Clinical trial NCT03198767
Conditions: Obesity
Keywords: obesity overweight body mass index BMI diarrhea
Sponsor: Novartis Pharmaceuticals
Start date: 2017-06-21; Completion date: 2017-09-04
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study was to determine if LIK066 taken with a meal containing low carbohydrate is associated with less diarrhea compared to a high carbohydrate meal and to assess the potential effects of supplements such as psyllium or calcium carbonate on alleviating diarrhea associated with LIK066.

Detailed description:

Arms: arm 1: Period 1 (Day 1-3): Daily dose of 50 mg LIK066 + 50% carbohydrate (CHO) Period 2 (Day 9-11): Daily dose of 50 mg LIK066 + 25% carbohydrate Period 3 (Day 17-19): Daily dose of 50 mg LIK066 + 0% carbohydrate arm 2: Period 1 (Day 1-3): Daily dose of 50 mg LIK066 + 25% carbohydrate (CHO) Period 2 (Day 9-11): Daily dose of 50 mg LIK066 + 0% carbohydrate Period 3 (Day 17-19): Daily dose of 50 mg LIK066 + 50% carbohydrate arm 3: Period 1 (Day 1-3): Daily dose of 50 mg LIK066 + 0% carbohydrate (CHO) Period 2 (Day 9-11): Daily dose of 50 mg LIK066 + 50% carbohydrate Period 3 (Day 17-19): Daily dose of 50 mg LIK066 + 25% carbohydrate arm 4: Period 1 (Day 1-3): Daily dose of 50 mg LIK066 + 8% carbohydrate (CHO) PROTOCOL DEVIATION: subjects received 8% CHO in error and were discontinued after Period 1. arm 5: Period 1 (Day 1-3): Daily dose of 50 mg LIK066+50% carbohydrate + no supplement (NS) Period 2 (Day 9-11): Daily dose of 50 mg LIK066+50% carbohydrate + 6 g psyllium (PS) Period 3 (Day 17-19): Daily dose of 50 mg LIK066+50% carbohydrate +1g calcium carbonate (CC) arm 6: Period 1 (Day 1-3): Daily dose of 50 mg LIK066+50% carbohydrate + 6 g psyllium (PS) Period 2 (Day 9-11): Daily dose of 50 mg LIK066+50% carbohydrate +1g calcium carbonate (CC) Period 3 (Day 17-19): Daily dose of 50 mg LIK066+50% carbohydrate + no supplement (NS) arm 7: Period 1 (Day 1-3): Daily dose of 50 mg LIK066+50% carbohydrate +1g calcium carbonate (CC) Period 2 (Day 9-11): Daily dose of 50 mg LIK066+50% carbohydrate + no supplement (NS) Period 3 (Day 17-19): Daily dose of 50 mg LIK066+50% carbohydrate + 6 g psyllium (PS)
Interventions: intervention 1: LIK066 intervention 2: Carbohydrate 50% intervention 3: Carbohydrate 25% intervention 4: Carbohydrate 8% intervention 5: Carbohydrate 0% intervention 6: Psyllium intervention 7: Calcium carbonate
Intervention descriptions: intervention 1: LIK066 50 mg tablets. Open-label, bulk, blister-pack. intervention 2: 50% carbohydrate in breakfast meal intervention 3: 25% carbohydrate in breakfast meal intervention 4: 8% carbohydrate in breakfast meal intervention 5: 0% carbohydrate in breakfast meal intervention 6: Powder 6 grams intervention 7: Liquid 1 gram (4 mL equivalent sugar free)

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LIK066
Clinical Trial Protocol CLIK066B2203 / NCT03198767
A randomized, open label, two-part, three-period, 
cross-over study to investigate the effects of carbohydrate 
in diet and to evaluate supplements on the gastrointestinal 
tolerability of LIK066 in overweight or obese subjects
Document type:
Amended Protocol Version
EUDRACT number:
N/A
Version number:
v01 (Clean)
Clinical Trial Phase:
II
Release date:
08-Aug-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not be part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below.  Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Drug Safety and Epidemiology (DS&E) 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 ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols.........................................................................10
Glossary of terms...............................................................................................................11
Amendment 1 (August 2017)............................................................................................13
Protocol synopsis...............................................................................................................14
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
18
19
1.3
Clinical data...........................................................................................................19
1.3.1
Human safety and tolerability data .......................................................19
20
1.3.3
Human pharmacodynamic data.............................................................20
1.4
Study purpose ........................................................................................................21
2
Study objectives and endpoints .........................................................................................21
2.1
Primary objective(s)...............................................................................................21
2.2
Secondary objective(s)...........................................................................................21
22
3
Investigational plan ...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale of study design.......................................................................................28
28
3.4
Rationale for choice of comparator .......................................................................29
3.5
Purpose and timing of interim analyses/design adaptations..................................30
3.6
Risks and benefits..................................................................................................30
3.6.1
Blood sample volumes..........................................................................31
4
Population..........................................................................................................................31
4.1
Inclusion criteria ....................................................................................................31
4.2
Exclusion criteria...................................................................................................32
5
Restrictions for Study Subjects .........................................................................................34


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5.1
Contraception requirements...................................................................................34
5.2
Prohibited treatment...............................................................................................34
5.3
Dietary restrictions and smoking...........................................................................35
5.4
Other restrictions ...................................................................................................36
6
Treatment...........................................................................................................................37
6.1
Study treatment......................................................................................................37
6.1.1
Investigational treatment and control drugs..........................................37
6.1.2
Additional study treatment....................................................................37
6.2
Treatment arms......................................................................................................37
6.3
Treatment assignment and randomization.............................................................38
6.4
Treating the subject................................................................................................39
6.5
Permitted dose adjustments and interruptions of study treatment.........................39
6.6
Emergency breaking of assigned treatment code ..................................................39
6.7
Treatment exposure and compliance .....................................................................39
6.8
Recommended treatment of adverse events ..........................................................39
6.9
Rescue medication.................................................................................................39
6.10
Concomitant treatment...........................................................................................40
7
Study completion and discontinuation ..............................................................................40
7.1
Study completion and post-study treatment ..........................................................40
7.2
Discontinuation of study treatment........................................................................40
7.3
Withdrawal of informed consent ...........................................................................42
7.4
Lost to follow-up ...................................................................................................42
7.5
Study Stopping rules..............................................................................................42
7.6
Early study termination by the sponsor .................................................................42
8
Procedures and assessments ..............................................................................................43
8.1
Assessment schedule .............................................................................................43
8.2
Informed consent procedures.................................................................................52
8.3
Subject screening...................................................................................................52
8.4
Subject demographics/other baseline characteristics.............................................52
8.5
Efficacy / Pharmacodynamics ...............................................................................53
8.5.1
Patient-Reported Outcome....................................................................53
8.6
Safety.....................................................................................................................54
8.6.1
Electrocardiogram (ECG) .....................................................................54
8.6.2
Vital Signs.............................................................................................54
8.6.3
Hematology...........................................................................................54
8.6.4
Physical Examination............................................................................54


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8.6.5
Clinical Chemistry ................................................................................55
8.6.6
Urinalysis ..............................................................................................55
8.6.7
Body Height ..........................................................................................55
8.6.8
Body Weight .........................................................................................55
55
56
56
9
Safety monitoring..............................................................................................................56
9.1
Adverse events.......................................................................................................56
9.2
Serious adverse event reporting.............................................................................58
9.2.1
Definition of SAE .................................................................................58
9.2.2
SAE reporting........................................................................................58
9.3
Liver safety monitoring .........................................................................................59
9.4
Renal safety monitoring.........................................................................................60
9.5
Reporting Medication errors including misuse/abuse ...........................................61
9.6
Pregnancy reporting...............................................................................................61
9.7
Early phase safety monitoring ...............................................................................62
9.8
Monitoring hypoglycemia .....................................................................................62
9.9
Monitoring orthostatic hypotension.......................................................................62
9.10
Monitoring ketoacidosis ........................................................................................62
10 Data review and database management.............................................................................63
10.1
Site monitoring ......................................................................................................63
10.2
Data collection.......................................................................................................63
10.3
Database management and quality control............................................................64
10.4
Data Monitoring Committee..................................................................................64
10.5
Adjudication Committee........................................................................................64
11 Data analysis......................................................................................................................65
11.1
Analysis sets ..........................................................................................................65
11.2
Subject demographics and other baseline characteristics......................................65
11.3
Treatments .............................................................................................................65
11.4
Analysis of the primary variable(s) .......................................................................65
11.4.1
Variable(s).............................................................................................65
11.4.2
Statistical model, hypothesis, and method of analysis..........................65
11.4.3
Handling of missing values/censoring/discontinuations.......................66
11.4.4
Sensitivity analyses ...............................................................................66
11.5
Analysis of secondary variable(s)..........................................................................66


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11.5.1
Efficacy / Pharmacodynamics...............................................................66
11.5.2
Safety.....................................................................................................67
11.5.3
Pharmacokinetic / pharmacodynamic interactions................................67
11.5.4
Other assessments .................................................................................67
68
68
69
11.7
Sample size calculation..........................................................................................69
11.8
Power for analysis of key secondary variables......................................................70
11.9
Interim analyses.....................................................................................................70
12 Ethical considerations........................................................................................................70
12.1
Regulatory and ethical compliance........................................................................70
12.2
Responsibilities of the investigator and IRB/IEC..................................................70
12.3
Publication of study protocol and results...............................................................71
13 Protocol adherence ............................................................................................................71
13.1
Protocol Amendments ...........................................................................................71
14 References .........................................................................................................................72
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................73
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................75
List of tables
 
20
Table 6-1
Definition of treatment sequences.........................................................38
Table 6-2
Randomization assignment numbering.................................................38
Table 8-1
Assessment Schedule ............................................................................43
Table 9-1
Summary of reporting requirements for medication errors...................61
Table 15-1
Liver Event Definitions.........................................................................73
Table 15-2
Actions required for Liver Events.........................................................74
Table 15-3
Exclusion of underlying liver disease ...................................................74
Table 16-1
Specific Renal Alert Criteria and Actions.............................................75
Table 16-2
Follow-up of renal events......................................................................76
List of figures
Figure 3-1
Part A: Effects of Carbohydrate in the Breakfast Meals.......................26
Figure 3-2
Part B: Effects of Supplements in the Breakfast Meals* ......................27


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List of abbreviations
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CDS
Core Data Sheet (for marketed drugs)
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CO2
carbon dioxide
COAR
Clinical Operations, Analytics & Regions
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CTRD
Clinical Trial Results Database
CV
coefficient of variation
DMC
Data Monitoring Committee
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
eSAE
Electronic Serious Adverse Event
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HIV
human immunodeficiency virus


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i.v.
intravenous
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDH
lactate dehydrogenase
LFT
Liver function test
LLN
lower limit of normal
LLQ
lower limit of quantification
MABEL
minimum anticipated biological effect level
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MRSD
maximum recommended starting dose
NCDS
Novartis Clinical Data Standards
o.d.
once a day
p.o.
oral
PA
posteroanterior
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
RBC
red blood cell(s)
RDC
Remote Data Capture
REB
Research Ethics Board
s.c.
subcutaneous
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin


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ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization


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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]
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
Clast
The last observed quantifiable concentration [mass / volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Tlast
The time point that corresponds to the last measurable concentration [time]
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)
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, 
and follow-up) which applies across all arms of a study.
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This includes any 
placebos, any active controls, as well as approved drugs used outside 
of their indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed 
by the protocol when used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IRT system.
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.


