Clinical trial NCT03131479
Conditions: Renal Impairment
Keywords: renal function sodium-glucose co-transporter pharmacokinetics decreased renal function decreased kidney function kidney disease urinary glucose excretion UGE
Sponsor: Novartis Pharmaceuticals
Start date: 2017-04-28; Completion date: 2018-01-16
Enrollment: 53 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial was to evaluate whether the study drug, LIK066, causes glucose excretion in urine in patients with varying degrees of decreased kidney function and in subjects with normal kidney function. Blood samples were collected to measure the concentrations of LIK066 and to study the pharmacokinetics of LIK066. Pharmacokinetics is meant to study how LIK066 is absorbed, distributed and eliminated, in other words what the body does to the drug. The results of this study may be used to help determine whether LIK066 can be used to treat people with reduced kidney function and the proper dosing regimen.

Detailed description:

Arms: arm 1: Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days. arm 2: Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days. arm 3: Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days. arm 4: Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days. arm 5: Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.
Interventions: intervention 1: LIK066
Intervention descriptions: intervention 1: LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LIK066
Clinical Trial Protocol CLIK066B2202 / NCT03131479
An open-label, parallel-group study to assess the effect of 
LIK066 on urinary glucose excretion, pharmacokinetics, 
safety and tolerability following multiple dose 
administration in patients with decreased renal function 
compared to subjects with normal renal function
Document type:
Clinical Trial Protocol
EUDRACT number:
2016-004770-18
Version number:
v00 (Original Protocol)
Clinical Trial Phase:
II
Release date:
11-Jan-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 SOM for further details on the method of reporting a 
SAE.

Complete SAE report

Submit SAE report within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The contact information are provided in the SOM. 


Novartis
Confidential
Page 3
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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...........................................................................9
Glossary of terms...............................................................................................................10
Protocol synopsis...............................................................................................................12
1
Introduction .......................................................................................................................16
1.1
Background............................................................................................................17
17
18
18
18
19
20
1.4
Study purpose ........................................................................................................20
2
Study objectives and endpoints .........................................................................................20
2.1
Primary objectives .................................................................................................20
2.2
Secondary objective...............................................................................................21
21
3
Investigational plan ...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale of study design.......................................................................................24
24
3.4
Rationale for choice of comparator .......................................................................24
3.5
Purpose and timing of interim analyses/design adaptations..................................25
25
3.6.1
Blood sample volumes ..........................................................................26
4
Population..........................................................................................................................26
4.1
Inclusion criteria ....................................................................................................26
4.1.1
All individuals.......................................................................................26
4.1.2
Patients with decreased renal function..................................................27
4.1.3
Subjects with normal renal function .....................................................27


Novartis
Confidential
Page 4
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
4.2
Exclusion criteria...................................................................................................28
4.2.1
All individuals.......................................................................................28
4.2.2
Patients with decreased renal function..................................................30
4.2.3
Subjects with normal renal function .....................................................31
5
Restrictions for Study Subjects .........................................................................................31
5.1
Contraception requirements...................................................................................31
5.2
Prohibited treatment...............................................................................................31
5.3
Dietary restrictions and smoking...........................................................................31
5.4
Other restrictions ...................................................................................................32
6
Treatment...........................................................................................................................32
6.1
Study treatment......................................................................................................32
6.2
Treatment arms ......................................................................................................32
6.3
Treatment assignment............................................................................................32
6.4
Treatment blinding.................................................................................................32
6.5
Treating the subject................................................................................................33
6.6
Permitted dose adjustments and interruptions of study treatment.........................33
6.7
Emergency breaking of assigned treatment code ..................................................33
6.8
Treatment exposure and compliance .....................................................................33
6.9
Recommended treatment of adverse events ..........................................................33
6.10
Rescue medication.................................................................................................33
6.11
Concomitant treatment...........................................................................................33
7
Study completion and discontinuation ..............................................................................34
7.1
Study completion and post-study treatment ..........................................................34
7.2
Discontinuation of study treatment........................................................................34
7.3
Withdrawal of informed consent ...........................................................................35
7.4
Lost to follow-up ...................................................................................................36
7.5
Study Stopping rules..............................................................................................36
7.6
Early study termination by the sponsor .................................................................36
8
Procedures and assessments ..............................................................................................37
37
8.2
Informed consent procedures.................................................................................41
8.3
Subject screening...................................................................................................41
8.4
Subject demographics/other baseline characteristics.............................................41
8.5
Efficacy / Pharmacodynamics ...............................................................................42
8.6
Safety.....................................................................................................................42
8.7
Pharmacokinetics...................................................................................................43


Novartis
Confidential
Page 5
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
44
44
9
Safety monitoring ..............................................................................................................44
9.1
Adverse events.......................................................................................................44
9.2
Serious adverse event reporting.............................................................................46
9.2.1
Definition of SAE .................................................................................46
9.2.2
SAE reporting........................................................................................47
9.3
Liver safety monitoring .........................................................................................48
9.4
Renal safety monitoring.........................................................................................49
49
49
9.7
Monitoring ketoacidosis ........................................................................................49
9.8
Reporting Medication errors including misuse/abuse ...........................................50
9.9
Pregnancy reporting...............................................................................................50
9.10
Early phase safety monitoring ...............................................................................50
10 Data review and database management.............................................................................51
10.1
Site monitoring ......................................................................................................51
10.2
Data collection.......................................................................................................51
10.3
Database management and quality control............................................................52
10.4
Data Monitoring Committee..................................................................................52
10.5
Adjudication Committee........................................................................................52
11 Data analysis......................................................................................................................53
11.1
Analysis sets ..........................................................................................................53
11.2
Subject demographics and other baseline characteristics......................................53
11.3
Treatments .............................................................................................................53
11.4
Analysis of the primary variable(s) .......................................................................53
11.4.1
Variable(s).............................................................................................53
11.4.2
Statistical model, hypothesis, and method of analysis..........................54
11.4.3
Handling of missing values/censoring/discontinuations.......................54
11.4.4
Summary statistics of pharmacokinetics...............................................55
11.4.5
Sensitivity analyses ...............................................................................55
11.5
Analysis of secondary variable(s)..........................................................................55
11.5.1
Efficacy / Pharmacodynamics...............................................................55
11.5.2
Safety.....................................................................................................55
11.5.3
Pharmacokinetic / pharmacodynamic interactions................................56
57


Novartis
Confidential
Page 6
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
11.7
Sample size calculation..........................................................................................58
11.8
Power for analysis of key secondary variables......................................................58
11.9
Interim analyses .....................................................................................................58
12 Ethical considerations........................................................................................................59
12.1
Regulatory and ethical compliance........................................................................59
12.2
Responsibilities of the investigator and IRB/IEC..................................................59
12.3
Publication of study protocol and results...............................................................59
13 Protocol adherence ............................................................................................................59
13.1
Protocol Amendments ...........................................................................................60
14 References .........................................................................................................................61
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................62
16 Appendix 2: Specific Renal Alert Criteria and Actions ....................................................64
List of tables
Table 1-1
Summary of plasma PK parameters following multiple dose 
administration of LIK066 to healthy subjects.......................................19
37
Table 15-1
Liver Event Definitions.........................................................................62
Table 15-2
Actions required for Liver Events.........................................................62
Table 15-3
Exclusion of underlying liver disease ...................................................63
Table 16-1
Specific Renal Alert Criteria and Actions.............................................64
Table 16-2
Follow-up of renal events......................................................................65
List of figures
Figure 3-1
Study design..........................................................................................22


Novartis
Confidential
Page 7
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
List of abbreviations
γ-GT
gamma-glutamyl transferase
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
b.i.d.
twice a day
BMI
body mass index
BUN
blood urea nitrogen
CFR
Code of Federal Regulation
CK
creatinine kinase
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTRD
Clinical Trial Results Database
CV
coefficient of variation
EC
Ethics Committee
ECG
electrocardiogram
EDxx
effective dose xx%
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
FDA
Food and Drug Administration
GCP
Good Clinical Practice
h
hour
HIV
Human Immunodeficiency Virus
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
LC-
liquid chromatography-mass spectrometry/mass spectrometry


