Conditions: Polycystic Ovary Syndrome
Keywords: Polycystic ovary syndrome PCOS hyperandrogenism insulin resistance overweight obesity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate whether LIK066 can be developed for the treatment of polycystic ovary syndrome (PCOS) in overweight and obese women.

Detailed description:

Arms:
arm 1: LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test arm 2: Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test

Interventions: intervention 1: LIK066 intervention 2: Placebo
Intervention descriptions: intervention 1: LIK066 tablets for oral administration intervention 2: Placebo tablets matching LIK066 tablets, for oral administration

Protocol document:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
LIK066
Clinical Trial Protocol CLIK066X2205
A randomized, subject-and investigator-blinded, 
placebo-controlled pharmacodynamic study of oral LIK066 
in overweight and obese womenwith polycystic ovary 
syndrome
Document type:  
Amended Protocol Version
EUDRACT number:
2017-001373-16
Version number:  
v02(Clean)
Clinical Trial Phase:  
II
Release date:
20-Sep-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below. Refer to Section9.2of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.
Complete SAE report
Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO& PS)
within 24 hours after awareness of the SAE
Notify the Novartis Medical Lead
The fax number(s) and email address(es) are located in the Site Operations Manual. 


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................6
List of figures......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................13
1 Introduction.......................................................................................................................17
1.1
Background............................................................................................................17
1.4
Study purpose........................................................................................................21
2 Objectives and endpoints...................................................................................................21
2.1
Primary objective...................................................................................................21
2.2
Secondary objectives.............................................................................................21
3 Investigational plan...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale of study design.......................................................................................25
3.3 Rationale for dose/regimen, route of administration and duration of treatment....26
3.4 
Rationale for choice of comparator.......................................................................27
3.6
Risks and benefits..................................................................................................27
3.6.1 
Blood sample volumes..........................................................................28
4 Population..........................................................................................................................28
4.1
Inclusion criteria....................................................................................................28
4.2
Exclusion criteria...................................................................................................
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5 Restrictions for Study Subjects.........................................................................................32
5.1
Contraception requirements...................................................................................32
5.2
Prohibited treatment...............................................................................................32
5.3
Dietary restrictions and smoking...........................................................................32
5.4
Other restrictions...................................................................................................33
6 Treatment...........................................................................................................................33
6.1
Study treatment......................................................................................................33
6.1.1 
Investigational treatment and control drug...........................................33
6.1.2 
Additional study treatment....................................................................33
6.2
Treatment arms......................................................................................................33
6.3
Treatment assignment and randomization.............................................................33
6.4
Treatment blinding.................................................................................................34
6.5
Treating the subject................................................................................................35
6.6
Emergency breaking of assigned treatment code..................................................35
6.7
Treatment exposure and compliance.....................................................................36
6.8
Recommended treatment of adverse events..........................................................36
6.9 Rescue medication.................................................................................................36
6.10 Concomitant treatment...........................................................................................37
7 Study completion and discontinuation..............................................................................37
7.1
Study completion and post-study treatment..........................................................37
7.2
Discontinuation of study treatment........................................................................37
7.3
Withdrawal of informed consent...........................................................................38
7.4
Lost to follow-up...................................................................................................
39
7.5
Study Stopping rules..............................................................................................39
7.6
Early study termination by the sponsor.................................................................39
8 Procedures and assessments..............................................................................................40
8.1
Assessment schedule.............................................................................................40
8.2
Informed consent procedures.................................................................................45
8.3