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Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned.
Randomization 
number
A 
unique 
identifier 
assigned 
to 
each 
randomized 
subject, 
corresponding to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part 
of the required study procedures; includes investigational drug, active 
drug run-ins or background therapy.
Study treatment
Any drug administered to the study participants as part of the required 
study procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
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 is defined as when a subject 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
biologic material


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Amendment 1 (August 2017)
Amendment Rationale: 
This Amendment is to provide minor adjustments and clarifications to the protocol.
Changes to the protocol: 

Section 3.6.1: In the protocol, it is defined “Approximately 400 mL of blood is planned to 
be collected over a period of 8 weeks including the Screening visit, from each subject as 
part of the study.”   However, inconsistencies were discovered showing that the total 
blood volume adds up ~560 mL based on the blood log (defined in the Site Operations 
Manual). This was due to the collection of banking samples for future use, if warranted by 
study results. The collection of banking samples are now removed (108mL), consequently, 
the total blood volume adds up to ~450 mL as originally defined in the protocol. 

Section 3.1, Section 6.1.1, and Section 8 (Table 8-1, footnote 13): The 1 gram tablet 
formulation of calcium carbonate was changed to liquid formulation (4 mL) due to 
difficulty in sourcing the tablet formulation.
 

Section 5.2:  To ensure consistency, changes were made in the Prohibited Treatment: “a 
stable regimen for approximately 6 weeks prior to randomization” to “a stable regimen for 
approximately 12 weeks prior to randomization”.

Section 8: To be consistent with the protocol language, the time points (2 and 4 hours) 
where VAS will be conducted is clarified in the Assessment schedule.
 
 
 

Minor corrections and updates were made as needed throughout the document.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol may require IRB/IEC approval prior to 
implementation.


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Protocol synopsis
Protocol number
LIK066B2203
Title
A randomized, open label, two-part, three-period, cross-over study to 
investigate the effects of carbohydrate in diet and to evaluate supplements on 
the gastrointestinal tolerability of LIK066 in overweight or obese subjects
Brief title
Effects of carbohydrate in diet and supplements on the GI tolerability of LIK066
Sponsor and 
Clinical Trial Phase
Novartis
Phase II
Intervention type
Investigational drug
Study type
Interventional 
Purpose and 
rationale
The purpose of this study is to 1) to assess whether or not a meal containing 
low carbohydrate in the form of glucose and galactose is associated with less 
diarrhea compared to a high carbohydrate meal; 2) to assess the potential 
effects of supplements such as psyllium or calcium carbonate on alleviating 
diarrhea. 
Primary 
Objective(s)

To assess the effects of meals with different carbohydrate content on 
diarrhea 

To assess the effects of supplements (psyllium and calcium carbonate) on 
diarrhea 
Secondary
Objectives
To assess the effects of LIK066 and carbohydrate in meal on fecal parameters
Study design
This randomized, open-label, two-part, three-period cross-over design will 
enroll approximately 24 overweight or obese subjects in each part (A and B) 
for a total of approximately 48 subjects over the course of the 25 day study. 
Part A will assess the effects of % carbohydrate (50%, 25% and 0%) in the 
breakfast meals on diarrhea when LIK066 is administered immediately before 
the breakfast.  Part B of the study will assess the effects of a concomitant 
treatment with a supplement (calcium carbonate or psyllium) on diarrhea when 
LIK066 is administered immediately before a breakfast meal with 50% 
carbohydrate. 
The study will consist of an up to 24 day screening period, a 3 day 
baseline/run in period, three periods of treatment of 3 days each with a 5 day 
washout  period in between each treatment period. Study completion will occur 
3 days after the last dose of LIK066.  The baseline, treatment, and washout 
periods will be conducted with subjects being domiciled (25 days 
consecutively). 
Diarrhea will be captured based on both reduced consistency (stools with 
Bristol Stool Chart (BSC) score of 6 or 7) and increased frequency (total 
number of bowel movements, total number of stools with BSC of 6 or 7).  
Symptoms such as urgency, bloating, flatus and abdominal pain will also be 
recorded for each bowel movement. The stool assessments include recording 
of the timing, weight, pH, consistency of stool using BSC according to the 
Assessment schedule. 
Population
Overweight and obese subjects will be enrolled in this study.


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Key Inclusion 
criteria

Male and female aged 18-65

Body mass index (BMI) of 25 - 50 kg/m2

HbA1c < 10% 

oral body temperature between 35.0-37.5 °C

sitting systolic blood pressure, 90-139 mm Hg

sitting diastolic blood pressure, 50-89 mm Hg

sitting pulse rate, 40 - 90 bpm
Key Exclusion 
criteria

Pre-existing, clinically significant gastrointestinal, liver, cardiovascular, 
renal (including familial glucosuria) or other chronic medical condition 
which is considered serious or unstable, other than stable cardiovascular 
disease, stable adequately treated hypertension, dyslipidemia or other 
stable chronic disorders

Clinically significant GI disorder related to malabsorption or that may affect 
drug or glucose absorption

History of significant gastrointestinal surgery that could affect intestinal 
glucose absorption (e.g. bariatric surgeries including, Roux en Y gastric 
bypass, sleeve gastrectomy, Nissen fundoplication)

Pregnant or lactating women

Type I diabetes
Study treatment

The investigational drug, LIK066 tablets will be prepared by Novartis. 
Efficacy/PD 
assessments

Diarrhea is the primary endpoint in this study.
Key safety 
assessments

Physical examination

Body temperature

Hematology

Blood chemistry

Urinalysis

Blood pressure

Pulse rate

ECG evaluation

Adverse events and serious adverse events
Other assessments

Stool pH, stool weight, and BSC score 

 

 





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Data analysis
The primary analysis will be performed by study part. The endpoint will be 
analyzed using a negative binomial mixed effects model with fixed effects of 
period, treatment, day, the period-by-day interaction, and the treatment-by-day 
interaction, and a random subject effect. An unstructured covariance matrix will 
be specified for the repeated observations on a subject within the same period. 
The least-squares mean and associated 80% CI for the number of diarrhea 
episodes per day for each treatment, and the estimated mean difference 
between each treatment, the p-value, and corresponding two-sided 80% CI, 
will be extracted from the model for each day, and summarized by a table and 
a line chart. Conclusions from the analysis will be based on treatment 
differences from all 3 days, collectively.
Key words
SGLT1/2, GI tolerability, carbohydrate


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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,
and 
importantly type 2 diabetes (T2DM). In contrast to the numerous medicines that are available 
to treat these obesity-related diseases, relatively few agents are available for the treatment of 
obesity itself that are effective, safe or scalable to the size of the affected population 
(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). In healthy 
subjects, virtually all of the filtered glucose is reabsorbed into the circulation and no glucose 
is detected in the urine. SGLT2 located in the segments 1 and 2 of the proximal tubule 
contributes to ~90% of reabsorption of the filtered glucose (Abdul-Ghani et al 2015). SGLT1 
is located in the more distal part of the proximal tubule, segment 3, and contributes to the 
remaining ~10% of filtered glucose. However, when SGLT2 is inhibited with empagliflozin 
(a SGLT2 inhibitor), SGTL1 compensates for the reabsorption of filtered glucose and SGLT1 
is capable of reabsorbing >40% of filtered glucose load in a mouse model 
(Abdul-Ghani et al 2015; Macha et al 2014). 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.
LIK066 is a potent dual inhibitor of SGLT1/2, which has been studied in healthy subjects, 
patients with T2DM, and obese patients with elevated BMI.  LIK066 is generally safe and 
well tolerated in the clinical studies being completed to date. LIK066 has a favorable 
pharmacokinetic profile (T1/2 10-16 hours), which allows once daily dosing.  LIK066 at 
150 mg daily dose (as qd, bid or tid) results in a significant weight loss in obese patients and 
~ 6% of body weight loss was demonstrated after 12 week treatment.
The most frequent adverse event observed in a 12 week study in obese patients 
(LIK066X2201) associated with LIK066 was diarrhea. The observed diarrhea adverse event is 
likely to be related to the complete inhibition of SGLT1 in the gut (Pfister et al 2011).  It is 
known that diarrhea observed in patients with SGLT1 inactivating mutation can be managed 
with elimination of glucose and galactose from the diet. Therefore, the observed 
LIK066-induced diarrhea may be managed by recommending a low carbohydrate (especially 
glucose and galactose) diet when LIK066 is administered. This study is designed to assess the 
effects of meals with different carbohydrate content and supplements on the incidence of 
diarrhea associated with LIK066 treatment, and to assess the potential effects of LIK066 on 
incretin hormones (GLP-1 and PYY) in overweight or obese subjects.


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The most relevant data for the present study are summarized in the sections below. 
For detailed information, please refer to the Investigator's Brochure. 


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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. Overall, single doses of up to 
350 mg and repeated doses of up to 300 mg for 14 days in healthy subjects were generally 
safe and tolerated. Treatment with LIK066 at 150 mg qd for 12 weeks was also shown to be 
safe and tolerated. AEs were predominantly diarrhea and related GI AEs after single doses 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.
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 of any specific laboratory abnormality, the number of subjects observed to 
have an abnormality, or in the magnitude of specific laboratory abnormalities. 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.


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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 led to significant efficacy
on lowering 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 


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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 most frequent adverse event observed in a 12 week study in obese patients 
(LIK066X2201) associated with LIK066 was diarrhea. This diarrhea is likely to be related to 
complete SGLT1 inhibition.  It is known that diarrhea related to SGLT1 inactivating mutation 
can be managed with elimination of glucose and galactose from the diet (Martin et al 1996). 
Therefore, the observed LIK066-induced diarrhea may be managed by recommending a low 
carbohydrate diet when taking LIK066. The purpose of this study is to assess the effects of 
meals with different carbohydrate content and supplements on the incidence of diarrhea 
associated with LIK066 treatment, 
 
 in overweight or obese subjects.
2
Study objectives and endpoints
The objectives of this study are: 1) to assess whether or not a meal containing low 
carbohydrate in the form of glucose and galactose is associated with less diarrhea compared to 
a high carbohydrate meal; 2) to assess the potential effects of supplements such as psyllium or 
calcium carbonate on alleviating diarrhea. 
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary 
objective(s)

To assess the effects of meals with different 
carbohydrate content on diarrhea 

Diarrhea (consistency and 
incidence)

To assess the effects of supplements (psyllium and 
calcium carbonate) on diarrhea 

Diarrhea  (consistency and 
incidence)
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the effects of LIK066 and 
carbohydrate in meal on  fecal 
parameters

Stool samples (timing, assessment of 
consistency with Bristol stool chart,  stool 
weight, stool pH)


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3
Investigational plan
3.1
Study design
This study employs a randomized, open-label, two-part, three-period, cross-over design. 
This is a non-confirmatory study. Each part of the study will enroll approximately 
24 overweight or obese subjects, thus, a total of approximately 48 subjects will be enrolled for 
the entire study. In each part of the study, each subject will be randomized to one of the 
3 treatment sequences shown in Figure 3-1 (Part A) and Figure 3-2 (Part B). 