Novartis
Confidential
Page 8
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
MS/MS
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantification
MDRD
Modification of Diet in Renal Disease Study equation
MedDRA
medical dictionary for regulatory activities
MI
myocardial infarction
NCDS
Novartis Clinical Data Standards
NOEL
no observed effect level
p.o.
oral
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
RBC
red blood cell(s)
REB
Research Ethics Board
RI
renal impairment
SAE
serious adverse event
SCr
serum creatinine
SD
standard deviation
SGLT
sodium glucose co-transporter
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
UGE
urinary glucose excretion
ULN
upper limit of normal
ULOQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization


Novartis
Confidential
Page 9
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Pharmacokinetic definitions and symbols
Ae0-t
Amount of drug (or defined metabolite) excreted into the urine from time 
zero to time 't' where t is a defined time point after administration [mass 
units or % of dose]
AUCinf
The area under the plasma concentration-time curve from time zero to 
infinity [mass x time / volume]
AUClast
The area under the plasma concentration-time curve from time zero to the 
time of the last quantifiable concentration [mass x time / volume]
AUCtau
The area under the plasma 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]
CLr
The renal clearance from plasma [volume / time]
Cmax
The observed maximum plasma concentration following drug administration 
[mass / volume]
F
Bioavailability of a compound. 
T1/2
The terminal elimination half-life [time]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]


Novartis
Confidential
Page 10
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
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, treatment, follow-up) which 
applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance”
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.
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.
Screen Failure
A subject who is screened but is not treated
Stage
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, 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)


Novartis
Confidential
Page 11
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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


Novartis
Confidential
Page 12
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Protocol synopsis
Protocol number
CLIK066B2202
Title
An open-label, parallel-group study to assess the effect of LIK066 on urinary 
glucose excretion, pharmacokinetics, safety and tolerability following multiple 
dose administration in patients with decreased renal function compared to 
subjects with normal renal function
Brief title
Study of pharmacodynamics, pharmacokinetics, safety and tolerability of 
LIK066 in patients with decreased renal function
Sponsor and Clinical 
Trial Phase
Novartis
Phase II
Intervention type
Investigational Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is: 1) to determine whether LIK066 displays a
similar effect on the urinary  glucose excretion in patients with varying 
degrees of reduced renal function as those with normal renal function, and 2) 
to assess the pharmacokinetics of LIK066 in patients with varying degrees of 
renal impairment as compared to those with normal renal function; to support 
development of LIK066 in patients with renal impairment
Primary Objectives

To assess the effect of a 7-day treatment with LIK066 on 24-hour urinary 
glucose excretion in subjects with decreased renal function compared to 
those with normal renal function.

To assess the pharmacokinetics of LIK066 on Day 1 and Day 7 in 
subjects with decreased renal function compared to those with normal 
renal function.
Secondary Objective

To assess the safety and tolerability of a 7-day treatment with LIK066 in 
subjects with decreased renal function compared to those with normal 
renal function.
Study design
An open-label, multiple-dose, parallel-group study in patients with varying 
degrees of decreased renal function (mild, moderate and severe renal 
impairment) and subjects with normal renal function. Each subject will 
participate in a screening period of up to 28 days, one baseline period, one 
treatment period of 7 days (including domicile and outpatient visits), a follow-
up period, and an end-of-study evaluation approximately 96 hours after the 
last drug administration.
Eligible subjects will be admitted to the study site at Baseline (Day -2). 
Meal contents including carbohydrates and salt will be standardized from 
Day -2 to the morning of Day 2, and then from Day 5 to Day 8, 
 
 
. LIK066 treatment will be administered once daily after an overnight 
fast, before breakfast from Day 1 to Day 7. Subjects can be domiciled during 
the study per the investigator discretion.   The study assessments will include 
24-hour urine collection and blood collections for pharmacokinetic, 
pharmacodynamics, safety 
 
Study completion evaluations will be performed after the last pharmacokinetic 
assessment is completed (Day 11), or in the case of early termination, prior 
to discharge from the study site.


Novartis
Confidential
Page 13
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Population
Ten (10) subjects each with mild (eGFR 60-89 ml/min/1.73 m2), Grade A 
moderate (eGFR 46-59 ml/min/1.73 m2), Grade B moderate (eGFR 30-45 
ml/min/1.73 m2), and normal renal function (eGFR≥90 ml/min/1.73 m2); and 
up to 10 patients with severe renal impairment (eGFR ≤29 ml/min/1.73 m2, 
not on dialysis) will be enrolled in this study.
Patients with varying degrees of decreased renal function will be enrolled 
first; subjects with normal renal function will be enrolled after approximately 
50% of the patients with decreased renal function (at least two in each group 
of patients with moderate renal impairment, and at least one patient in the 
group of patients with severe renal impairment) have been enrolled. The 10
subjects with normal renal function will be matched to 10 of the enrolled 
patients with decreased renal function by age, weight, and, if possible, 
diabetic status.
Key Inclusion 
criteria
All individuals:

Male and female subjects age 18 to 78 years, inclusive, with BMI 
≤50 kg/m2 and with controlled health condition as determined by past 
medical history, physical examination, electrocardiogram, and laboratory 
tests at screening.

For patients with Type 2 diabetes, HbAc1<10% at screening. If treated 
with antidiabetic medications (other than prohibited medications), 
patients must be on a stable dose for approximately 6 weeks prior to 
starting the study treatment and maintain the dose until the end of the 
study.
Patients with decreased renal function:

Patients must have stable renal disease without evidence of active 
progression at screening (for the purpose of this study stable renal 
disease will be defined as no significant change of eGFR for 12 weeks, 
per the discretion of the investigator upon reviewing the medical history 
or previous lab assessments). 

Mild renal impairment: eGFR from 60 to 89 ml/min/1.73 m2

Grade A moderate renal impairment: eGFR from 46 to 59 
ml/min/1.73 m2

Grade B moderate renal impairment: eGFR from 30 to 45 
ml/min/1.73 m2

Severe renal impairment: eGFR of ≤29 ml/min/1.73 m2 , not on 
dialysis
Subjects with normal renal function:

Normal renal function reflected by an eGFR of  ≥90 ml/min/1.73m2.

Subjects will be matched to 10 of the enrolled patients with decreased 
renal function by age (approximately ± 10 years), weight (approximately 
± 20%), and, if possible, diabetic status.


Novartis
Confidential
Page 14
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Key Exclusion 
criteria
All individuals:

Pregnant or nursing (lactating) women. Women of child-bearing potential, 
unless they are using basic methods of contraception during the study.

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.

Evidence of urinary obstruction or difficulty in voiding at screening

Symptomatic genital or urinary tract infection (UTI) in the 4 weeks prior to 
screening or the presence of active UTI at screening

Any finding during screening assessments (physical examination, vital 
signs, ECG 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, per the 
investigator’s judgment, in case of participation in the study.

Clinically significant GI disorder related to malabsorption or GI surgery 
that may affect drug or glucose absorption (e.g. swallowing disorder, 
severe GI motility disorder, chronic diarrhea, glucose/galactose/lactose 
intolerance)

Use of prohibited medications
Patients with decreased renal function:

Hemoglobin levels <8.0 g/dl at screening
Subjects with normal renal function:

Hemoglobin levels <12.0 g/dl for males, or <11.0 g/dl for females at 
screening
Study treatment
The investigational drug, LIK066 tablets will be prepared by Novartis. This is 
an open label nonrandomized study. All subjects will receive LIK066 50 mg 
once daily before breakfast for 7 days.
Efficacy/PD 
assessments

Urinary glucose excretion
Key safety 
assessments

Physical examination

Body temperature

Hematology

Blood chemistry

Urinalysis

Blood pressure

Pulse rate

ECG evaluation

Adverse events and serious adverse events


Novartis
Confidential
Page 15
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Data analysis
The primary analyses will assess the effect of reduced renal function on 
24-hour urinary glucose excretion (UGE24) and on the PK of LIK066. 
The change from baseline in UGE24 will be analyzed using an analysis of 
covariance model with diabetic status, renal impaired group, day, and all 
associated interactions (where possible) as fixed factors and age, baseline 
body weight, and baseline fasting plasma glucose as covariates. Each of the 
log-transformed PK parameters will be analyzed using the same model but 
without the baseline covariates.
Key words
Decreased renal function. Urinary glucose excretion. Pharmacokinetics 