Subject screening...................................................................................................46
8.4
Subject demographics/other baseline characteristics.............................................46
8.6
Safety.....................................................................................................................46
8.8
Other assessments..................................................................................................47
8.8.2 
Meal record...........................................................................................
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9 Safety monitoring..............................................................................................................48
9.1
Adverse events.......................................................................................................48
9.2
Serious adverse event reporting.............................................................................50
9.2.1 
Definition of SAE.................................................................................50
9.2.2 
SAE reporting........................................................................................51
9.3
Liver safety monitoring.........................................................................................51
9.4
Renal safety monitoring.........................................................................................52
9.5
Reporting of study treatment errors including misuse/abuse................................53
9.6
Pregnancy reporting...............................................................................................53
9.7
Early phase safety monitoring...............................................................................54
10 Data review and database management.............................................................................54
10.1 Site monitoring......................................................................................................54
10.2 Data collection.......................................................................................................55
10.3 Database management and quality control............................................................55
10.4 Data Monitoring Committee..................................................................................56
10.5 Adjudication Committee........................................................................................56
11 Data analysis......................................................................................................................56
11.1 Analysis sets..........................................................................................................56
11.2 Subject demographics and other baseline characteristics......................................56
11.3 Treatments.............................................................................................................56
11.4 Analysis of the primary variable(s).......................................................................56
11.4.1
Primary Variable(s)...............................................................................56
11.4.2
Statistical model, hypothesis, and method of analysis..........................57
11.4.3
Handling of missing values/censoring/discontinuations.......................57
11.4.4
Sensitivity analyses...............................................................................57
11.5 Analysis of secondary variable(s)..........................................................................57
11.5.1
Efficacy / Pharmacodynamics...............................................................57
11.5.2
Safety.....................................................................................................58
11.7 Sample size calculation..........................................................................................60
11.8 Power for analysis of key secondary variables......................................................
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12 Ethical considerations........................................................................................................60
12.1 Regulatory and ethical compliance........................................................................60
12.2 Responsibilities of the investigator and IRB/IEC..................................................61
12.3 Publication of study protocol and results...............................................................61
12.4 Quality Control and Quality Assurance.................................................................61
13 Protocol adherence............................................................................................................62
13.1 Protocol Amendments...........................................................................................62
14 References.........................................................................................................................63
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................65
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................67
List of tables
Table 8-1  
Assessment schedule.............................................................................40
Table 15-1   
Liver Event Definitions.........................................................................65
Table 15-2  
Actions requiredfor Liver Events.........................................................66
Table 15-3  
Exclusion of underlying liver disease...................................................66
Table 16-1  
Specific Renal Alert Criteria and Actions.............................................67
Table 16-2  
Follow-up of renal events......................................................................68
List of figures
Figure 3-1  
Study design..........................................................................................
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List of abbreviations
ADR
adverse drug reaction
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CMO&PS
Chief Medical Office andPatient Safety
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CV
coefficient ofvariation
DHEA
dehydroepiandrosterone
DHEAS
dehydroepiandrosterone sulfate
ECG
electrocardiogram
EDxx
effective dose xx%
EDC
Electronic Data Capture
ELISA
enzyme-linked immunosorbent assay
FAI
free androgen index
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HOMA-IR
homeostatic model assessment ofinsulin resistance
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDH
lactate dehydrogenase
LFT
liver function test
LH
luteinizing hormone
LLN
lower limit of normal
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities