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Part A of the study will assess the effects of % carbohydrate (50%, 25% and 0%) in the 
breakfast meals on diarrhea when LIK066 is administered immediately before the breakfast.  
Part B of the study will assess the effects of a concomitant treatment with a supplement 
(calcium carbonate or psyllium) on diarrhea when LIK066 is administered immediately before 
a breakfast meal with 50% carbohydrate. 
The primary endpoint of this study is the diarrhea events. Diarrhea is usually defined by 
reduced consistency and/or increased frequency of stools. Normal stool frequency ranges 
from 3 per week to 2 per day. Bristol Stool Chart (BSC) is frequently used as a measure of 
consistency, and a score of 6 or 7 (pourable or watery stool) is considered abnormal.  
Diarrhea events will be captured based on both reduced consistency (stools with BSC score of 
6 or 7) and increased frequency (total number of bowel movements, total number of stools 
with BSC of 6 or 7).  Symptoms such as urgency, bloating, flatus, and abdominal pain will 
also be recorded for each bowel movement.
The study will consist of an up to 24 day screening period, a 3 day baseline/run in period, and 
three periods of treatment of 3 days each with a 5 day washout  period in between each 
treatment period. Study completion will occur 3 days after the last dose of LIK066.  
The baseline, treatment and washout periods will be conducted with subjects being domiciled 
for approximately 25 days (see Figure 3-1 and Figure 3-2). 
Screening (Day-28 to Day -4)
Potential study subjects will present to the clinical site for a screening visit where eligibility 
for the study will be evaluated.
Baseline/Run In (Day-3 to Day -1)
Subjects who meet the inclusion/exclusion criteria at screening will be admitted to the clinical 
site on Day -3. A survey for food preference of each subject will be conducted so that meal 
menus can be provided to accommodate the usual diet habits of each individual. As diet 
changes may impact on the bowel movement habits, subjects participating in this study will 
be encouraged to follow their usual dietary habit whenever possible.  
During the baseline period, a standardized breakfast meal (600 calories with 
50% carbohydrate, 15% protein and 35% fat) will be served; for lunch and dinner, menu 
options will be offered so that each subject can follow their usual diet following the standard 
nutritional guidance. 
Starting on Day-3 and continuing through the 25 days of domiciling period, stool assessments 
will take place whenever a subject has a bowel movement (Assessment schedule). 
Starting from Day -2 at approximately 07.00, a 24-hour stool collection will be done for each 
subject. During Day -2 through Day 22, daily bowel movements will be monitored and 
collected, and stored in a refrigerated container and will be assessed by the study staff 
according to the Bristol Stool Chart and bowel movement record. 


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The stool assessments include recording of the timing, weight, pH, consistency of stool using 
Bristol Stool Chart, 
 
according to the 
Assessment schedule.
Day -1 Baseline Assessment
Twenty-four (24) hour baseline stool samples will be collected from Day-1 to Day 1 morning 
(approximately 07.00 to 07.00) for various assessments of fecal parameters according to the 
Assessment schedule.
 
 
 
On Day -1, at approximately 07.30, a 600 calorie standardized breakfast meal containing 50% 
carbohydrate, 15% protein, and 35% fat will be served, and subjects will drink 250 mL water 
immediately before breakfast during treatment periods. The time of drinking water will be 
defined as time zero for the measurement of baseline PD endpoints.  Each subject will 
consume the designated breakfast within 15 mins. 
 
 
 Lunch will be served at approximately 13.00 (after completion of the PD 
sample collection and at least 5 hours from breakfast), and dinner will be served at 
approximately 18.30. The timing of meals should be harmonized on all days (Day -1, Day 3, 
Day 11, and Day 19) when PD are measured to minimize the effects of diurnal rhythm.
 
All other samples and measurements will be taken according to the Assessment schedule.
Part A:  Effects of Carbohydrate in the Breakfast Meals
Treatment Period I (Day 1 to Day 3); Period II (Day 9 to Day 11); Period III (Day 17 to 
Day 19)
Starting on the morning of Day 1 and through Day 3 of each treatment period, each subject 
will receive LIK066 50 mg qd in the morning immediately before the assigned breakfast meal 
according to their assigned treatment sequence. All subjects will take 50 mg LIK066 once daily with 
their assigned breakfast meal containing either 50% carbohydrate, 25% carbohydrate, or no 
carbohydrate. For lunch and dinner, menu options will be offered so that the participants can follow 
their usual dietary habits. These menus will be designed in accordance with the current
Recommended Dietary Guidelines (United States Department of Agriculture 2015). 
The estimated calories consumed will be documented for each meal and for each subject. 
As with the baseline period, 24-hr stool collection will be done and stool assessment will be 
recorded for every bowel movement of every subject according to the Assessment schedule.


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Twenty-four (24) hour stool samples will be collected from Day 3 to Day 4 morning 
(approximately 07.00 to 07.00) of each treatment period for various assessments of fecal 
parameters according to the Assessment schedule.
 
arious assessments including 
UGE24 and electrolytes according to the Assessment schedule.
 
 
At approximately 07.30, a 600 calorie standardized breakfast meal containing 
either 50% or 25% or 0% carbohydrate as designated will be served, and LIK066 50 mg will 
be administered immediately before the breakfast meal. Each subject will consume the 
designated breakfast within 15 mins. 
 
 
 
Lunch will be served at approximately 13:00 (after completion of the PD sample collection 
and at least 5 hours from breakfast), and dinner will be served at approximately 18.30. 
The timing of meals should be harmonized on all days (Day -1, Day 3, Day 11, and Day 19) 
when PD are measured to minimize the effects of diurnal rhythm.
All other measurements and blood samples will be taken according to the 
Assessment schedule.
Washout Period I (Day 4 to Day 8); Period II (Day 12 to Day 16); Period III (Day 20 to 
Day 22) 
Study subjects will also remain domiciled at the clinical site during the washout periods and 
no LIK066 will be administered. There are no particular restrictions for the meals during the 
washout time period, and subjects can choose foods according to their eating habits and 
preference (meal menu to be provided offering varied choices). The estimated calories 
consumed will be documented for each meal for each subject.  As with the run-in and baseline 
period, all stool samples will be collected and bowel movement assessments will be recorded 
for every subject. 
On Day 22, following the end of study assessments, subjects will be discharged from the 
clinical site.
During the study, safety assessments will include physical examinations, vital signs, standard 
clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), adverse event 
and serious adverse event
monitoring, as recorded in the Assessment schedule. 
 


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Figure 3-1
Part A: Effects of Carbohydrate in the Breakfast Meals
Screening 
Period 
Day-28 to 
-4
Baseline 
Day -3 to 
-1
Sequence
Treatment 
Period 1 
Day 1-3
Washout 
5 Days
Treatment 
Period II 
Day 9-11
Washout 
5 Days
Treatment 
Period III 
Day 17-19
Washout 
EOS Day 
20-22
Run-In
1 (n=8)
50% CHO
25% CHO
0% CHO
Run-In
2 (n=8)
25% CHO
0% CHO
50% CHO
Run-In
3 (n=8)
0% CHO
50% CHO
25% CHO
CHO = % carbohydrate content in the standardized breakfast meal
LIK066 50mg QD will be given in the morning immediately before the breakfast meal
Part B: Effects of Supplements (Psyllium and Calcium carbonate)
The same Assessment Schedule will apply to Part B of the study as described for Part A.  
Each subject will consume one of the three supplement treatment options  (6 g psyllium, 
1g calcium carbonate (to be provided in a 4mL liquid, sugar free formulation), or no 
supplement) according to the randomization assignment immediately after administration of 
50 mg LIK066, and before having the standardized breakfast meal, containing 50% 
carbohydrate (Figure 3-2).  All supplement products will be the sugar free version.
Treatment Period I (Day 1 to Day 3); Period II (Day 9 to Day 11); Period III (Day 17 to 
Day 19)
Starting on the morning of Day 1 and through Day 3 of each treatment period, each subject 
will receive LIK066 50 mg qd in the morning, and then consume the designated supplements 
(6 g psyllium or 1g calcium carbonate or no supplement) according to their randomization 
assignment sequence. Immediately after administration of LIK066 50 mg and the supplement, 
a 600 calorie breakfast meal containing 50% carbohydrate will be served. For lunch and 
dinner, menu options will be offered for the participants to choose following their usual 
dietary habits. These menus will be designed in accordance with the current Recommended 
Dietary Guidelines. The estimated calories consumed will be documented for each meal and 
for each subject. As with the baseline period, all stools will be collected and assessment will 
be recorded for every bowel movement of every subject according to the Assessment schedule.
Twenty-four (24) hour stool samples will be collected from Day 3 to Day 4 morning 
(approximately 07.00 to 07.00) of each treatment period for various assessments of fecal 
parameters according to the Assessment schedule.
 
 
 


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On Day 3 of each treatment period, at approximately 07.30 in the morning, each subject will 
take LIK066 50 mg and then consume the supplement (6 g psyllium or 1g calcium carbonate 
or no supplement) as designated immediately before the breakfast. A 600 calorie breakfast 
meal containing 50% carbohydrate will be served and each subject will consume the breakfast 
within 15 mins. 
 
 Lunch will be 
served at approximately 13.00 (after completion of the PD sample collection and at least 
5 hours from breakfast), and dinner will be served at approximately 18.30. The timing of 
meals should be harmonized on all days (Day -1, Day 3, Day 11, and Day 19) when PD are 
measured to minimize the diurnal rhythm.
 
All other samples and measurements will be taken according to the Assessment schedule.
Washout Period I (Day 4 to Day 8); Period II (Day 14 to Day 16); Period III (Day 20 to 
Day 22) 
Study subjects will remain at the clinical site from the Day 4 through Day 8 of each treatment 
period for a washout period. During this time, no LIK066 will be administered. As with the 
run-in and baseline period, stool samples will be collected and bowel movement assessments 
will be recorded for every subject. 
On Day 22, following the end of study assessments, subjects will be discharged from the 
clinical site.
During the study, safety assessments will include physical examinations, vital signs, standard 
clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), adverse event 
and serious adverse event monitoring, as recorded in the Assessment schedule. 
 