Novartis
Confidential
Page 16
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
1
Introduction
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). 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 of 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; 
~ 6% decrease in body weight was demonstrated after 12 week treatment.
All selective SGLT2 inhibitors being approved in the clinical practice are either not 
recommended or contraindicated in patients with moderate or severe renal impairment 
(either eGFR<60; or eGFR<45 mL/min) primarily due to lack of efficacy and certain safety 
concerns. Dual inhibition of SGLT1 and SGLT2 leads to further caloric wasting of glucose 
attributed to reduced absorption of glucose from the intestine and enhanced inhibition of 
glucose reabsorption from the kidneys, which is a major mechanistic differentiation from a 
selective SGLT2 inhibitor. This study is designed to assess the potential efficacy of LIK066 in 
patients with moderate or severe chronic kidney disease using 24-hour urinary glucose 
excretion (UGE24) as the primary surrogate endpoint. The design of this study will also 
evaluate the PK of LIK066 in patients with reduced renal function. Safety and tolerability of 
LIK066 at 50 mg qd for 7 days will also be assessed in this patient population with reduced 
renal function.


Novartis
Confidential
Page 17
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
1.1
Background
The most relevant data for the present study are summarized in the sections below. 
For detailed information, please refer to the Investigator's Brochure.


Novartis
Confidential
Page 18
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202


Novartis
Confidential
Page 19
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202


Novartis
Confidential
Page 20
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
1.4
Study purpose
The purpose of this study is: 1) to determine whether LIK066 displays a similar effect on the 
urinary glucose excretion in patients with varying degrees of reduced renal function as those 
with normal renal function, and 2) to assess the pharmacokinetics of LIK066 in patients with 
varying degrees of renal impairment as compared to those with normal renal function; to 
support development of LIK066 in patients with kidney disease.
2
Study objectives and endpoints
2.1
Primary objectives
Primary objectives
Endpoints related to primary objectives

To assess the effect of a 7-day treatment with 
LIK066 on 24-hour urinary glucose excretion 
(UGE) in subjects with decreased renal function 
compared to those with normal renal function

24-hour urinary glucose excretion 
on Day 7

To assess the pharmacokinetics of LIK066 on 
Day 1 and Day 7 in subjects with decreased 
renal function compared to those with normal 
renal function 

Cmax, Tmax, AUCtau, AUClast, 
AUCinf, T1/2, CL/F, Vz/F, CLr


Novartis
Confidential
Page 21
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
2.2
Secondary objective
Secondary objective
Endpoints related to secondary objective

To assess the safety and tolerability of a 7-
day treatment with LIK066 in subjects with 
decreased renal function compared to those 
with normal renal function  

Adverse events


Novartis
Confidential
Page 22
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
3
Investigational plan
3.1
Study design
This study employs an open-label, multiple-dose, parallel-group design in patients with 
varying degrees of decreased renal function (mild, moderate and severe renal impairment) and 
subjects with normal renal function. The most common cause of chronic kidney disease is 
diabetes, which accounts for roughly 50% of all cases. Approximately 50% of the patients 
enrolled in each group of the mild, moderate and severe renal impairment are expected to be 
patients with T2DM.  
Each subject will participate in a screening period of up to 28 days, one baseline period, 
one treatment period of 7 days (including domicile and outpatient visits), a follow-up period, 
and an end-of-study evaluation approximately 96 hours after the last drug administration.
Ten (10) subjects each with mild (eGFR 60-89 ml/min/1.73 m2), Grade A moderate 
(eGFR 46-59 ml/min/1.73 m2), Grade B moderate (eGFR 30-45 ml/min/1.73 m2), and normal 
renal function (eGFR≥90 ml/min/1.73 m2); and up to 10 patients with severe renal impairment 
(eGFR ≤29 ml/min/1.73 m2, not on dialysis) will be enrolled.
Figure 3-1
Study design
Patients with varying degrees of decreased renal function will be enrolled first; subjects with 
normal renal function will be enrolled after approximately 50% of the patients with decreased 
renal function (at least two in each group of patients with moderate renal impairment, and at 
least one patient in the group of patients with severe renal impairment) have been enrolled. 
Because body weight and age are covariates in the estimation of eGFR formula, the 
10 subjects with normal renal function will be matched to 10 of the enrolled patients with 


Novartis
Confidential
Page 23
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
decreased renal function by age (approximately ± 10 years), weight (approximately ± 20%), 
and, if possible, diabetic status. The 10 patients with decreased renal function on whom the 
matching will be based will be selected so as to cover as broad age range as possible. 
The enrolled patients will be ranked by age and selected, beginning with the youngest and 
ending with the oldest, in an increment that yields 10 total patients. Efforts will be made to 
match the diabetic status, where possible, to ensure representation of both diabetic and non-
diabetic populations in the group of subjects with normal renal function.
The renal function (eGFR) will be assessed based on the MDRD equation (Levey et al 2006) 
during the screening visit. The MDRD equation (Serum creatinine levels in mg/dl) to be used 
is as follows:
eGFR = 175 x Serum Creatinine-1.154 x Age-0.203 x [1.212 if Black] x [0.742 if Female]
Additional details about the eGFR equations and the standardized creatinine assays will be 
provided in the SOM. 
Each subject will attend Screening visit(s) when the inclusion/exclusion criteria will be 
assessed. Eligible subjects will be admitted to the study site at Baseline (Day -2), where 
eligibility for enrollment into the study will be confirmed as needed. All baseline safety 
evaluation results must be available and reviewed prior to dosing when screening is 
performed more than 7 days prior to dosing.  Each subject will receive once daily LIK066 at 
50 mg dose for 7 days.  Meal contents including carbohydrates and salt will be standardized 
from Day -2 to the morning of Day 2, and then from Day 5 to Day 8,
 
 Detailed information on 
meal recommendation is provided in the SOM. Baseline twenty-four hour urine samples will 
be collected. Study participants must be fasted for approximately 10 hours before Day 1 
dosing of LIK066.
Standardized breakfast will be provided immediately after the 
administration of LIK066 in the morning. 
Following the first dose on Day 1, subjects will remain domiciled for at least 24 hours for 
collection of urine and blood samples for urinary glucose excretion, pharmacokinetic, 
pharmacodynamic and safety assessments. Subjects will either remain domiciled 
(mandatory for subjects with severe renal impairment) or return in the morning to the study 
site every day (Day 3 to Day 5) to receive their medication after approximately 10 -hour 
fasting overnight, per the investigator discretion as described in the SOM. A standardized 
breakfast will be served immediately after administration of LIK066 every day. Subjects will 
be domiciled from Day 5 and will be fasted for approximately 10 hours before the final dose 
on the morning of Day 7 at the site. Subjects will remain domiciled up to Day 8 to complete 
24-hour collection of urine and blood for urinary glucose excretion, pharmacokinetic, 
pharmacodynamic and safety assessments after the final dose. Blood and urine samples for 
pharmacokinetic assessments will be taken on Days 9, 10 and 11 (up to 96 hours post the final 
dose). Study completion evaluations will be performed after the last pharmacokinetic 
assessment is completed (Day 11), or in the case of early termination, prior to discharge from 
the study site.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (blood chemistry, urinalysis, hematology), and adverse event and 
serious adverse event monitoring. See the assessment schedule for further details.


Novartis
Confidential
Page 24
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
3.2
Rationale of study design
The design of this study addresses the primary objective of assessing the effects of LIK066 on 
urinary glucose excretion and the pharmacokinetics of LIK066 in subjects with reduced renal 
function as compared to those with normal renal function. The 24-hour urinary glucose 
excretion (UGE24) is zero in healthy subjects and ~10 g in patients with T2DM in the absence 
of a SGLT inhibitor such as LIK066. The UGE24 is ~100 g when LIK066 is given to patients 
with T2DM, therefore, the diabetic status is expected to have little impact on the assessment 
of UGE24. In addition, the assessment of UGE24 will be based on the changes corrected by 
baseline UGE24. The matching of subjects with normal renal function to a subset of the 
subjects with reduced renal function will be done to minimize bias in the comparison due to 
confounding factors of age, body weight, and diabetic status. An open-label design without a 
placebo comparator is appropriate as the primary endpoints, 24-hour urinary glucose excretion 
and pharmacokinetics, are objective parameters.   
3.4
Rationale for choice of comparator
Not applicable.