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mg
milligram(s)
mL
milliliter(s)
NOEL
no observed effect level
p.o.
oral
PCOS
polycystic ovary syndrome
PD
pharmacodynamic(s)
RBC
red blood cell(s)
SAE
serious adverse event
SD
standard deviation
SGLT
sodium glucose co-transporter
SHBG
sex hormone-binding globulin
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
T
testosterone
T2D
type 2 diabetes mellitus
TBL
total bilirubin
t.i.d.
three times a day 
ULN
upper limit of normal
ULQ
upper limit of quantification
UTI
urinary tract infection
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
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Glossary of terms
Assessment  
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response sy
stems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up) which applies 
across all arms of a study.
Investigational drug
The studydrug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance”
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Screen Failure  
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participantsas 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identifythe subject throughout the study for all data 
collected, sample labels, etc.
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, anddoes not want any further 
visits or assessments, anddoes not want any further study related contact, 
anddoes not allow analysis of already obtained biologic material


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Protocol summary
Protocol number
CLIK066X2205
Full Title
A randomized, subject- and investigator-blinded, placebo-controlled 
pharmacodynamic study of oral LIK066 in overweight and obese women with 
polycystic ovary syndrome
Brief title
Study of pharmacodynamics of LIK066 in overweight and obese women with 
polycystic ovary syndrome
Sponsor and Clinical 
Trial Phase
Novartis
PhaseII
Intervention type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of the study is to evaluate whether LIK066 can be developed for 
the treatment of polycystic ovary syndrome (PCOS) in overweight and obese 
women
Primary Objective(s)
To assess the  treatment effect of LIK066 on hyperandrogenism at Day 15 in 
subjects with  PCOS
Secondary 
Objectives
To assess the safety and tolerability of LIK066 in  subjects with PCOS
To evaluate the treatment effect of LIK066 on gonadotropins and sex steroid 
levels on Day 15
Study design
This is a randomized, subject-and investigator-blinded, placebo-controlled, 
parallel group, non-confirmatory study in overweight and obese PCOS 
subjects.
Approximately 24 subjects will be randomized in a 1:1 ratio toLIK066 or 
placebo (12 subjects on LIK066; 12 on placebo). The treatment period is 2 
weeks; dosing is oral, 50 mg of LIK066 or matching placebo three times daily 
before meals for 14 days and a single dose on Day 15 in the morning before 
the test meal.
Each subject will participate in a screening period of up to 6 weeks, a 
baseline assessment, a treatment period of 2 weeks, and a follow-up period 
of about 1 week with an end of study visit on approximately Day 22. At 
screening, subjects should report to the study site after an overnight fast of at 
least 8 hrs. Blood samples for eligibility criteria should be collected preferably 
before 8 am. The baseline visit includes an optional overnight stay (starting 
Day -2). Serial blood samples for hormone levels will be collected between 
approximately 6 am and 8 am on the following morning (Day -1), followed by 
a test meal for breakfast (without drug administration) and serial post-prandial 
blood sampling over a 4hour period.
The investigator must randomize eligible subjects on, or prior to, Day 1. 
During the treatment period, a follow-up visit should be conducted on Day 8 
to check tolerability, safety and compliance. This visit may be conducted 
either by phone or in person at the site, at the discretion of the investigator. 
On Day 14, subjects should return to the site for a repeat optional overnight 
stay to include an overnight fast of at least 8 hours. On Day 15, serial blood 
samples will be collected during fasting between approximately 6 am and 
8am. This will be followed by last dose administration and by a repeat 


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breakfast test meal, similar in composition to the baseline one. Serial blood 
samples will be collected over the 4 hour post-prandial period. 
Theinvestigator will discharge subjects after completing Day 15 
assessments. The End-of study visit occurs on approximately Day 22, for 
study completion evaluations. This visit may be performed earlier in the case 
of early termination.
Population
Approximately 24 subjects with polycystic ovary syndrome (PCOS) will be 
enrolled in the study. Replacement subjects should be enrolled if subjects are 
discontinued from the study for reasons other than safety. If more than 
2subjects experience menstrual bleeding during the study, additional 
subjects may be enrolled to account for those subjects in case they are 
excluded from the pharmacodynamic analysis set (if ovulation is confirmed 
based on progesterone assessment). The number of enrolled subjects; 
excluding replacements, should not exceed 30.
Key Inclusion 
criteria
Overweight/obese women with PCOS aged 18 to 40 years, inclusive
PCOS diagnosed as: 
Hyperandrogenism, clinical OR biochemical, AND
Amenorrhea or oligomenorrhea (less than 8 menses within the 
last 12 months) AND
Exclusion of other causes of hyperandrogenism (see exclusion 
criteria)
Indicators of reduced insulin sensitivity at screening defined as: 
Sex hormone binding globulin, SHBG < LLN OR
Fasting insulin above the  median of normal range of assay 
used
Overweight/obese female subjects with BMI ≥27kg/m2andstable 
weight +/-3kg over previous 3 month (by history)
Subjects must use non-hormonal methods of contraception from 
enrollment until one week after last dose.