Figure 3-2
Part B: Effects of Supplements in the Breakfast Meals*
Screening 
Period 
Day-28 to 
-4
Baseline 
Day -3 to 
-1
Sequence
Treatment 
Period 1 
Day 1-3
Washout 
5 Days
Treatment 
Period II 
Day 9-11
Washout 
5 Days
Treatment 
Period III 
Day 17-19
Washout 
EOS Day 
20-22
Run-In
I (n=8)
NS
Psyllium
CC
Run-In
II (n=8)
Psyllium
CC
NS
Run-In
III (n=8)
CC
NS
Psyllium
*CHO = % carbohydrate content in the standardized breakfast meal (50%) for all groups 
LIK066 (50 mg QD) and supplement will be administered immediately before the breakfast meal
NS = No supplement
CC = Calcium Carbonate (1 gram)
Psyllium = 6 grams


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3.2
Rationale of study design
This is a mechanistic study to investigate the effect of percentage carbohydrate in the 
breakfast meal on the LIK066-induced diarrhea and potential treatments with a supplement in 
overweight or obese subjects. The study will use a randomized, open-label, two-part, 
three-period, cross-over design in each part of the study.

An open label design is considered appropriate because all the primary and secondary 
endpoints assessed in this study are objective measures in nature. A crossover design is 
ideal as comparisons among treatment groups are based on within-subject differences 
which are associated with less variability than between-subject differences. The main 
objective is to assess whether or not the diarrhea adverse event can be alleviated by 
reducing or removing carbohydrate containing glucose and galactose in the meal or by 
concomitant administration of supplements, therefore, placebo control is not needed.

The design of two parts (Part A and Part B) with 3 treatment periods, cross-over design is 
preferred because a single part, six treatment periods cross-over design requires longer 
duration of domiciling which may lead to operational complexity such as difficulty in 
recruitment and higher drop-out rates. The two parts, three periods design is also preferred 
from statistical perspective because it yields the most statistically efficient design for 
addressing the clinical questions.

A five day washout period is considered sufficient based on the fact that limited diarrhea 
episodes were observed on the following day after the last dose of 50 mg qd (one out of
40 patients showed diarrhea on day 15 after 14 day dosing in LIK066X2201).

A standardized breakfast meal (together with menu options for lunch and dinner) enables 
each subject to choose the diets following their usual eating habits during the run-in will 
normalize the bowel movement habit of each subject under similar meal conditions for the 
purpose of comparison during the treatment periods.

The overweight or obese subjects in this study will closely represent the patient population 
for LIK066, which is being developed as a pharmacotherapy for obesity.
Therefore, the study design is considered adequate and appropriate to address the primary 
objectives, the stool consistency and incidence of diarrhea associated with LIK066 treatment, 
which are endpoints that can be measured objectively.


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3.4
Rationale for choice of comparator
Not applicable.


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3.5
Purpose and timing of interim analyses/design adaptations
An interim analysis is not planned, but may be conducted before all subjects complete the 
study if deemed necessary. Depending on the progress of the trial, the analysis may be 
conducted to support decision making concerning the current clinical study, the sponsor’s 
clinical development strategy in general, or in case of any safety concerns. 
3.6
Risks and benefits
There is no anticipated therapeutic benefit expected for subjects participating in this study. 
The risk to participants 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 7.5.
Risks of LIK066 administration in human subjects may include the development of 
gastrointestinal adverse reactions, postural hypotension due to volume depletion, ketoacidosis, 
urinary tract infection, genitourinary infection, renal and hepatic toxicity, and changes in 
calcium homeostasis with subsequent effects on bones, hyperglycemia and hypoglycemia.
Doses of LIK066 proposed in this study have been tested and deemed safe in healthy subjects, 
patients with T2DM and obese patients. Subjects should be closely monitored and treated 
according to the standard of care if deemed necessary by the principle investigator.  LIK066 is 
considered an aneugen at extremely high doses. With the doses and treatment duration 
proposed in this study, more than 10-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 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.
The supplements used in this study are generally well tolerated and widely used as the OTC 
supplements. Potential risks associated with psyllium are bloating and flatulence, and those 
associated with calcium carbonate are constipation, gas and burping. 
Blood samples will be collected frequently during the study either via venipuncture or cannula. 
Additional samples for monitoring of any safety findings would be in addition to this. This is 
not considered to be a risk for this population. 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.
There may be unknown risks to LIK066 which may be serious and unforeseen.


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3.6.1
Blood sample volumes
Approximately 450 mL of blood is planned to be collected over a period of 8 weeks including 
the Screening visit, from each subject as part of the study. Additional samples for monitoring 
of any safety findings would be in addition to this. This is not considered to be a risk for this 
population.
Timings of blood sample collection are outlined in the Assessment Schedule, Section 8.1.
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage, and shipment information.
See Section 8.9 regarding the potential use of residual samples. 
4
Population
The study population will consist of male and female overweight or obese subjects. 
A total of approximately 48 patients will be enrolled in the study and randomized. At least 
36 subjects are expected to complete the study. 
The investigator must ensure that all subjects meet the subsequent eligibility criteria at 
screening. No additional criteria should be applied by the investigator to ensure that the study 
population is representative of all eligible subjects. A relevant record (e.g. checklist) of the 
eligibility criteria must be stored with the documentation at the study site. 
Deviation from any entry criterion excludes a patient from enrollment into the study.
4.1
Inclusion criteria
Overweight or Obese Subjects eligible for inclusion in this study must fulfill all of the 
following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female subjects age 18 to 65 years, with stable health condition as determined 
by past medical history, physical examination, electrocardiogram, and laboratory tests at 
screening.
3. Subjects with a body mass index (BMI) of 25 - 50 kg/m2 at screening 
4. HbA1c < 10% at screening. If treated with antidiabetic medications (other than prohibited 
medications), subjects must be on a stable dose for 12 weeks prior to randomization and 
maintain the dose until the end of the study.
5. Able to communicate well with the Investigator, to understand and comply with the 
requirements of the study.


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6. At screening and baseline,  vital signs (systolic and diastolic blood pressure and pulse rate) 
will be assessed in the sitting position after the subject has rested for at least three (3) 
minutes, and again when required after three (3) minutes in the standing position 
Investigators can be guided by the following ranges:
oral body temperature between 35.0-37.5 °C
sitting systolic blood pressure, 90-139 mm Hg
sitting diastolic blood pressure, 50-89 mm Hg
sitting pulse rate, 40 - 90 bpm
If vital signs are out-of-range, the Investigator may obtain two additional readings, so that 
up to three (3) consecutive assessments are made, each after at least 30 minutes (one hour 
is recommended), and with the subject seated quietly during the five (5) minutes 
preceding the assessment. At least the last reading must be within the ranges provided 
above in order for the subject to qualify.
When blood pressure and pulse will be taken again after 3 minutes standing, there shall be 
no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in diastolic blood pressure 
and increase in heart rate (>20 bpm) associated with clinical manifestation of postural 
hypotension.
All blood pressure measurements at other time-points should be assessed with the subject 
seated, unless stated otherwise in the protocol design, and utilizing the same arm for each 
determination.
4.2
Exclusion criteria
Overweight or Obese Subjects fulfilling any of the following criteria are not eligible for 
inclusion in this study:
1. Pre-existing, clinically significant gastrointestinal, liver, cardiovascular, renal (including 
familial glucosuria) or other chronic medical condition which is considered serious or 
unstable, other than stable cardiovascular disease, stable adequately treated hypertension, 
dyslipidemia or other stable chronic disorders
2. Clinically significant GI disorder related to malabsorption or that may affect drug or 
glucose absorption (e.g. swallowing disorder, severe GI motility disorder, chronic diarrhea, 
glucose/galactose/lactose intolerance)
3. History of significant gastrointestinal surgery that could affect intestinal glucose 
absorption (e.g. bariatric surgeries including, Roux en Y gastric bypass, sleeve 
gastrectomy, Nissen fundoplication)
4. History of hypersensitivity to the study drugs, or to drugs of similar chemical classes.
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test
6. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
study treatment.


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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 (hysterectomy is acceptable) 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 (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).

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) or tubal ligation (hysterectomy is 
acceptable) 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
7. Patients with type 1 diabetes, or history of acute diabetic complications such as 
ketoacidosis or hyperosmolar state (coma) within the 6 months prior to screening
8. Evidence of significant diabetic complications such as symptomatic neuropathy, severe 
diabetic retinopathy, diabetic nephropathy, diabetic gastroparesis or enteropathy
9. Use of prohibited medications, refer to Section 5.2.
10. Evidence of clinically significant renal or liver disease/injury including:

eGFR less than 60 mL/min/1.73m2 at screening.

Patients with macroalbuminuria as determined by spot urine albumin:creatinine 
ratio >300 mg/g at screening.
Abnormal liver function tests at screening:

ALT, AST, GGT, alkaline phosphatase > 2 x ULN.

serum bilirubin > 1.5 x ULN
11. Evidence of urinary obstruction or difficulty in voiding at screening 
12. Symptomatic genital or urinary tract infection in the 4 weeks prior to first study visit
13. Any uncontrolled endocrinopathy including thyroid disease. Patients with an underlying 
endocrinopathy should be on stable treatment for 3 months prior to screening
14. Evidence or medical history of clinically significant ECG abnormalities 


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15. Any of the following within 6 months of screening:

Acute coronary syndrome (ACS)

coronary artery bypass surgery, balloon angioplasty, coronary stent(s) in situ

peripheral arterial disease

congestive heart failure NYHA class I- IV
16. History of autonomic dysfunction (e.g. history of fainting, clinically significant orthostatic 
hypotension, clinically significant sinus arrhythmia).
17. Significant blood loss equaling at least one unit of blood (500 ml) or a blood transfusion 
within 3 months prior to screening
18. Evidence of immunodeficiency diseases, including a positive HIV (ELISA and Western 
blot) test at screening
19. History of drug or alcohol abuse within the 12 months prior to initial dosing or evidence 
of such abuse as indicated by the laboratory assays conducted during the screening or tests 
conducted during baseline evaluations
20. Malignancy including leukemia and lymphoma (not including basal cell skin cancer) 
within 5 years prior to screening
21. Any finding during screening assessments (physical examination, vital signs, or clinical 
lab assessments), surgical or medical condition which might significantly alter the 
absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the 
subject, in the investigator’s judgment, in case of participation in the study.
22. Subjects who experienced ketoacidosis, lactic acidosis, or hyperosmolar coma within 
6 months of Screening Visit, or between Screening Visit and Baseline Day -1. 
No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible subjects.
5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the restrictions outlined in this section.
5.1
Contraception requirements
Please refer to exclusion criteria (Section 4.2) for details of contraception requirements for the study.
5.2
Prohibited treatment
Except for medication which may be required to treat adverse events, no medication including 
OTCs other than study drugs will be allowed from the first dosing until all of the 
Study Completion evaluations have been conducted. If needed, acetaminophen or ibuprofen is 
acceptable for incidental and limited use. Aspirin, antihypertensive, dyslipidemia, COPD and 
GERD medications including PPIs are allowed but subjects must be on a stable regimen for 
12 weeks or more prior to randomization (Section 6.10).