Novartis
Confidential
Page 25
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
3.5
Purpose and timing of interim analyses/design adaptations
An interim analysis may be initiated once approximately half of the enrolled subjects have 
completed the study. The purpose of the analysis will be to assess the impact of reduced renal 
function on UGE24 in order to inform development decisions for LIK066. Actions such as 
early termination of the study should objectives be met, adjustments to the sample size, and/or 
revisions of the dose may be made. Additional interim analyses may be conducted to support 
decision making concerning the current clinical study, the sponsor’s clinical development 
projects in general or in case of any safety concerns. The clinical team may communicate 
interim results to relevant Novartis teams for information, consulting and/or decision purposes.


Novartis
Confidential
Page 26
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
3.6.1
Blood sample volumes
Approximately up to 200 mL of blood is planned to be collected from each subject over 2 -3 
weeks during 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 SOM, 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
4.1
Inclusion criteria
4.1.1
All individuals
Subjects with normal and decreased renal function 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 78 years, inclusive, with controlled health condition as 
determined by past medical history, physical examination, electrocardiogram, and 
laboratory tests at screening.
3. For patients with Type 2 diabetes, HbAc1<10% at screening.
4. If treated with antidiabetic medications (other than prohibited medications), patients must 
be on a stable dose for approximately 6 weeks prior to starting the study treatment and 
maintain the dose until the end of the study.
5. Body mass index (BMI)≤50 kg/m2 at Screening.
6. Able to communicate well with the Investigator, to understand and comply with the 
requirements of the study.


Novartis
Confidential
Page 27
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
4.1.2
Patients with decreased renal function
7. Patients must have stable renal disease at screening without evidence of active progression 
(for the purpose of this study stable renal disease will be defined as no significant change 
of eGFR for 12 weeks, per the discretion of the investigator upon reviewing the medical 
history or previous lab assessments).

Mild renal impairment: eGFR from 60 to 89 ml/min/1.73 m2

Grade A moderate renal impairment: eGFR from 46 to 59 ml/min/1.73 m2

Grade B moderate renal impairment: eGFR from 30 to 45 ml/min/1.73 m2

Severe renal impairment: eGFR of ≤29 ml/min/1.73 m2, not on dialysis
8. Vital signs (after 3 minutes resting measured in the supine position). The Investigator 
should be guided by the following ranges:
oral body temperature between 35.0-37.8 °C
systolic blood pressure, 100-180 mm Hg
diastolic blood pressure, 50-110 mm Hg
pulse rate, 45-100 bpm
Blood pressure and pulse will be taken again in a standing position. 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 associated with clinical manifestation of symptomatic postural hypotension.
4.1.3
Subjects with normal renal function
9. Except for the medical conditions allowed in the inclusion/exclusion criteria (e.g. diabetes 
or hypertension), no other significant medical conditions at screening or baseline as 
determined by medical history and physical examination.
10. Normal renal function reflected by an eGFR of ≥90 ml/min/1.73m2.
11. Vital signs (after 3 minutes resting measured in the supine position).  The Investigator 
should be guided by the following ranges:
oral body temperature between 35.0-37.2°C
systolic blood pressure, 100-150 mm Hg
diastolic blood pressure, 60-100 mm Hg
pulse rate, 45-100 bpm
Blood pressure and pulse will be taken again in a standing position. 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 associated with clinical manifestation of no symptomatic postural hypotension.
12. Subjects will be matched to 10 of the enrolled patients with decreased renal function by 
age (approximately ± 10 years), weight (approximately ± 20%), and, if possible, diabetic 
status.


Novartis
Confidential
Page 28
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
4.2
Exclusion criteria
4.2.1
All individuals
Subjects with normal and decreased renal function fulfilling any of the following criteria are 
not eligible for inclusion in this study:
1. 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.
2. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during the study. 
Basic contraception methods include:

Total abstinence when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (i.e., 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)), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 m prior to screening). The vasectomized male partner 
should be the sole partner for that subject.

Barrier methods of contraception: Condom or Occlusive cap. For UK: 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 or 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.
3. 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.
4. Evidence of clinically significant  abnormal liver function tests for any of the labs at 
screening, confirmed by a repeat measure within 7 days :

ALT, AST, γ-GT, alkaline phosphatase > 3 x ULN.

serum bilirubin > 1.5 x ULN.
5. Evidence of urinary obstruction or difficulty in voiding at screening.


Novartis
Confidential
Page 29
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
6. Symptomatic genital or urinary tract infection (UTI) in the 4 weeks prior to the first study 
visit or the presence of active UTI at screening.
7. Evidence or medical history of clinically significant ECG abnormalities.
8. Any of the following within 6 months of screening:

myocardial infarction (MI)

coronary artery bypass surgery, balloon angioplasty, coronary stent(s) in situ

unstable angina

peripheral arterial disease

congestive heart failure NYHA class II- IV
9. History of autonomic dysfunction (e.g. history of fainting, clinically significant orthostatic 
hypotension, clinically significant sinus arrhythmia).
10. Significant blood loss equaling at least one unit of blood (500 ml) or a blood transfusion 
within 3 months prior to screening.
11. Evidence of immunodeficiency diseases, including a positive HIV (ELISA and Western 
blot) test result at screening.
12. History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such 
abuse as indicated by the laboratory assays conducted during the screening or tests 
conducted during baseline evaluations.
13. Malignancy including leukemia and lymphoma (not including basal cell skin cancer which 
has not been adequately treated) within 5 years prior to screening.
14. Any finding during screening assessments (physical examination, vital signs, ECG 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.
15. Patients undergoing any method of dialysis (hemodialysis or peritoneal dialysis).
16. History of hypersensitivity to the study drug, or to drugs of similar chemical classes.
17. 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).
18. 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).
19. Subjects who experienced ketoacidosis, lactic acidosis, or hyperosmolar coma within 6 
months of Screening Visit, or between Screening Visit and Baseline Day -1.


Novartis
Confidential
Page 30
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
20. Use of prohibited medications:

Use of SGLT2 or alpha-glucosidase inhibitors within 2 weeks prior to dosing and 
during the study. If treated with other oral antidiabetic medications, patients must be 
on a stable regimen for at least 6 weeks prior to starting the study treatment

Use of potassium-binders within 3 days prior to dosing and during the study

Treatment with drugs that have a high incidence of diarrhea during the study

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

Strong inhibitors of CYP3A4/5 including boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and 
voriconazole within 7 days prior to the study treatment and during the study

Strong CYP3A inducers including avasimibe, carbamazepine, phenytoin, rifampin, St. 
John’s wort within 7 days prior to the study treatment and during the study

General UGT inhibitors including probenecid, valproic acid within 7 days prior to the 
study treatment and during the study

Use of other investigational drugs at the time of enrollment, or within 30 days or 
5 half-lives of starting the study treatment or longer if required by local regulations. 
Any other limitation of participation in an investigational trial based on local 
regulations

Use of any medications that are contraindicated in patients with renal impairment

Use of any drugs with known toxicity to a major organ system within the past 
3 months (i.e., cytostatic drugs) 

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. If needed, acetaminophen or ibuprofen is acceptable for incidental 
and limited use.
Such medications must be documented in the Concomitant medications / significant non-
drug therapies page of the CRF.
4.2.2
Patients with decreased renal function
Patients with decreased renal function fulfilling any of the following criteria are not eligible 
for inclusion in this study:
21. Hemoglobin levels <8.0 g/dl at screening.


Novartis
Confidential
Page 31
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
4.2.3
Subjects with normal renal function
Subjects with normal renal function fulfilling any of the following criteria are not eligible for 
inclusion in this study:
22. Hemoglobin levels <12.0 g/dl for males, or <11.0 g/dl for females at screening.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the restrictions outlined in this section.
5.1
Contraception requirements
Please refer to exclusion criteria (Section 4.2) for details of contraception requirements for the study.
5.2
Prohibited treatment
Please refer to the exclusion criteria (Section 4.2). 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 for 8 hours before certain visits as noted in the 
SOM.

