p.1-14.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al (2015). Farnesoid X nuclear receptor 
ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet p. 956-65.
Ratziu V, Harrison SA, Francque S, et al (2016). Elafibranor, an Agonist of the Peroxisome 
Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis 
Without Fibrosis Worsening. Gastroenterology p. 1147-1159.e5.
Turk E, Zabel B, Mundlos S, et al (1991). Glucose/galactose malabsorption caused by a 
defect in the Na+/glucose cotransporter. Nature p. 354-6.
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al (2015). Weight Loss Through 
Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. 
Gastroenterology p. 367-78.e5; quiz e14-5.
Younossi ZM, Koenig AB, Abdelatif D, et al (2016). Global epidemiology of nonalcoholic 
fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. 
Hepatology p. 73-84.

SAP_001.pdf: 
Biostatistics & Statistical Programming /  
Novartis Institutes for BioMedical Research 
LIK066 
CLIK066X2204 
A 12-week randomized, patient and investigator blinded, 
placebo-controlled, parallel group study to investigate the 
efficacy of LIK066 in obese patients with non-alcoholic 
steatohepatitis (NASH) 
Statistical Analysis Plan (SAP) 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Author(s): 
Document type: 
SAP Documentation – NIBR 
Document status: 
Final 
Release date: 
22-July-2019
Number of pages: 
18 
Personal Protected Data


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SAP 
CLIK066X2204 
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CLIK066X2204 
Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 4 
List of figures ...................................................................................................................... 4 
1 
Introduction ......................................................................................................................... 5 
1.1 
Scope of document .................................................................................................. 5 
1.2 
Study reference documentation ............................................................................... 5 
1.3 
Study objectives ....................................................................................................... 5 
1.3.1. Primary objective(s)....................................................................................... 5 
1.3.2. Secondary objective(s) .................................................................................. 5 
1.3.3. Exploratory objective(s) ................................................................................ 6 
1.4 
Study design and treatment ...................................................................................... 7 
2 
First interpretable results (FIR) ........................................................................................... 7 
3 
Interim analyses ................................................................................................................... 8 
4 
Statistical methods: Analysis sets ........................................................................................ 9 
5 
Statistical methods for Pharmacokinetic (PK) parameters ................................................ 10 
5.1 
Variables ................................................................................................................ 10 
5.2 
Descriptive analyses .............................................................................................. 10 
5.3 
Statistical model, assumptions and hypotheses ..................................................... 10 
6 
Statistical methods for Pharmacodynamic (PD) parameters ............................................. 11 
6.1 
Primary objective ................................................................................................... 11 
6.1.1 
Variables ............................................................................................... 11 
6.1.2 
Descriptive analyses .............................................................................. 11 
6.1.3 
Statistical model, assumptions and hypotheses ..................................... 11 
6.2 
Secondary objectives ............................................................................................. 12 
6.2.1 
Variables ............................................................................................... 12 
6.2.2 
Descriptive analyses .............................................................................. 13 
6.2.3 
Statistical model, assumptions and hypotheses ..................................... 13 
6.3 
Exploratory objectives ........................................................................................... 13 
6.3.1 
Variables ............................................................................................... 13 
6.3.2 
Descriptive analyses .............................................................................. 15 
6.3.3 
Statistical model, assumptions and hypotheses ..................................... 15 
7 
Statistical methods for safety and tolerability data ............................................................ 16 
7.1 
Variables ................................................................................................................ 16 
7.2 
Descriptive analyses .............................................................................................. 16 
7.3 
Graphical presentation ........................................................................................... 17 


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8 
Statistical methods for Pharmacokinetic/Pharmacodynamic/Pharmacogenetic 
interactions ........................................................................................................................ 17 
10 Derivations ........................................................................................................................ 17 
List of tables 
List of figures 
Figure 1-1:                 Study Design ............................................................................................ 7 
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1 
Introduction  
1.1 
Scope of document 
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLIK066X2204”. 
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol. 
1.2 
Study reference documentation 
Amendment study protocol (v01) is available at the time of finalization of Statistical Analysis 
Plan. 
1.3 
Study objectives 
The purpose of this study is to assess the effects of LIK066 on a variety of metabolic and 
inflammation biomarkers in patients with NASH. 
1.3.1. Primary objective(s) 
Primary objective(s) 
Endpoints related to primary objectives 
•
To determine the effect of LIK066 on
Liver Function Test (LFT) after 12 weeks
of treatment
•
Circulating alanine aminotransferase
(ALT) levels
1.3.2. Secondary objective(s) 
Secondary objective(s) 
Endpoints related to secondary objective(s) 
•
To determine the effect of LIK066 on
intrahepatic lipid after 12 weeks of
treatment.
• Percent (%) Liver fat as measured by
Magnetic Resonance Imaging (MRI
PDFF)
•
To determine the effect of LIK066 on total
body weight after 12 weeks of treatment.
• Percent change in total body weight
•
To determine the effect of LIK066 on non-
invasive markers of liver fibrosis after 12
weeks of treatment.
• Enhanced liver fibrosis panel (ELF:
PIIINP, TIMP-1, and Hyaluronic acid)
•
To determine the safety and tolerability of
LIK066.
• Adverse events, safety laboratory tests
including basic chemistry profile and
liver biochemical tests
•
To evaluate the pharmacokinetics (PK) of
LIK066 in NASH patients
• Cmax, Tmax, AUClast