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The following medications are prohibited during the study:

Antidiabetic drugs including injectable antidiabetic medications (such as insulin and 
GLP-1 agonists), SGLT and alpha-glucosidase inhibitors are NOT allowed during the 
study. Patients must be on a stable regimen for approximately 12 weeks prior to 
randomization if treated with other oral antidiabetic medications.

Treatment with drugs that affect gastric motility (e.g. erythromycin)

Treatment with drugs that have a high incidence of diarrhea

Drugs which act primarily in the GI tract (e.g. Orlistat, acarbose)

Chronic systemic steroid treatment or systemic steroids for > 7 consecutive days for 
worsening of an underlying condition within 4 weeks of screening. Use of topical or 
inhaled steroids is permitted

Use of other investigational drugs at the time of enrollment, or within 30 days or 
5 half-lives of enrollment, or longer if required by local regulations, and for any other 
limitation of participation in an investigational trial based on local regulations

Unless allowed by the study protocol, use of any other prescription drugs, new herbal 
supplements, within four (4) weeks prior to initial dosing, and/or over-the-counter (OTC) 
medication, new dietary supplements (vitamins included), within 3 days prior to initial 
dosing. 
Subjects may need to discontinue the study treatment if treated with any of the prohibited 
medications during the study. Concomitant and prior medications (dose, regimen, indication 
and treatment duration) must be recorded in the CRF.
5.3
Dietary restrictions and smoking
 
 

No alcohol for approximately 24 hours before the study visits until the Study Completion 
evaluation.

No cigarettes/use of nicotine products are allowed on the study.

No grapefruit or grapefruit juice is to be consumed for approximately 7 days prior to 
dosing until 7 days following the last dose. 
 
 


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While domiciled, subjects will be provided a standardized breakfast meal according to their 
randomization assignment below for Part A and B:
Part A: Effects of carbohydrate in the breakfast meal

The breakfast meal will contain 600 calories providing 50% carbohydrate, 15% protein 
and 35% fat. This meal will be served at approximately 07.30, immediately after LIK066 
administration. The breakfast meal should be consumed within 15 mins.

The breakfast meals during each treatment period will include the following and according 
to the randomization assignment:

600 calories - 50% carbohydrate, 15% protein, and 35% fat

600 calories - 25% carbohydrate, 40% protein, and 35% fat

600 calories - 0% carbohydrate, 65% protein, and 35% fat
Part B: Effects of supplements

All breakfast meals in Part B treatment periods will include approximately 600 calories 
containing 50% carbohydrate, 15% protein, and 35% fat, and served at approximately 
07.30 immediately after administration of LIK066, then the designated supplements 
(psyllium, calcium carbonate or no supplement) according to randomization.
In both study parts and during each treatment period, lunch will be served at approximately 
13.00 (after completion of the PD sample collection and at least 5 hours from breakfast), and 
dinner will be served at approximately 18.30. The timing of meals should be harmonized on 
all days (Day -1, Day 3, Day 11, and Day 19) when PD are measured to minimize the effects 
of diurnal rhythm.  A snack may be served at approximately 20.00 if needed.
Lunch and dinner meals will be provided as a menu option, and study participants can choose 
from the menu based on their usual eating habits.
Further details on the specified meals and potential meal menu options will be provided in the 
SOM.
A meal record will confirm timing and consumption of meal. A copy of the diet with content 
and nutritional information (e.g., amount of protein, sodium, carbohydrates, fat and calories 
for each meal) will be provided to the Sponsor upon request.
5.4
Other restrictions

No strenuous physical exercise (e.g. weight training, aerobics, football) for 3 days before 
dosing until after Study Completion evaluation.

During the domiciled period, study participants are encouraged to maintain usual activity 
level in the study site (e.g., light to moderate walking) to minimize altered bowel habits 
associated with inactivity. 


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6
Treatment
6.1
Study treatment
The investigational drug, LIK066, 50 mg tablets, will be prepared by Novartis and supplied to 
the Investigator as open labeled bulk medication. Supplements (Sugar Free version) including 
psyllium and calcium carbonate will be sourced by the Site. 
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 drugs
Formulation
Unit Dose
Packaging
Provided by
LIK066
Tablet
50 mg
Open-label, bulk, blister-pack
Novartis
Psyllium
Powder
6 grams
Over the counter
Sourced by site
Calcium carbonate
Liquid
1 gram
(4 mL 
equivalent 
sugar free 
formulation)
Over the counter
Sourced by site
6.1.2
Additional study treatment
No additional treatment beyond the investigational drug LIK066 and the supplements 
(psyllium and calcium carbonate) are included in this trial.
6.2
Treatment arms
Study treatments are defined as:

A:  Daily dose of 50 mg LIK066+50% carbohydrate

B:  Daily dose of 50 mg LIK066+25% carbohydrate

C:  Daily dose of 50 mg LIK066+0% carbohydrate

D: Daily dose of 50 mg LIK066+50% carbohydrate+ 6 g psyllium

E: Daily dose of 50 mg LIK066+50% carbohydrate+1g calcium carbonate (1 g calcium 
carbonate in 4mL liquid sugar-free formulation)
In each part of the study, subjects will be randomized to one of the following 3 treatment 
sequences in the ratio of 1:1:1.


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Table 6-1
Definition of treatment sequences
Part A
Sequence
Period 1
Period 2
Period 3
1
A
B
C
2
B
C
A
3
C
A
B
Part B
Sequence
Period 1
Period 2
Period 3
4
A
D
E
5
D
E
A
6
E
A
D
6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual subjects by way of a randomization 
number, which will be in the range of 
 and 
 in Part A and Part B, 
respectively.
The randomization number is only used to identify which treatment the subjects have been 
randomized to receive.  The Subject number assigned to a subject at screening remains the 
unique identifier for the subject throughout the study.  For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.
Replacement randomization numbers will be in the range of 
 for Part A and 
 for Part B. If a subject requires a replacement, the replacement subject will be 
assigned a randomization number corresponding to the original subject (e.g. Subject 
 
would replace Subject 
).  Any additional subjects enrolled will use sequential subject 
numbering.
The table below details the general details of the numbering of the subjects once randomized 
to treatment:
Table 6-2
Randomization assignment numbering
Cohort
Randomization numbers
Replacement randomization numbers
Part A (n=24)
Part B (n=24)
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. Treatment allocation cards will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of treatment arms to randomization numbers in the specified ratio.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
There will be no stratification of randomization. Block randomization will be used to generate 
the treatment allocation cards.


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Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.
6.4
Treating the subject
LIK066 50 mg will be administered to the subject orally by the study personnel at the 
investigator site.  See the Site Operations Manual for further details.
6.5
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted. 
For subjects who are unable to tolerate the protocol-specified dosing scheme, treatment 
should be discontinued. These changes must be recorded on the Dosage Administration 
Record CRF.
6.6
Emergency breaking of assigned treatment code
This is an open label, non-placebo control study; therefore emergency code breaks are not 
applicable. 
6.7
Treatment exposure and compliance
Study medication will be given at the site by study personnel as subjects will be domiciled 
during the entire study treatment periods.
 
6.8
Recommended treatment of adverse events
Based on prior clinical experience with LIK066, which was administered to more than 
200 subjects at doses up to 350 mg single dose or up to 150 mg for 12 weeks, LIK066-related 
AEs can be managed by clinical monitoring including vital signs and blood tests. If diarrhea 
occurs, it can be treated with oral rehydration therapy if needed. More aggressive treatment, 
if required, will be performed at the discretion and direction of the investigator, with timely 
communication with the sponsor. Stopping rules (Section 7.4) will be applied as appropriate. 
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.9
Rescue medication
This is not a therapeutic study; therefore, rescue medication use is not applicable.


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6.10
Concomitant treatment
Except for medication which may be required to treat adverse events, no medication including 
OTCs other than study drugs will be allowed from the first dosing until all of the 
Study Completion evaluations have been conducted. If needed, acetaminophen or ibuprofen is 
acceptable for incidental and limited use. Aspirin, antihypertensive, dyslipidemia, COPD and 
GERD medications are allowed but subjects must be on a stable regimen for 12 weeks or 
more prior to randomization.
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 subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All subjects 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.  
If unable to contact the subject, documentation of attempts should be recorded in the source 
documentation.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject 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.


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Study treatment must be discontinued under the following circumstances:

Subject decision - subjects may choose to discontinue study treatment for any reason at 
any time.

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the subject’s safety.

Pregnancy

Use of prohibited treatments.
Study treatment of individual subject will be discontinued when that subject experiences:

Clinically significant diarrhea, suspected to be related to the study drug, that may put the 
subject at risk at the discretion of the investigator and in consultation with the sponsor

Clinically significant 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 the 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 in consultation with the sponsor if deemed necessary.

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 bodies in 
both plasma and urine. 

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study.

Any hospitalization, or other SAE, that is suspected to be related to the study treatment.
If discontinuation of study treatment occurs, the investigator must determine the primary 
reason for the subject’s premature discontinuation of study treatment and record this 
information on the Dosage Administration CRF.
Subjects 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. Where possible, they should return for the assessments 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 subject/pre-designated 
contact. This contact should preferably be done according to the study visit schedule.


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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 from the study is defined as when a subject:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material.
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the 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.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject cannot be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.
7.5
Study Stopping rules
The principal investigator and the sponsor will continually review adverse events and 
laboratory findings throughout the study. The study will be placed on hold and based on full 
review of the clinical data and discussion with the investigator may be halted if the principal 
investigator and the sponsor consider that the number and/or severity of adverse events justify 
discontinuation of the study; including cumulative cases of clinically significant diarrhea, 
urinary tract infections, severe adverse events, clinically significant laboratory changes 
suspected to be related to the study drug, or serious adverse event suspected to be related to 
the study drug.
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, subjects must 
be seen as soon as possible and treated as a prematurely withdrawn subject. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration is 
given to the protection of the subject’s interests. The investigator will be responsible for informing 
IRBs/IECs of the early termination of the trial.