No grapefruit or grapefruit juice is to be consumed for approximately 7 days prior to 
dosing until 7 days following the last dose. 

In order to avoid wide variations in urine volumes on UGE and PK collection days, 
subjects should be encouraged to have a fluid intake of approximately 240 mL every 
4 hours during their waking hours, in addition to the fluid taken with meals and 
medication.
While domiciled, patients will follow a standard diet or a diet recommended for patients with 
kidney disease with the following guidelines.

Approximately 2,200 calories daily, adjusted by body weight; ~50% from carbohydrates, 
~30% from fat and ~20% from protein, with consistent and within recommended amounts 
of sodium, potassium, calcium and phosphorus, and free access to water.

Identical meals should be served on days (Baseline: Day -1 to Day 1; Treatment: Day 7 to 
Day 8) when 24 hour PD endpoints (UGE24, electrolytes and 
) are 
assessed.


Novartis
Confidential
Page 32
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202

No food other than that specified in the protocol and the SOM will be consumed during 
confinement.  
A meal record will confirm timing and consumption of meal. A copy of the diet with content 
and nutritional information (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 evaluations.
6
Treatment
6.1
Study treatment
The investigational drug, LIK066 tablets, will be prepared by Novartis and supplied to the 
Investigator as open labeled bulk medication. No control drugs will be used in this study.
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 SOM.
6.2
Treatment arms
This is an open label nonrandomized study. Subjects will be assigned to one of the following 
5 treatment arms according to their disease status. All subjects will receive LIK066 50 mg qd 
before breakfast for 7 days.

Group 1 (n=10, mild renal impairment)

Group 2 (n=10, moderate renal impairment grade A)

Group 3 (n=10, moderate renal impairment grade B)

Group 4 (n= up to 10, severe renal impairment)

Group 5 (n=10, subjects with normal renal function)
6.3
Treatment assignment
The Subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. Treatment numbers will be assigned in ascending, sequential 
order to eligible subjects according to the disease status as described in the SOM. The 
investigator will enter the treatment number on the (e)CRF.
If a subject requires a replacement, the replacement subject will be assigned a treatment 
number corresponding to the original number (e.g. Subject 6103 would replace Subject 5103).  
Any additional subjects enrolled will use sequential subject numbering.
6.4
Treatment blinding
This is an open label non-randomized study.


Novartis
Confidential
Page 33
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
6.5
Treating the subject
LIK066 will be administered to the subject orally at the investigator site. See the SOM for 
further details
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted. 
For patients 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.
6.7
Emergency breaking of assigned treatment code
Not applicable as this is an open label study. 
6.8
Treatment exposure and compliance
Study medication will be given at the site by study personal during domiciling or patients will 
return to the investigator site on a daily basis during the study. PK parameters (measures of 
treatment exposure) will be determined in all patients treated with LIK066, ensuring treatment 
exposure and compliance.
6.9
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.
6.10
Rescue medication
This is not a therapeutic study.  Rescue medication use is not allowed.
Use of medications other than the study drug during the study must be recorded on the 
Concomitant medications/Significant non-drug therapies CRF.
6.11
Concomitant treatment
Patients with T2DM on antidiabetic medications (other than prohibited medications) are 
allowed to participate in the study if they are on a stable dose for at least 6 weeks prior to 
dosing and maintain the dose until the end of the study.
Antihypertensive, dyslipidemia and GERD medications are allowed but patients must be on a 
stable regimen for 3 months or more prior to dosing and maintain the dose until the end of the 
study.
Aspirin and antianginal medications (other than ranolazine) are allowed.


Novartis
Confidential
Page 34
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 enrolling 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.
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.
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.


Novartis
Confidential
Page 35
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Study treatment of individual subject will be placed on hold and, based on full review of the 
clinical data and discussion with the investigator, discontinuation of study treatment may 
occur when that subject experiences:
 
 
 
 
 

Clinically significant urinary tract or genitourinary infections, at the discretion of the 
investigator and consult 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). 

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, 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 by an asterisk 
(*) 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.
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.


Novartis
Confidential
Page 36
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 events 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.


Novartis
Confidential
Page 37
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
8
Procedures and assessments


Novartis
Confidential
Page 38
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202


Novartis
Confidential
Page 39
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202


Novartis
Confidential
Page 40
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202


Novartis
Confidential
Page 41
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the 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 SOM.
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 and not symptoms should be recorded.
Patients 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 
the Assessment schedule. Results will be available as Source data and will not be recorded 
within the eCRF.


Novartis
Confidential
Page 42
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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
Urinary glucose excretion (UGE) is the primary pharmacodynamic (PD) endpoint in this 
study. PD samples will be obtained and 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 SOM regarding sample collection, numbering, processing and shipment.
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment Schedule (Section 8.1) detailing when each assessment is to be 
performed.
Physical examination
Vital signs

Body temperature

Blood pressure (BP)

Pulse
Height and weight

Height

Body weight

Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
Laboratory evaluations
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.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured.
Clinical chemistry
Albumin, alkaline phosphatase, AST, ALT, total bilirubin, bicarbonate/CO2, chloride, 
creatinine, CK, γ-GT, glucose, LDH, inorganic phosphorus, lipase, amylase, calcium, 
magnesium, potassium,  sodium, cholesterol (including total cholesterol, HDL-C and LDL-C), 
triglycerides, total protein, BUN and uric acid.


Novartis
Confidential
Page 43
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
If the total bilirubin concentration is increased above 2 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated.
Urinalysis
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/hemoglobin
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
Electrocardiogram (ECG)
PR interval, QRS duration, heart rate, RR, QT, QTc.
The Fridericia QT correction formula (QTcF) should be used for clinical decisions
8.7
Pharmacokinetics
PK samples will be obtained and evaluated in all subjects. PK samples will be collected at the 
timepoints defined in the Assessment schedule, Section 8.1. Follow instructions outlined in 
the SOM regarding sample collection, numbering, processing and shipment. See Section 8.9
regarding the potential use of residual samples.
Plasma samples will be assayed for LIK066 concentrations by Novartis or a designated CRO 
using validated liquid chromatography-tandem mass spectrometry assays (LC-MS/MS). 
The method will have an LLOQ of at least 5 ng/mL for LIK066. 
Concentrations will be expressed in mass per volume units and will refer to LIK066 plasma 
concentrations.
 
 
 
The following plasma pharmacokinetic parameters will be determined using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin 
(Version 6.2 or higher), as applicable:
Cmax, Tmax, AUClast, AUCtau, AUCinf, T1/2, CL/F, Vz/F, as relevant, from the plasma 
concentration-time data.


Novartis
Confidential
Page 44
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Additional PK parameters (Racc, T1/2acc, Cmin,ss, Cav,ss, Tlast, Clast etc.) may be 
calculated or reported as appropriate. The linear trapezoidal rule will be used for AUC 
calculation.
The total amount of LIK066 excreted into urine (Ae0-t) will be used to calculate the renal 
clearance (CLr) of LIK066 based on both plasma and urine data if the data allows.
Plasma sample will be collected for protein binding analysis in order to determine the 
unbound fraction of LIK066. Accordingly, unbound PK parameters [AUC,u and Cmax,u] 
may be calculated.
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.


Novartis
Confidential
Page 45
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
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). .


Novartis
Confidential
Page 46
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 
reported to Novartis.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the existing condition, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that has not worsened 
since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the 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 


Novartis
Confidential
Page 47
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual reporting 
to Novartis Chief Medical Office and Patient Safety (CMO&PS) as per Section 9.2.2.
9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.
Note: SAEs reported by subjects deemed to be screen failures are only collected from time 
sign ICF until when subject is deemed a screen failure, with appropriate information also 
captured in the CRFs as specified in the SOM.
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 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 and is thought to be 
related to the study treatment a Chief Medical Office and Patient Safety 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 SOM 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.


Novartis
Confidential
Page 48
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 γ-GT) 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).  

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 γ-GT. 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.