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•
To determine the effect of LIK066 on
aspartate aminotransferase (AST) after 12
weeks of treatment
• Circulating aspartate aminotransferase
(AST) levels
1.3.3. Exploratory objective(s) 
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1.4 
Study design and treatment 
This is a non-confirmatory, multicenter, patient and investigator blinded, randomized, placebo-
controlled, parallel group study in patients with NASH. Randomization will be stratified by 
BMI at baseline (<30 kg/m2 or ≥ 30 kg/m2 for patients with an Asian race, or <35 kg/m2 or ≥ 
35 kg/m2 for all other patients). 
At the beginning of the study after eligibility has been confirmed, patients will be randomized 
in a 2:1 ratio to receive either LIK066 at 150 mg qd  OR matching placebo qd, by oral 
administration. A third, 30 mg qd arm will be initiated  after 33 patients have been enrolled in 
the initial two arm portion of the study. For the entire study, patients will be randomized to 
either LIK066 at 150 mg qd, 30 mg qd or matching placebo at a ratio of 2:2:1.Figure 1-1 depicts 
the steps that will be followed in the study, starting from a 28-day screening period, then a 
baseline period of 14 days, a treatment period of 12 weeks, and a study completion evaluation 
approximately 28 days after the last drug administration 
Figure 1-1: Study Design 
*30 mg dose arm to start after 33 patients have enrolled into initial two arms of 150mg and placebo cohorts at a
2:1 randomization ratio. After the enrollment of these 33 patients, the randomization will change to a 2:4:1 ratio
(150 mg: 30 mg: placebo) to maintain a 2:2:1 ratio across the three arms (150 mg:30 mg: placebo) at study end.
Total of approximately 110 subjects will enroll in the study.
2 
First interpretable results (FIR) 
First interpretable results (FIR) will be provided for this trial. 
FIR will focus on the following analyses: 
•
Analysis populations (if needed)
•
Subject disposition
•
Demographics and baseline characteristics. Baseline characteristics include, but not
limited to:
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o
Age, Weight/Height/BMI, liver function tests: ALT, AST, waist circumference,
hip circumference, ELF and its 3 components, HOMA-IR, FIB-4 score. APRI
score
•
Safety results include but are not limited to:
o
Number and percentage of subjects with adverse events by body system and
preferred term with a breakdown by treatment
•
Pharmacokinetic (PK) results for plasma:
o
Arithmetic mean (SD) plasma PK concentration-time plot per treatment.
o
Summary statistics for PK parameters.
•
Pharmacodynamic (PD) analyses include, but are not limited to:
o
Model estimated treatment effect in change from baseline to Week 12 in ALT
o
Arithmetic mean (SE) ALT plot per treatment (overlaying) over time
o
Model estimated treatment effects of key secondary parameters (Percent liver
fat as measured by MRI, Total body weight, anthropometric assessments, ®,
ELF panel and AST at Week 12
o
Arithmetic mean (SE) plots of key secondary parameters (Percent liver fat as
measured by MRI, Total body weight, anthropometric assessments, ELF panel
per treatment and AST (overlaying) and over time.
3 
Interim analyses 
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4 
Statistical methods: Analysis sets 
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5 
Statistical methods for Pharmacokinetic (PK) parameters 
All subjects within the PK analysis set will be included in the PK data analysis. 
5.1 
Variables 
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or 
higher): Cmax, Tmax, AUClast and other parameters as relevant (e.g. AUC0-24h) from the 
plasma concentration-time data. 
5.2 
Descriptive analyses 
5.3 
Statistical model, assumptions and hypotheses 
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6 
Statistical methods for Pharmacodynamic (PD) parameters 
All subjects within the PD analysis set will be included in the PD data analysis. 
6.1 
Primary objective 
The primary objective of this study is to assess the efficacy of LIK066 on ALT in NASH 
patients during 12 weeks of treatment. 
6.1.1 
Variables 
Change from baseline to Week 12 in ALT is the primary efficacy variable. ‘Baseline’ is defined 
as the mean of measurements taken at the Screening (V1) and Baseline (V101) visits. 
6.1.2 
Descriptive analyses 
6.1.3 
Statistical model, assumptions and hypotheses 
Bayesian approach 
Repeated measures approach 
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6.1.3.1 
Model checking procedures 
Model checking will not be performed in this exploratory study. 
6.1.3.2 
Sensitivity analysis 
6.2 
Secondary objectives 
6.2.1 
Variables 
The secondary PD variables of this study are: 
•
Intrahepatic lipid: Percent (%) Liver fat as measured by Magnetic Resonance Imaging
(MRI).
•
Anthropometric assessments: Weight, BMI, waist-to-hip (WTH) ratio, waist
circumference
•
AST: Change from baseline, with the Week 12 visit being of primary interest
•
Non-invasive markers of liver fibrosis:
o
Enhanced liver fibrosis panel (ELF)
Baseline for all secondary parameters is defined as the last measurement prior to the first dose 
except for AST where baseline is the mean at Screening (V1) and Baseline (V101)  
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6.2.2 
Descriptive analyses 
6.2.3 
Statistical model, assumptions and hypotheses 
6.3 
Exploratory objectives 
6.3.1 
Variables 
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6.3.2 
Descriptive analyses 
6.3.3 
Statistical model, assumptions and hypotheses 
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7 
Statistical methods for safety and tolerability data 
All subjects within the Safety analysis set will be included in the safety data analysis. 
7.1 
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information. 
7.2 
Descriptive analyses 
Subject demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject. 
Treatment 
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject. 
Vital signs 
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time. 
ECG evaluations 
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by treatment and 
visit/time. 
Adverse events 
All information obtained on adverse events will be displayed by treatment and subject. 
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment. 
Separate tables and listings will be presented indicating event toxicity grade and study drug 
relationship. 


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7.3 
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created. 
8 
Statistical methods for 
Pharmacokinetic/Pharmacodynamic/Pharmacogenetic 
interactions 
10 
Derivations 
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