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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.
Table 8-1
Assessment Schedule
Epoch Screening
Run In
Treatment Period 1
Treatment Period 2
Visit Name Screening
Baseline/Run-in
Treatment
Washout
Treatment
Visit Numbers1
1
101 102
199
201 202
203
204 205 206 207 299 301 302
303
Study Day(s)
-28 to -4
-3
-2
-1
1
2
3
4
5
6
7
8
9
10
11
Time (post-dose)
-
-
-
Predose: 0 H 0.5h 2h
4h
-
-
Predose: 0 H 2h
4h
-
-
-
-
-
-
-
Predose: 0 H 2h
4h
Informed consent
X
Inclusion / Exclusion 
criteria
S
S2
Medical history/current 
medical conditions
X
X
Demography
X
Physical Examination
S
S
S
S
Hepatitis and HIV Screen
S
Alcohol Test, Drug Screen, 
and Cotinine Test
S
S
Electrocardiogram (ECG)
X
X
X
X
Pregnancy test
X3
X4
Vital Signs5
X
X
X
X
Body Weight
X
X
X
X


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Epoch Screening
Run In
Treatment Period 1
Treatment Period 2
Visit Name Screening
Baseline/Run-in
Treatment
Washout
Treatment
Visit Numbers1
1
101 102
199
201 202
203
204 205 206 207 299 301 302
303
Study Day(s)
-28 to -4
-3
-2
-1
1
2
3
4
5
6
7
8
9
10
11
Time (post-dose)
-
-
-
Predose: 0 H 0.5h 2h
4h
-
-
Predose: 0 H 2h
4h
-
-
-
-
-
-
-
Predose: 0 H 2h
4h
Body Height
X
Hematology
X
X
X
X
Clinical Chemistry
X
X
X
X
Urinalysis
X
X
X
X
24 hour stool collection9
X
X
X
Bowel movements10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Meal11
X12
X
X
X
X
X
X
X
X
Supplements13
X
X
X
X
X
X
Dose administration14
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
Serious Adverse Events
As Required
Adverse Events
As Required


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Epoch Screening
Run In
Treatment Period 1
Treatment Period 2
Visit Name Screening
Baseline/Run-in
Treatment
Washout
Treatment
Visit Numbers1
1
101 102
199
201 202
203
204 205 206 207 299 301 302
303
Study Day(s)
-28 to -4
-3
-2
-1
1
2
3
4
5
6
7
8
9
10
11
Time (post-dose)
-
-
-
Predose: 0 H 0.5h 2h
4h
-
-
Predose: 0 H 2h
4h
-
-
-
-
-
-
-
Predose: 0 H 2h
4h
Subjects domiciled
Domiciled
Study completion 
information
Comments
As Required
Safety Follow up Call


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Epoch
Treatment Period 2
Treatment Period 3
End of Study
Visit Name
Washout
Treatment
Washout
EOS
Visit Numbers1
304
305
306
307
399
401
402
403
404
499
599
Study Day(s)
12
13
14
15
16
17
18
19
20
21
22
Time (post-dose)
-
-
-
-
-
-
-
Predose: 0 H
2h
4h
-
-
-
Informed consent
Inclusion / Exclusion criteria
Medical history/current medical 
conditions
Demography
Physical Examination
S
S
Hepatitis and HIV Screen
Alcohol Test, Drug Screen, and 
Cotinine Test
Electrocardiogram (ECG)
X
X
Pregnancy test
X
Vital Signs5
X
X
Body Weight
X
X
Body Height
Hematology
X
X
Clinical Chemistry
X
X
Urinalysis
X
X
24 hour stool collection9
X
X
Bowel movements10
X
X
X
X
X
X
X
X
X
Meal11
X
X
X


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Epoch
Treatment Period 2
Treatment Period 3
End of Study
Visit Name
Washout
Treatment
Washout
EOS
Visit Numbers1
304
305
306
307
399
401
402
403
404
499
599
Study Day(s)
12
13
14
15
16
17
18
19
20
21
22
Time (post-dose)
-
-
-
-
-
-
-
Predose: 0 H
2h
4h
-
-
-
Supplements13
X
X
X
Dose administration14
X
X
X
Concomitant medications
X
Serious Adverse Events
As Required
Adverse Events
As Required
Subjects domiciled
Domiciled
X
Domiciled
X
X
X
Study completion information
X
Comments
As Required
Safety Follow up Call
X19


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S – to be collected only as Source data
1 Visit structure given for internal programming purpose only
2 Review of inclusion and exclusion criteria and current medical conditions is required before baseline evaluation
3 Serum pregnancy test at Screening and EOS
4 Urine pregnancy test
5 pulse, blood pressure, temperature
 
 
9 24-hour Stool collection:  stool pH, 
10 To collect time, mass, and symptoms such as urgency, bloating; the Bristol Stool Chart will be used to document the consistency of the stool at each bowel movement
11 PART A: Standardized breakfast meal contains 600 calories of either 50% CHO, 15% Protein, 35% Fat OR 25% CHO, 40% Protein, 35% Fat OR 0% CHO, 65% 
Protein, 35% Fat; all breakfast meals will be taken immediately after dosing with 50 mg LIK066 once daily
12 Standardized breakfast meal to be given Day -1 through Day -3 (600 calories: 50% CHO; 15% Protein, 35% fat).
13 PART B: All standardized breakfast meals (600 calories) will contain 50% CHO, 15% Protein, and 35% Fat and will be given immediately after LIK066 50 mg qd; the 
supplements given include either Psyllium 6 grams qd OR calcium carbonate 1 gram to be provided in a 4mL sugar free liquid formulation
14 50 mg LIK066 
 
 
 
 
19 A follow up call is required 30 days after EOS to check for SAEs 


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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Novartis will review the Investigators proposed informed consent form to ensure it complies 
with the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for 
this study. Any further changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
Ensure subjects 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
In general it is permissible to re-screen a subject if s/he fails the initial screening; however, 
each case must be discussed and agreed with the Sponsor on a case-by-case basis.
Information on what data should be collected for screening failures is outlined in the 
Site Operations Manual.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses should be recorded rather than symptoms.
Subjects will be tested for substances of abuse (e.g., alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates), hepatitis B and C and HIV as noted in 
Table 8-1 (Assessment Schedule). Results will be available as Source data and will not be 
recorded within the eCRF. 


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Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
8.5
Efficacy / Pharmacodynamics
Diarrhea is the primary endpoint in this study. PD parameters including glucose, insulin, 
glucagon and incretin hormones will be evaluated in all subjects. PD samples will be collected 
at the time points defined in the Assessment schedule, Section 8.1. Follow instructions 
outlined in the Site Operations Manual regarding sample collection, numbering, processing 
and shipment.
8.5.1
Patient-Reported Outcome
8.5.1.3
Bowel movements
All bowel movements in this study will be captured in a stool diary and CRF that will include 
timing, weight, and symptoms such as urgency, bloating, flatus, and abdominal pain. 
In addition, the Bristol Stool Chart will be used to assess the stool consistency to determine 
the categorization of diarrhea.


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8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule (Section 8.1) detailing when each 
assessment is to be performed.
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
8.6.1
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTc
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated in-house. Unless auto-calculated by the 
ECG machine, the investigator must calculate QTcF at the Screening and/or Baseline visit(s) 
(as applicable) to assess eligibility.
Clinically significant abnormalities must be reported in the AE CRF.
8.6.2
Vital Signs

Body temperature

Blood pressure (BP) systolic and diastolic

Pulse Rate
8.6.3
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differentials 
(e.g., neutrophils, basophils, eosinophils, monocytes, and lymphocytes), erythrocyte 
sedimentation rate, and platelet count will be measured.
8.6.4
Physical Examination
See Site Operations Manual for details.


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8.6.5
Clinical Chemistry
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, CK, glucose, total 
cholesterol, triglycerides. If the total bilirubin concentration is increased above 1.5 times the 
upper limit of normal, direct and indirect reacting bilirubin should be differentiated.
8.6.6
Urinalysis
Dipstick measurements for specific gravity, ketones, albumin, protein, glucose and blood will 
be performed. Microscopy, WBC, RBC and sediments will also be assessed in case of an 
abnormal dipstick test.
8.6.7
Body Height
Height will be measured.
8.6.8
Body Weight

Body weight will be measured.

Body mass index (BMI) will be calculated as (Body weight (kg) / [Height (m)]2)


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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 subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the 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 subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination 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.


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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 subjects
with underlying disease. Investigators have the responsibility for managing the safety of 
individual subject and identifying adverse events. Alert ranges for liver and kidney related 
events are included in Appendix 1 and Appendix 2, respectively.
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 severity grade  

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
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)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Information about common side effects already known about the investigational drug can be 
found in the Investigator'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 subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
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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: 

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 subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject 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 
subject 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.
9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days [after the last study visit/ following the last 
administration of study treatment if there are post-treatment follow-up visits with no required 
procedures] 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.


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Note: SAEs reported by subjects 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 
subject 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 subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1. 

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and γGT) to confirm 
elevation within 48-72 hours.  
These liver chemistry repeats should be performed using the local laboratory used by the 
site. Repeat laboratory test results must be reported as appropriate via an electronic data 
transfer (if applicable), or entered on the appropriate unscheduled local laboratory CRF.   


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
If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study 
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include: 

Repeating liver chemistry tests two or three times weekly. Testing should include 
ALT, AST, ALP, PT/INR, and 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 can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the subject is asymptomatic. 
Retesting should be continued up to resolution. 

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
9.4
Renal safety monitoring
Renal events are defined as one of the following:

Confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25 % compared to baseline 
during normal hydration status, and deemed as a new onset renal events in subjects with 
reduced renal function at the discretion of investigator(s)

A doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine 
ratio (PCR).

New onset (≥1+) proteinuria or hematuria 
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Section 16-Appendix 2.


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9.5
Reporting Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
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 9-1
summarizes the reporting requirements.
Table 9-1
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose 
Administration (DAR) CRF
Document in AE 
CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, 
please see Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
To ensure subject 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.


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The study drug must be discontinued, though the subject 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 subject 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 (e-mail) 
and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
9.8
Monitoring 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 will be discontinued 
and the patient will be treated by the clinical staff according to standard of care for 
hypoglycemia.
During the course of the study, if any patient experiences symptoms of hypoglycemia 
(shakiness, nervousness, hunger, nausea, palpitations, dizziness, or confusion), they will be 
instructed to seek immediate medical evaluation and treatment.  
9.9
Monitoring 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).
9.10
Monitoring ketoacidosis
In rare cases, SGLT-2 inhibitors can lead to ketoacidosis. Therefore, investigators must pay 
close attention for any signs of ketoacidosis. Signs and symptoms of ketoacidosis may include 
deep and rapid breathing, nausea, vomiting, severe abdominal pain, confusion, unusual fatigue 
or sleepiness, and coma. All signs and/or symptoms and results from relevant laboratory tests 
must be reported on the AE eCRF. If ketoacidosis is confirmed, the study treatment should be 
discontinued as per Section 7.2 (Discontinuation of study treatment) and appropriate measures 
must be taken to correct the acidosis and monitor glucose levels according to standard of care.


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Every case of ketoacidosis must be reported to the Ketoacidosis Adjudication Committee 
(see Section 10.5).
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
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 CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the 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 Novartis or the CRO working on behalf of Novartis. The Investigator 
must certify that the data entered into the Electronic Case Report Forms are complete and 
accurate. After database lock, the investigator will receive 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 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.


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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff or CRO working on behalf of Novartis who will make the correction to 
the database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed locally and the results will be sent electronically to Novartis 
(or a designated CRO).
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
COAR Analytics NIBR Franchise Head and the relevant NIBR TA Head.
10.4
Data Monitoring Committee
Not applicable.
10.5
Adjudication Committee
An Adjudication Committee for monitoring ketoacidosis will be established to assess 
suspected cases of ketoacidosis as described in the SOM.