Novartis
Confidential
Page 49
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 patients 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 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.
9.7
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 
discontinued as per Section 7.2 and appropriate measures must be taken to correct the acidosis
and monitor glucose levels according to standard of care.


Novartis
Confidential
Page 50
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Every case of ketoacidosis must be reported to the Ketoacidosis Adjudication Committee 
(see Section 10.5).
9.8
Reporting Medication errors including misuse/abuse
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 Chief Medical Office and Patient Safety department if the treatment error 
is associated with an SAE.
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.9
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 Chief Medical Office and Patient Safety Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the 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.
9.10
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.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.


Novartis
Confidential
Page 51
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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. Validation checks 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 SOM
and 
Assessment schedule and can be recorded directly on the CRFs. All other data captured for
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


Novartis
Confidential
Page 52
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
10.3
Database management and quality control
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site via the EDC system. 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 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 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 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 will be established to assess suspected cases of ketoacidosis as 
described in the SOM.


Novartis
Confidential
Page 53
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
11
Data analysis
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 PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all 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 renal function 
(mild impairment, Grade A moderate impairment, Grade B moderate impairment, severe 
impairment, or normal) and subject. Summary statistics will be provided by renal function.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by renal function and subject.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed renal function and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary PD endpoint will be UGE24.
The primary PK endpoints will be the Cmax, Tmax, AUCtau, AUClast, AUCinf, T1/2, CL/F 
of LIK066.
The secondary PK endpoints will be Vz/F and CLr of LIK066.


Novartis
Confidential
Page 54
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
11.4.2
Statistical model, hypothesis, and method of analysis
The primary analyses will assess the effect of reduced renal function on UGE24 and on the 
PK of LIK066.
UGE24
The change from baseline in UGE24 will be analyzed using an analysis of covariance 
(ANCOVA) model with diabetic status, renal impaired group, day, and all associated 
interactions (where possible) as fixed factors and age, baseline body weight, and baseline 
fasting plasma glucose as covariates. Baseline fasting plasma glucose and baseline body 
weight will be the measurements on Day 1 0-hour. An unstructured covariance matrix will be used.
The least-square mean change from baseline will be estimated for each diabetic status by renal 
function by day combination. In addition, the mean difference between each renal impaired 
group and the group with normal renal function and the corresponding two-sided 90% 
confidence interval and p-value for the difference will be extracted for each diabetic status by 
day combination.
UGE24 will be summarized by diabetic status, renal function, and day. The change from 
baseline and % change from baseline will also be summarized. 
The relationship between eGFR and UGE24 will be assessed graphically, separately by day.
PK
Each of the log-transformed PK parameters (Cmax, AUCtau, AUClast, AUCinf as applicable) 
will be analyzed using the same model described above for UGE24 but without the baseline 
covariates. For each parameter, the least-square geometric mean will be estimated for each 
diabetic status by renal function by day combination. In addition, the geometric mean ratio of 
each renal impaired group to the group with normal renal function (expressed as a percent 
relative difference) and the corresponding two-sided 90% confidence interval and p-value for 
the ratio will be extracted for each diabetic status by day combination.
Statistical analysis may be performed to compare the free fraction (fu) across the treatment 
groups. If statistically significant difference exists in fu across treatment groups, the same 
analysis (as planned for total parameters) will also be performed to compare the AUC,u and 
Cmax,u between treatment groups.
 
The summary of PK parameters is described below in Section 11.4.4.
11.4.3
Handling of missing values/censoring/discontinuations
All drug concentrations below the lower limit of quantification (LLOQ) will be reported as 
“zero” and will be treated as zero for calculation of PK parameters. No other imputation of 
missing values will be performed.


Novartis
Confidential
Page 55
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
11.4.4
Summary statistics of pharmacokinetics
LIK066 plasma concentration data will be listed by renal function, subject, and visit/sampling 
time point. Descriptive statistics will be provided by renal function and visit/sampling time 
point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. Concentrations below LLOQ will be treated as 
zero in the summary statistics. A geometric mean will not be reported if the dataset includes 
zero values.
Each of the PK parameters will be listed by renal function, subject, and day and summarized 
by renal function and day. Descriptive statistics will include mean (arithmetic and geometric), 
SD, CV (arithmetic and geometric), median, minimum, and maximum. An exception to this is 
Tmax where median, minimum, and maximum will be presented.
11.4.5
Sensitivity analyses
Two sensitivity analyses of UGE24 may be performed:
(1) a similar analysis as the primary UGE analysis, except that natural logarithm of the ratio to 
baseline in UGE24 will be modeled instead of the change from baseline. For this analysis, the 
least-square geometric mean will be estimated for each diabetic status by renal function by 
day combination, in addition to the geometric mean ratio of each renal impaired group to the 
group with normal renal function (expressed as a percent relative difference) and the 
corresponding two-sided 90% confidence interval and p-value, separately for each diabetic 
status by day combination.
(2) the same analysis described for the primary UGE analysis, except that baseline UGE24 
will be used as a covariate in place of baseline fasting plasma glucose. Baseline UGE24 will 
be the collection taking place on Day -1. The same model-based quantities described for the 
primary analysis will be extracted.
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
See Section 11.4.2.
11.5.2
Safety
Vital signs
All vital signs data will be listed by renal function, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by renal function and visit/time.
ECG evaluations
All ECG data will be listed by renal function, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by renal function and visit/time.


Novartis
Confidential
Page 56
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Clinical laboratory evaluations
All laboratory data will be listed by renal function, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
renal function and visit/time.
Adverse events
All information obtained on adverse events will be displayed by renal function and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by renal function. A subject with multiple adverse 
events within a body system is only counted once towards the total of this body system.
Anion gap
From measurements of sodium, chloride, and bicarbonate in serum, the anion gap will be 
derived as sodium – (chloride + bicarbonate) and will be an additional safety variable. 
The anion gap and change from baseline in anion gap will be summarized by diabetic status, 
renal function, and day. 
For each subject, the maximum post-baseline value and the maximum change from baseline 
will be extracted and will be summarized by diabetic status and renal function. 
11.5.3
Pharmacokinetic / pharmacodynamic interactions
The relationship between UGE24 
 and each of the 
primary PK parameters may be assessed graphically, in addition to the relationship between 
eGFR and each of the primary PK parameters.


Novartis
Confidential
Page 57
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202


Novartis
Confidential
Page 58
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
11.7
Sample size calculation
The sample size was chosen to provide adequate precision around the estimated mean 
difference in change from baseline UGE24 between a renal impaired group and the group of 
normal controls. 
After 7 days of treatment of LIK066 15 mg once daily in patients with type-2 diabetes in the 
first-in-human study LIK066X2101, the mean and standard deviation of the change from 
baseline in UGE24 was approximately 98 g and 24 g respectively. If we observe similar 
variability in this study, with 10 enrolled subjects in the mild and moderate renal impaired 
groups and in the group of normal controls and at least 8 completers in each of these groups, a 
two-sided 90% CI for the difference of means will extend no more than 22.7 g from the 
observed difference. As an example, in the renal impairment study for the SGLT2 inhibitor 
empagliflozin (Macha et al 2014), the observed difference between the moderate impaired 
group and the normal controls was 42 g, representing a 43% decrease in UGE24. If we see a 
similar reduction in our study, the CI for the difference would extend to no more than 19.3 g 
to 64.7 g. We consider this as adequate precision for the estimation of the difference in change 
from baseline UGE24 between the groups.
The sample size also provides adequate precision for a comparison of the primary 
PK variables between groups. After a single dose of LIK066 50 mg in healthy volunteers in 
LIK066X2101, the coefficient of variation of the Cmax of LIK066 was approximately 22%. 
Assuming similar variability in this study, with at least 8 completers in each group, a 
two-sided 90% CI for the ratio of means will have a lower bound that extends to no less than 
0.81 times the observed ratio and an upper bound to no more than 1.23 times the observed 
ratio. We consider this as adequate precision for the estimation of the ratio of Cmax between 
the groups.
11.8
Power for analysis of key secondary variables
Not applicable.
11.9
Interim analyses
Refer to Section 3.5. Statistical details of the interim analysis will be described in the
Statistical Analysis Plan (SAP).