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11
Data analysis
All data analyses will be performed by study part. 
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
 
 
The PD analysis set will include all subjects 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 sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
11.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment 
sequence and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary endpoint will be the number of episodes of diarrhea per day.  It is defined as the 
total number of stools with a BSC score of 6 or 7 per day.
11.4.2
Statistical model, hypothesis, and method of analysis
The primary analysis will be performed by study part. The daily number of diarrhea will be 
analyzed using a negative binomial mixed effects model with fixed effects of period, 
treatment, day, the period-by-day interaction, and the treatment-by-day interaction, and a 
random subject effect. An unstructured covariance matrix will be specified for the repeated 
observations on a subject within the same period. The least-squares mean and associated 80% 
CI for the number of diarrhea episodes per day for each treatment, and the estimated mean 
difference between each treatment, the p-value, and corresponding two-sided 80% CI, will be 
extracted from the model for each day, and summarized by a table and a line chart. 
Conclusions from the analysis will be based on treatment differences from all 3 days, 
collectively.


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11.4.3
Handling of missing values/censoring/discontinuations
The primary analysis will be performed on all available data. There will be no imputation of 
missing data. 
11.4.4
Sensitivity analyses
As a sensitivity analysis, the interaction between treatment and day will be assessed, and if 
non-significant, the results from the 3 days will be averaged and corresponding model-based 
quantities extracted. 
Covariates such as baseline number of diarrhea may be included in the model when 
appropriate. 
The model assumption of negative binomial distribution will be examined, especially if over-
dispersion (i.e. variance>mean) exists. If the data doesn’t fit negative binomial distribution or 
over-dispersion doesn’t exist, other models such as Poisson regression will be explored.  
The model assumption of no first-order carry-over effect may be evaluated by incorporating 
first-order carry-over effects into the above statistical model, and performing a type 3 test for
the first-order carry-over effect. 
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
The three-day total number of episodes of diarrhea per period will be summarized by 
treatment, and analyzed using a negative binomial model with fixed effects of subject, period 
and diet.  The least-squares mean and associated 80% CI for the three-day total number of 
diarrhea episodes per period for each treatment, and the estimated mean difference between 
each treatment, the p-value, and corresponding two-sided 80% CI, will be extracted from the 
model, and summarized by a table and a line chart.
The model assumption of no first-order carry-over effect and the negative-binomial 
distribution may be evaluated in a similar fashion as the primary endpoint. 
Other secondary endpoints include average consistency with Bristol stool chart, average stool 
pH, average stool weight over each 24 hour collection period. They will be summarized by 
treatment, and analyzed by a linear mixed model with fixed effects of subject, period, 
treatment, and baseline measurement.  The least-squares mean and associated 80% CI for 
each treatment, and the estimated mean difference between each treatment, the p-value, and 
corresponding two-sided 80% CI, will be extracted from the model, and summarized by a 
table and a line chart.


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11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment sequence, subject, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. 
Summary statistics for both observed values and change from baseline will be provided by 
treatment and visit.
ECG evaluations
All ECG data will be listed by treatment sequence, subject and visit/time, abnormalities will 
be flagged. Summary statistics for both observed values and change from baseline will be 
provided by treatment and visit.
Clinical laboratory evaluations
All laboratory data will be listed by treatment sequence, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit.
Adverse events
All information obtained on adverse events will be displayed by treatment sequence 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. An adverse event starting in one 
period/epoch and continuing into the next period/epoch is counted only in the onset period. 
A subject with multiple adverse events within a body system and treatment period/epoch is 
only counted once towards the total of this body system and treatment.
Other safety evaluations
Immunogenicity
Not applicable.
11.5.3
Pharmacokinetic / pharmacodynamic interactions
Not applicable.
11.5.4
Other assessments
Not applicable.


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11.7
Sample size calculation
The sample size justification for this study is based on internal data from Part 2 of the LIK066 
obesity PoC study (LIK066X2201) on the 50 mg tid treatment regimen.
For patients on the 50 mg tid regimen, a mean (range) of 3.5 (0-12), 4.8 (0-18), and 3.9 (0-18) 
daily episodes of diarrhea were observed for Days 1, 2 and 3, respectively, of which 
3.2 episodes occurred between the 1st and 2nd dose on Day 1. If the true effect of the low 
carb diet or of the supplements is a reduction in the number of episodes per day from a mean 
of 3 episodes per day on the high carb diet to 1.5 episodes per day, or from a mean of 
5 episodes per day to 3 per day, then 5 subjects per sequence per study part (30 subjects total) 
with complete data will provide 80% power to detect the reduction. Assuming a drop-out rate 
of 37.5%, 8 subjects per sequence (48 total subjects) should be enrolled. 


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These results are based on 1000 simulated trials. For each simulated trial, the number of daily 
diarrhea episodes was generated from a Poisson distribution, where period-specific means, 
adjusted by the treatment effect, share a common gamma-distributed random subject effect in 
order to reflect a correlation between observations from the same subject. Only a single 
observation per-period for each subject was generated, reflecting one day of treatment. 
Each trial was analyzed using the GLIMMIX procedure in SAS, using a negative binomial 
model with fixed effects of treatment and period and normally distributed random subject 
effects, and assuming no carryover effects from one period to the next.
Two plausible scenarios for the variability of the number of daily diarrhea episodes were 
considered: (1) assuming the variability is as was observed in LIK066X2201, reflected by a 
dispersion parameter in the negative binomial model of 2.4, and (2) assuming the endpoint is 
less variable, reflected by a dispersion parameter of 1. In both scenarios, the power for 
detecting the reductions is at least 80%. Simulations were also performed under two
additional scenarios where non-zero period effects were assumed (a sequential 
increase/decrease of 0.1 in the log scale), and these also demonstrated sufficient power with
5 completers per sequence.
11.8
Power for analysis of key secondary variables
Power for key secondary variables doesn’t apply since there will be no formal hypothesis 
testing for the secondary variables. 
11.9
Interim analyses
Refer to Section 3.5.
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 


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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 around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of 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.
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
Abdul-Ghani MA, Norton L, DeFronzo RA (2015) Renal sodium-glucose cotransporter 
inhibition in the management of type 2 diabetes mellitus. Am. J. Physiol. Renal Physiol. p. 
F889-900.
Chao EC, Henry RR (2010) SGLT2 inhibition – a novel strategy for diabetes treatment. Nat 
Rev Drug Discov. p. 553. 
Macha S, Mattheus M, Halabi A, et al (2014) Pharmacokinetics, pharmacodynamics and 
safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with 
renal impairment. Diabetes Obes Metab p. 215-22.
Martín MG, Turk E, Lostao MP, et al (1996) Defects in Na+/glucose cotransporter (SGLT1) 
trafficking and function cause glucose-galactose malabsorption. Nat. Genet. p. 216-20.
Morgen CS, Sørensen TI (2014) Obesity: global trends in the prevalence of overweight and 
obesity. Nat Rev Endocrinol p. 513-4.
Pfister M, Whaley JM, Zhang L, et al (2011) Inhibition of SGLT2: a novel strategy for 
treatment of type 2 diabetes mellitus. Clin. Pharmacol. Ther. p. 621-5.
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.
U.S Department of Health and Human Services and U.S Department of Agriculture. 2015 –
2020 Dietary Guidelines for Americans. 8th Edition. December 2015. 


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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase 
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST £ 8 x ULN

3 x ULN < ALT/AST £ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity


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Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to 
≤8 × ULN

If confirmed, consider interruption or discontinuation of 
study drug

If elevation persists for more than 2 weeks, 
discontinue the study drug

Establish causality

Complete CRFs per liver event guidance
Isolated ALT or AST elevation > 3 to 
≤5 × ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; 
if >50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or 
discontinuation

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance
Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, 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


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


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

SAP_001.pdf: 
Clinical Development
LIK066
Clinical Trial Protocol CLIK066B2203 / NCT03198767
Randomized, open label, two-part, three-period,
cross-over study to investigate the effects of carbohydrate 
in diet and to evaluate supplements on the gastrointestinal 
tolerability of LIK066 in overweight or obese subjects
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
 
Document type:
SAP Documentation
Document status:
v02
Release date:
27-Sep-2017
Number of pages:
19
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
21-
June-
2017
Prior 
to 
DB 
lock
Creation of 
initial
version
N/A – First version
NA
21-
Sep-
2017
Prior 
to 
DB 
lock
Daily number of bowel movements is added 
as another variable for the primary endpoint, 
three-day total number of bowel movements 
is added as another variable for the 
secondary endpoint
Section 6.1
21-
Sep-
2017
Prior 
to 
DB 
lock
Study 
conduct 
issues
Method to impute missing urine volume is 
updated 
Section 6.3.3.1


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................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)................................................................................6
1.3.2
Secondary objective(s)............................................................................6
6
1.4
Study design and treatment......................................................................................7
2
First interpretable results (FIR) ...........................................................................................8
3
Interim analyses...................................................................................................................8
4
Statistical methods: Analysis sets........................................................................................8
9
9
10
10
6
Statistical methods for Pharmacodynamic (PD) parameters .............................................10
6.1
Primary objective...................................................................................................10
6.1.1
Variables ...............................................................................................10
6.1.2
Descriptive analyses..............................................................................10
6.1.3
Statistical model, assumptions and hypotheses.....................................11
6.2
Secondary objectives .............................................................................................12
6.2.1
Variables ...............................................................................................12
6.2.2
Descriptive analyses..............................................................................12
6.2.3
Statistical model, assumptions and hypotheses.....................................12
13
13
14
15


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7
Statistical methods for safety and tolerability data............................................................15
7.1
Variables................................................................................................................15
7.2
Descriptive analyses ..............................................................................................15
7.3
Graphical presentation...........................................................................................17
17
9
Reference list.....................................................................................................................19
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................9


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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 “CLIK066B2203”. 
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Protocol version used for this SAP is final version v01 dated 08-Aug-2017.
1.3
Study objectives
The objectives of this study are: 1) to assess whether or not a meal containing low 
carbohydrate in the form of glucose and galactose is associated with less diarrhea compared to 
a high carbohydrate meal; 2) to assess the potential effects of supplements such as psyllium or 
calcium carbonate on alleviating diarrhea. 