Novartis
Confidential
Page 59
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis 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.


Novartis
Confidential
Page 60
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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.


Novartis
Confidential
Page 61
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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. 551-9.
Levey AS, Coresh J, Greene T, et al (2006) Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann. Intern. Med. p. 247-54.
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.
Morgen CS, Sørensen TI (2014) Obesity: global trends in the prevalence of overweight and 
obesity. Nat Rev Endocrinol p. 513-4.
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.


Novartis
Confidential
Page 62
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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
New onset ALT or AST elevation 
with coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
New onset ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤8 x ULN

3 x ULN < ALT/AST ≤5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance
New onset ALT or AST elevation with 
coagulopathy
New onset 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


Novartis
Confidential
Page 63
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
Criteria
Actions required
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


Novartis
Confidential
Page 64
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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 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.)
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


Novartis
Confidential
Page 65
Clinical Trial Protocol (Version No. 00)
Protocol No. CLIK066B2202
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.

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.
*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.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LIK066
CLIK066B2202 / NCT03131479
An open-label, parallel-group study to assess the effect of 
LIK066 on urinary glucose excretion, pharmacokinetics, 
safety and tolerability following multiple dose 
administration in patients with decreased renal function 
compared to subjects with normal renal function
Statistical Analysis Plan (SAP)
Author(s):
, Trial Statisticians
Document type:
SAP Documentation – NIBR 
Document status:
Amendment v0.1
Release date:
15 February 2018
Number of pages:
16
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP-Amendment 1
CLIK066B2202
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
29-
Sep-
2017
Prior 
to
DB 
lock
Creation of 
initial version
N/A - First version
NA
3-Jan-
2017
Prior 
to 
DB 
lock
Parameters 
not available
 
Section 6.2.1
3-Jan-
2017
Prior 
to 
DB 
lock
Parameters 
not available
 
Section 7.1
2-Feb-
2018
Prior 
to 
DB 
lock
Additional 
statistical 
analysis
Overall statistical analysis for diabetic 
status is added, and the model doesn’t 
include the diabetic status and renal 
function interaction since there were no 
diabetic subjects enrolled for normal renal 
function
Section 6.1.2, 6.1.3, 
6.1.3.1, 6.2.2, 6.2.3


Novartis
For business use only
Page 3
SAP-Amendment 1
CLIK066B2202
Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of figures ......................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary objectives...................................................................................5
1.3.2
Secondary objectives...............................................................................5
5
1.4
Study design and treatment......................................................................................6
2
First interpretable results (FIR) ...........................................................................................7
3
Interim analyses...................................................................................................................8
4
Statistical methods: Analysis sets........................................................................................8
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses ................................................................................................9
5.3
Statistical model, assumptions and hypotheses .......................................................9
5.3.1
Graphical presentation of results...........................................................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.....................................10
11
11
12
12
7
Statistical methods for safety and tolerability data............................................................13
7.1
Variables................................................................................................................13
7.2
Descriptive analyses ..............................................................................................13
7.3
Graphical presentation...........................................................................................15
8
Statistical methods for Pharmacokinetic/Pharmacodynamic interactions.........................15
15


Novartis
For business use only
Page 4
SAP-Amendment 1
CLIK066B2202
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................8
List of figures
Figure 1-1: Study Design............................................................................................................6


Novartis
For business use only
Page 5
SAP-Amendment 1
CLIK066B2202
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 “CLIK066B2202” as well 
as for the Interim Analysis.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Study documents available at the time of finalization of this Statistical Analysis Plan include 
the study protocol v00, the eCRF (Version 7.0), and the Data Management Plan (Version 4.0).
1.3
Study objectives
1.3.1
Primary objectives

To assess the effect of a 7-day treatment with LIK066 on 24-hour urinary glucose 
excretion (UGE) in subjects with decreased renal function compared to those with normal 
renal function
o
24-hour urinary glucose excretion on Day 7

To assess the pharmacokinetics of LIK066 on Day 1 and Day 7 in subjects with decreased 
renal function compared to those with normal renal function.
o
Cmax, Tmax, AUCtau, AUClast, AUCinf, T1/2, CL/F, Vz/F, CLr
1.3.2
Secondary objectives

To assess the safety and tolerability of a 7-day treatment with LIK066 in subjects with 
decreased renal function compared to those with normal renal function.  
o
Adverse events


Novartis
For business use only
Page 6
SAP-Amendment 1
CLIK066B2202
1.4
Study design and treatment
This study employs an open-label, multiple-dose, parallel-group design in patients with 
varying degrees of decreased renal function (mild, moderate and severe renal impairment) and 
subjects with normal renal function.
Ten (10) subjects each with mild (eGFR 60-89 ml/min/1.73 m2), Grade A moderate 
(eGFR 46-59 ml/min/1.73 m2), Grade B moderate (eGFR 30-45 ml/min/1.73 m2), and normal 
renal function (eGFR≥90 ml/min/1.73 m2); and up to 10 patients with severe renal impairment 
(eGFR ≤29 ml/min/1.73 m2, not on dialysis) will be enrolled.
As it can be seen from Figure 1-1, each subject will participate in a screening period of up to 
28 days, one baseline period, one treatment period of 7 days (including domicile and 
outpatient visits), a follow-up period, and an end-of-study evaluation approximately 96 hours 
after the last drug administration.
Figure 1-1: Study Design
Patients with varying degrees of decreased renal function will be enrolled first; subjects with 
normal renal function will be enrolled after approximately 50% of the patients with decreased 


Novartis
For business use only
Page 7
SAP-Amendment 1
CLIK066B2202
renal function have been enrolled. Because body weight and age are covariates in the 
estimation of eGFR formula, the 10 subjects with normal renal function will be matched to 10 
of the enrolled patients with decreased renal function by age (approximately ± 10 years), 
weight (approximately ± 20%), and, if possible, diabetic status. The enrolled patients will be 
ranked by age and selected, beginning with the youngest and ending with the oldest, in an 
increment that yields 10 total patients.
Since this is a non-randomized study, subjects will be assigned to one of the following 5 
groups according to their disease status. All subjects will receive LIK066 50 mg qd before 
breakfast for 7 days.

Group 1 (n=10, mild renal impairment)

Group 2 (n=10, moderate renal impairment grade A)

Group 3 (n=10, moderate renal impairment grade B)

Group 4 (n= up to 10, severe renal impairment)

Group 5 (n=10, subjects with normal renal function)
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/LIK066B2202/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. 
FIR will focus on the following analyses:

Analysis of populations (if needed)

Subject disposition

Demographics and baseline characteristics. Baseline characteristics include, but not 
limited to:
o
Age, Weight/Height/BMI, Diabetes status, UGE24

Safety results include, but are not limited to:
o
Number and percentage of subjects with adverse events by body system and 
preferred term with a breakdown by renal function

Pharmacokinetic (PK) results for plasma:
o
Arithmetic mean (SD) plasma PK concentration-time plot per renal function
(overlaying).
o
Summary statistics for PK parameters.

Pharmacodynamic (PD) analyses include, but are not limited to:


Novartis
For business use only
Page 8
SAP-Amendment 1
CLIK066B2202
o
Model estimated renal function comparison in UGE24, change from baseline 
and % change from baseline in UGE24.
o
Arithmetic mean (SD) UGE24 plot per renal function (overlaying) over time
3
Interim analyses 
An interim analysis may be initiated once approximately half of the enrolled subjects have 
completed the study. The purpose of the analysis will be to assess the impact of reduced renal 
function on UGE24 in order to inform development decisions for LIK066. Actions such as 
early termination of the study should objectives be met, adjustments to the sample size, and/or 
revisions of the dose may be made. 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general or in case of any 
safety concerns. The clinical team may communicate interim results to relevant Novartis 
teams for information, consulting and/or decision purposes.
4
Statistical methods: 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 PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations that impact on PK data.
The PD analysis set will include all subjects with available PD data, who received any study 
drug and experienced no protocol deviations with relevant impact on PD data.
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
COMD01
Subject received prohibited concomitant
medication
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.


Novartis
For business use only
Page 9
SAP-Amendment 1
CLIK066B2202
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
5.1
Variables 
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher) from the plasma concentration-time data: 

Primary PK endpoints: Cmax, Tmax, AUCtau, AUClast, T1/2, CL/F 

Secondary PK endpoints: Vz/F and CLr 
Additional PK parameters (Racc, T1/2acc, Cmin,ss, Cav,ss, Tlast, Clast etc.) may be
calculated or reported as appropriate. 
The total amount of LIK066 excreted into urine (Ae0-t) will be used to calculate the renal
clearance (CLr) of LIK066 based on both plasma and urine data if the data allows.
Plasma sample will be collected for protein binding analysis in order to determine the
unbound fraction of LIK066. Accordingly, unbound PK parameters [AUC,u and Cmax,u]
may be calculated.
5.2
Descriptive analyses
LIK066 plasma concentration data will be listed by renal function, diabetic status, subject, and 
visit/sampling time point. Descriptive statistics will be provided by renal function and 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. Concentrations below LLOQ will be treated as 
zero in the summary statistics. A geometric mean will not be reported if the dataset includes 
zero values.
Each of the PK parameters will be listed by renal function, subject, and day and summarized 
by renal function and day. Descriptive statistics will include mean (arithmetic and geometric), 
SD, CV (arithmetic and geometric), median, minimum, and maximum. An exception to this is 
Tmax where median, minimum, and maximum will be presented.
5.3
Statistical model, assumptions and hypotheses
The natural logarithm of each PK parameter will be analyzed using a MMRM model with 
diabetic status, renal function group, day, and all associated interactions (where possible) as 
fixed factors and age as covariate. An unstructured covariance matrix will be used.
For each parameter, the least-square geometric mean will be estimated for each diabetic status 
by renal function by day combination. In addition, the geometric mean ratio of each renal 
impaired group to the group with normal renal function and the corresponding two-sided 90% 


Novartis
For business use only
Page 10
SAP-Amendment 1
CLIK066B2202
confidence interval and p-value for the ratio will be extracted for each diabetic status by day 
combination.
Statistical analysis may be performed to compare the free fraction (fu) across the renal 
function groups. If statistically significant difference exists in fu across renal function groups, 
the same analysis (as planned for total parameters) will also be performed to compare the 
AUC,u and Cmax,u between renal function groups. 
 
5.3.1
Graphical presentation of results
Arithmetic mean (SD) and geometric mean (90% CI) plasma concentration-time plots will be 
produced.
Overlaid individual plasma concentration-time profiles will be generated.
6
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the PD analysis set will be included in the PD data analysis.
6.1
Primary objective
The primary objective of this study is to assess the effect of a 7-day treatment with LIK066 on 
24-hour urinary glucose excretion (UGE24) in subjects with decreased renal function 
compared to those with normal renal function.
6.1.1
Variables 
The primary PD endpoint will be UGE24.
6.1.2
Descriptive analyses
UGE24 will be listed and summarized by renal function, day, diabetic status and overall. The 
change from baseline and % change from baseline in UGE24 will also be listed and 
summarized. Summary statistics for raw, change from baseline and % change from baseline in 
UGE24 will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), 
median, minimum and maximum as appropriate. Arithmetic mean (SD) plot and spaghetti plot 
of individuals’ observed data will be produced by renal function group for overall and for 
each diabetic status.
Baseline UGE24 is defined to be the measurement collected on Day -1.
6.1.3
Statistical model, assumptions and hypotheses
The primary PD analysis will assess the effect of reduced renal function on UGE24.
The change from baseline in UGE24 will be analyzed using a MMRM with diabetic status, 
renal function group, day, and all associated interactions (where possible) as fixed factors and 
age, baseline body weight, and baseline fasting plasma glucose as covariates. Baseline fasting 
plasma glucose and baseline body weight will be the measurements on Day 1 0-hour. An 
unstructured covariance matrix will be used.


Novartis
For business use only
Page 11
SAP-Amendment 1
CLIK066B2202
The least-square mean change from baseline will be estimated for each diabetic status by renal 
function by day combination. In addition, the mean difference between each renal impaired 
group and the group with normal renal function (or other least severe group with data) and the 
corresponding two-sided 90% confidence interval and p-value for the difference will be 
extracted for each diabetic status by day combination.
Additionally, the change from baseline in UGE24 will be analyzed for the overall group, 
using a MMRM with diabetic status, renal function group, day, and interaction terms of renal 
function*day and diabetic*day as fixed factors and age, baseline body weight and baseline 
fasting plasma glucose as covariates. An unstructured covariate matrix will be used. 
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.  
Normal distribution of UGE24 will be examined. In case there is strong deviation from 
normal distribution, a supportive analysis, similar to the primary UGE analysis, except that 
natural logarithm of the ratio to baseline in UGE24 will be modeled instead of the change 
from baseline, and baseline fasting plasma glucose will also be log transformed. For this 
analysis, the least-square geometric mean will be estimated for each diabetic status by renal 
function by day combination, in addition to the geometric mean ratio of each renal impaired 
group to the group with normal renal (or other least severe group with data) function and the 
corresponding two-sided 90% confidence interval and p-value, separately for each diabetic 
status by day combination.
In addition, another supportive analysis similar to the primary UGE analysis, except that 
baseline UGE24 will be used as a covariate in place of baseline fasting plasma glucose. 
Baseline UGE24 will be the collection taking place on Day -1. The same model-based 
quantities described for the primary analysis will be extracted.
Same analysis, for both supportive analysis models, will be repeated for overall diabetic status, 
without including the interaction of renal function*diabetic status. 
6.1.3.2
Graphical presentation of results
A bar chart showing the least-square mean and mean difference from normal renal function 
(or other least severe group with data) with two-sided 90% CI at each day will be generated 
for change from baseline in UGE24 by renal function group for each diabetic status. In 
addition, similar plot will be produced for ratio to baseline in UGE24 based on the ratio to 
baseline analysis.  
The relationship between eGFR and UGE24 will be assessed by scatterplots and linear 
regression line with both diabetic statuses overlaying, separately by day.


Novartis
For business use only
Page 12
SAP-Amendment 1
CLIK066B2202


Novartis
For business use only
Page 13
SAP-Amendment 1
CLIK066B2202
7
Statistical methods for safety and tolerability data
All subjects within the safety analysis set will be included in the safety data analysis.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, anion gap, urine ketones (dipstick), 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 renal function, diabetic 
status and subject. Summary statistics will be provided by renal function. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by renal function and subject.


Novartis
For business use only
Page 14
SAP-Amendment 1
CLIK066B2202
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by renal function and subject.
Vital signs
All vital signs data will be listed by renal function, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by renal function and visit/time.
ECG evaluations
All ECG data will be listed by renal function, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by renal function and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by renal function, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
renal function and visit/time.
Adverse events
All information obtained on adverse events will be displayed by renal function and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by renal function. A subject with multiple adverse 
events within a body system is only counted once towards the total of this body system.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than 1% and on 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.
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. 


Novartis
For business use only
Page 15
SAP-Amendment 1
CLIK066B2202
Other safety evaluations
Anion gap
From measurements of sodium, chloride, and bicarbonate in serum, the anion gap in mmol/L
will be derived as sodium – (chloride + bicarbonate) in mmol/L and will be an additional 
safety variable.
The anion gap and change from baseline in anion gap will be summarized by diabetic status, 
renal function, and day. Baseline will be derived from the Day 1 0-hour measurements. 
Summary statistics will include sample size, mean, standard deviation, minimum, median, and 
maximum. 
For each subject, the maximum post-baseline value and the maximum change from baseline 
will be extracted and will be summarized by diabetic status and renal function. Summary 
statistics will include sample size, mean, standard deviation, 90% confidence interval, 
minimum, median, and maximum.
The frequency of patients with a maximum post-baseline value < / ≥ 11 will be tabulated by 
diabetic status and renal function.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Statistical methods for Pharmacokinetic/Pharmacodynamic 
interactions
The relationship between UGE24 
 and each of the 
primary PK parameters may be assessed graphically, in addition to the relationship between 
eGFR and each of the primary PK parameters. Modelling approach may also be used to 
explore the PK/PD interactions.


Novartis
For business use only
Page 16
SAP-Amendment 1
CLIK066B2202