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1.3.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the effects of meals with 
different 
carbohydrate 
content 
on 
diarrhea 

Diarrhea (consistency and incidence)

To assess the effects of supplements 
(psyllium and calcium carbonate) on 
diarrhea 

Diarrhea  (consistency and incidence)
1.3.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the effects of LIK066 and 
carbohydrate in meal on fecal parameters

Stool samples (timing, assessment of 
consistency with Bristol stool chart,  stool 
weight, and stool pH)


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1.4
Study design and treatment
This study employs a randomized, open-label, two-part, three-period, cross-over design.
This is a non-confirmatory study. Each part of the study will enroll approximately 24 
overweight or obese subjects, thus, a total of approximately 48 subjects will be enrolled for
the entire study. In each part of the study, each subject will be randomized to one of the 3 
treatment sequences shown in Figure 1-1 (Part A) and Figure 1-2 (Part B). Blocked 
randomization within each study part will be used. 
Part A of the study will assess the effects of % carbohydrate (50%, 25% and 0%) in the
breakfast meals on diarrhea when LIK066 is administered immediately before the breakfast.
Part B of the study will assess the effects of a concomitant treatment with a supplement
(calcium carbonate or psyllium) on diarrhea when LIK066 is administered immediately before 
a breakfast meal with 50% carbohydrate.
The study will consist of an up to 24 day screening period, a 3 day baseline/run in period, and
three periods of treatment of 3 days each with a 5 day washout p eriod in between each
treatment period. Study completion will occur 3 days after the last dose of LIK066.
The baseline, treatment and washout periods will be conducted with subjects being domiciled
for approximately 25 days (see Figure 1-1 and Figure 1-2).
Figure 1-1 Part A: Effects of Carbohydrate in the Breakfast Meals*
* CHO = % carbohydrate content in the standardized breakfast meal
LIK066 50mg QD will be given in the morning immediately before the breakfast meal


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Figure 1-2 Part B: Effects of Supplements in the Breakfast Meals**
** CHO = % carbohydrate content in the standardized breakfast meal (50%) for all groups 
LIK066 (50 mg QD) and supplement will be administered immediately before the breakfast meal
NS = No supplement
CC = Calcium Carbonate (1 gram)
Psyllium = 6 grams
There will be no interim analyses planned for the study.
2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
The study FIR template (mock slides) can be found in CREDI in the study RAP folder 
Cabinets/CREDI Projects/L/LIK066/CREDI Studies/LIK066B2203/Administrative Files 
(study level)/RAP or RAMP Meeting/.
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list. 
3
Interim analyses 
Not applicable.
4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatments received.
The safety analysis set will include all subjects that received any study drug. All subjects in 
the safety analysis set will be included in the safety data analysis.
 
 
The PD analysis set will include all subjects in safety analysis set with available PD (diarrhea) 
data post baseline and no protocol deviations with relevant impact on PD data. All subjects in 
the PD analysis set will be included in the PD data analysis.


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For subjects for which the actual sequence of treatments received does not match the 
randomized sequence of treatments, the actual sequence will be used for analysis involving a 
sequence component if the actual sequence is one of the sequences planned in the study 
design. If the actual sequence is not one of the sequences planned in the study design, the 
randomized sequence will be used for analysis involving a sequence component but data 
points from periods in which the subject has not received the randomized treatment will be 
excluded from the analysis. 
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD and PK analysis in case of 
these protocol deviations:
Exclude subject from PD
and PK analysis set
All inclusion and exclusion criteria 
deviations
TRT01
Subject received treatment sequence that 
do not belong to ones specified for the 
study
Only data points from
periods different from 
randomized sequence will 
be excluded
TRT02
Subject doesn’t have sufficient wash out 
per protocol
COMD01
Subject received prohibited concomitant 
medication
Summary of frequency of subjects in each analysis set will be provided and subjects excluded 
from each analysis set will be listed with reasons being excluded. All protocol deviation will
be listed together with corresponding analysis set(s) being excluded when applicable. 
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.


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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 objectives of this study are to assess the efficacy of:

Meals with different carbohydrate content on diarrhea

Supplements such as (psyllium and calcium carbonate) on diarrhea
when LIK066 is administrated immediately before the breakfast.
6.1.1
Variables 
The primary endpoint diarrhea will be assessed by the below two variables
1. Daily number of stools with a BSC score of 6 or 7.
2. Daily number of bowel movements
6.1.2
Descriptive analyses
Daily number of stools with a BSC score of 6 or 7 and daily number of bowel movements will 
be listed by treatment sequence, subject, and visit/sampling time point. Descriptive summary 
statistics for the observed value and change from baseline will be provided by treatment and 
visit. Summary statistics will include mean (arithmetic), SD, median, minimum and maximum. 


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Observed Mean (SD) plot and spaghetti plot of individuals’ observed data will be produced by 
treatment. 
6.1.3
Statistical model, assumptions and hypotheses
The primary efficacy hypotheses are that the mean daily number of stools with a BSC score of 
6 or 7 /change from baseline in daily number of bowel movements in:
1. the 50% carb group is higher than other groups with lower carbs 
2. the no supplement group is higher than other groups with supplement.
The primary analysis will be performed by study part. The daily number of stools with a BSC 
score of 6 or 7 will be analyzed using a negative binomial mixed effects model with fixed 
effects of period, treatment, day, the period-by-day interaction, and the treatment-by-day 
interaction, and a random subject effect. An unstructured covariance matrix will be specified 
for the repeated observations on a subject within the same period. The least-squares mean and 
associated 80% CI for the daily number of stools with a BSC score of 6 or 7 for each 
treatment, and the estimated mean difference between each treatment, the p-value, and 
corresponding two-sided 80% CI, will be extracted from the model for each day, and 
summarized. Mean difference will then be exponentiated as ratio between treatments means.
Conclusions from the analysis will be based on treatment differences from all 3 days, 
collectively.
Change from baseline in daily number of bowel movements will be analyzed by a linear 
mixed effects model with fixed effects of baseline daily number of bowel movements, period, 
treatment, day, the period-by-day interaction, and the treatment-by-day interaction, and a 
random subject effect. An unstructured covariance matrix will be specified for the repeated 
observations on a subject within the same period. Baseline is defined by the last daily 
measurement before dosing. If day -1 measurement is missing, day -2 or day -3 measurements 
will be used instead. The least-squares mean and associated 80% CI for each treatment, and 
the estimated mean difference between each treatment, the p-value, and corresponding two-
sided 80% CI, will be extracted from the model and summarized.
6.1.3.1
Model checking procedures
Missing data will be assumed to be missing at random and thus the above analysis will be 
performed on all available data. There will be no imputation of missing data.  
The interaction between treatment and day will be assessed, and if non-significant, the results 
from the 3 days will be averaged and corresponding model-based quantities extracted.
The model assumption of negative binomial distribution will be examined, especially if over-
dispersion (i.e. variance>mean) exist. If the data doesn’t fit negative binomial distribution or 
over-dispersion doesn’t exist, other models such as Poisson regression will be explored.  
The model assumption of no first-order carry-over effect may be evaluated by incorporating 
first-order carry-over effects into the above statistical models, and performing a type 3 test for 
the first order carry-over effect. In addition, descriptive summary statistics will also be 
provided by treatment sequence and visit in order to assess carry-over effect. 


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6.1.3.2
Graphical presentation of results
Least-square mean and least-square mean difference between treatments with 80% confidence 
intervals will be plotted by treatment for daily number of stools with a BSC score of 6 or 7 
and daily number of bowel movements. 
6.2
Secondary objectives
6.2.1
Variables 

Three-day total number of stools with a BSC score of 6 or 7 per period

Three-day total number of bowel movements per period
Over each 24 hour collection period: 

Average stool consistency with Bristol stool chart
It is defined as arithmetic average of consistency for all stools collected during 24 hour 
period.

Average stool pH 
It is defined as arithmetic average of PHs for all stools collected during 24 hour period.

Average stool weight 
It is defined as arithmetic average of weights for all stools collected during 24 hour 
period.
6.2.2
Descriptive analyses
All secondary endpoints will be listed by treatment sequence, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided for the observed values and change 
from baseline by treatment and visit/period. Summary statistics for the three-day total number 
of episodes of diarrhea, average stool consistency, pH, and weight will include mean 
(arithmetic), SD, median, minimum and maximum. Observed Mean (SD) plot will be 
produced for all secondary endpoints. 
6.2.3
Statistical model, assumptions and hypotheses
Three-day total number of stools with a BSC score of 6 or 7 per period will be analyzed by a
negative binomial mixed effects model with random effect of subject and fixed effects of 
period and treatment. Change from baseline in three-day total number of bowel movements 
per period will be analyzed by a linear mixed effects model with random effect of subject and 
fixed effects of period, treatment and baseline three-day total number of bowel movements. 
Secondary endpoints including average stool consistency, PH and weight will be analyzed by 
a linear mixed effects model with random effect of subject and fixed effects of period, 
treatment, and baseline measurement. The least-squares mean and associated 80% CI for each 
treatment, and the estimated mean difference between each treatment, the p-value, and 
corresponding two-sided 80% CI, will be extracted from the model, and summarized.


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6.2.3.1
Model checking procedures
The model assumption of no first-order carry-over effect and negative binomial distribution 
will be examined for three-day total number of stools with a BSC score of 6 or 7 per period
and three-day total number of bowel movements per period similarly to the primary endpoint.
Missing data will be assumed to be missing at random and thus the above analyses will be 
performed on all available data. There will be no imputation of missing data.  
6.2.3.2
Graphical presentation of results
Least-square mean and least-square mean difference between treatment groups with 80% 
confidence intervals will be plotted for all secondary endpoints by treatment. 


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7
Statistical methods for safety and tolerability data
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 sequence and 
subjects in the safety analysis set. Summary statistics will be provided for all subjects in the 
safety analysis dataset, as well as for each treatment sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.


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Subject disposition (frequency of completion/discontinuation and reasons for early 
discontinuation) will be summarized by epoch and treatment sequence. 
Treatment
Data for study drug administration and meal/supplement dosing and concomitant therapies 
will be listed by treatment sequence and subject. Number of dose administration will be 
summarized by treatment.
Vital signs
All vital signs data will be listed by treatment sequence, 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 (AEs)
All information obtained on adverse events will be listed by treatment sequence 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. An adverse event starting in one 
period/epoch and continuing into the next period/epoch is counted only in the onset period. A 
subject with multiple adverse events within a body system and treatment period/epoch is only 
counted once towards the total of this body system and treatment. If AE dates are needed to 
assign onset period and the dates are missing, AE date will be imputed by the following rule:  
if year is missing there will be no imputation of date. Otherwise missing month will be 
imputed by January, and missing day will be imputed by 1st. 
Serious adverse events and adverse events leading to early discontinuation will be listed by 
treatment sequence and subject.
Adverse events leading to death will be listed by treatment sequence and subject.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment/treatment emergent adverse events which are not serious adverse events with an 
incidence greater than 1% and on on-treatment/treatment emergent serious adverse events and 
SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population.


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If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT. 
Immunogenicity
Not applicable
7.3
Graphical presentation 
There will be no graphic presentation of the safety data.


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9
Reference list
Svedlund J, Sjodin I, Dotevall G. GSRS - a clinical rating scale for gastrointestinal symptoms 
in patients with irritable bowel syndrome and peptic ulcer disease. Dig. Dis. Sci. 1988; 33: 
129-34.
Dimenas E, Glise H, Hallerback B, Hernqvist H, Svedlund J, Wiklund Well-being and 
gastrointestinal symptoms among patients referred to endoscopy owing to suspected duodenal 
ulcer. Scand J Gastroenterol 1995, 30:1046-1052.