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Key Exclusion 
criteria
Subjects with pre-existing type 1 or type 2 diabetes mellitus, 
Cushing’s syndrome, congenital adrenal hyperplasia, ovarian or 
adrenal androgen-secreting tumor, uncontrolled thyroid disease, 
untreated obstructive sleep apnea
Subjects with oophorectomy or exogenous causes of hirsutism (such 
as drug-induced)
Menstruationin the 30 days prior to screening or prior to the initiation 
of treatment (Day 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
Abnormal screening labs defined as: 
Early morning total testosterone levels ≥2.5×ULN or 
≥200ng/dl
DHEAS > 2×ULN or > 700mcg/dl
Prolactin > ULN on early AM sample (allow repeat ×1 for 
borderline levels, enroll based on 1 normal level)
17-OHP levels (early AM sample)  > 200ng/dl
TSHlevels > 10 uUI/ml and clinical symptoms of 
hypothyroidism.  Subjects with sub clinical hypothyroidism do 
not need to be excluded.  Subjectswell controlled on thyroid 
medication can be enrolled
Symptomatic genital or urinary tract infection (UTI) in the 4 weeks 
prior to screening or the presence of active UTI at screening
On-going participation in a weight loss program such as with 
exercise, diet or drugs.
History of significant gastrointestinal surgery or current clinically 
significant GI disorders
Use of prohibited medications.
Study treatment
The investigational drug, LIK066 50 mg and matching placebo tablets will be 
prepared by Novartis and supplied as single blinded patient specific kits, to 
be dispensed by the unblinded pharmacist at the investigator site according 
to the randomization schedule. Subjects will receive either:
LIK066 50 mg three times daily before breakfast, lunch and dinner.
Matching placebo tablets three times daily before breakfast, lunch 
Efficacy/PD 
assessments
Average of morning fasting free testosterone concentrations
Secondary variables include gonadotropins and sex steroids
Key safety 
assessments
Vital signs, ECG and laboratory assessments including serum 
electrolytes and hematocrit
Physical examination
Adverse events
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Data analysis
The primary efficacy endpoint is the average of the three fasting am free 
testosterone samples. The primary analysis will assess the treatment effect of 
LIK066 on free testosterone at Day15. The ratio ofDay 15 to baseline free 
testosterone will be analyzed in an analysis of covariance model with 
treatment as a categorical factor and baseline free testosterone as a 
covariate. The logarithm of the ratio and of baseline free testosterone will be 
applied prior to the analysis. The geometric mean of the ratio to baseline for 
free testosterone will be estimated from the model for LIK066 and placebo, 
along with the treatment ratio and the associated p-value and two-sided 90% 
confidence interval. From these quantities, the following criteria will be 
assessed:
1. the upper confidence limit of the 90% CI is less than 1, and
2. the estimated treatment ratio is less than 0.75.
The first criterion addresses with high certainty whether the effect of LIK066 
on free testosterone reduction is superior to placebo. The second criterion 
addresses whether the observed treatment effect of LIK066 on free 
testosterone reduction is at least 25%. An effect size of 20-25 % on 
hyperandrogenism is considered to be clinically meaningful in PCOS as it 
correlates with improved ovulation and fertility.
Key words
Polycystic ovary syndrome, overweight, obese, testosterone, insulin
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1  
Introduction
1.1  
Background
Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women, 
affecting approximately 5–10% of women throughout their reproductive age 
(Legroetal2013). The various definitions of PCOS share common features of 
hyperandrogenism, clinical and/or biochemical and amenorrhea/oligomenorrhea. The NIH 
definition of PCOS will be used in this study (Legroetal2013).
About 28% of obese women have PCOS based on an obese population referred for weight 
loss interventions (SirmansandPate2014). Obesity is also a risk factor for PCOS, with 
weight gain reported prior to the diagnosis of PCOS. Weight loss is commonly used as a 
therapeutic approach for PCOS. Insulin resistance affects 50%–70%of women with PCOS 
and occurs independently of obesity (Dunaif et al 1989). However, the effect of obesity on 
insulin resistance is additive to that of PCOS. Clinical manifestations of PCOS can be 
heterogenous and include features such as hirsutism, acne, obesity, menstrual dysfunction, 
infertility, and metabolic syndrome (Legro et al 2013). Over time, women with PCOS are at 
an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease 
(Legroetal2013). There is no cure for PCOS. Treatment involves management of symptoms 
by lifestyle modification such as weight loss, cosmetic interventions, pharmacotherapy for 
hirsutism, menstrual irregularities and infertility treatments. Metabolic modulation 
(e.g.,metformin) is also used off-label (Legroetal2013).
Insulin resistance is a common feature of PCOS across the weight spectrum,partly reflecting 
an intrinsic element of resistance with exacerbation by obesity. The insulin resistance appears 
to be tissue specific primarily affecting skeletal muscle and adipose tissue, but not ovarian and 
adrenal tissues. The compensatory hyperinsulinism has tissue-selective effects, which include 
aggravation of hyperandrogenism, primarily by stimulating activity of the cytochrome P450c 
17α in the ovary (RosenfieldandEhrmann2016). Hyperinsulinism also actson the liver to 
decrease the production of sex hormone binding globulin (SHBG), thus leading to increased 
circulating levels of free androgens; and possibly at the level of the pituitary gonadotropes, by 
increasing production of luteinizing hormone (LH), which in turn stimulates ovarian 
steroidogenesis (RosenfieldandEhrmann2016).
Interventions that reduce serum insulin levels such as metformin, insulin-sensitizing 
thiazolidinediones, and weight loss result in significant improvement of hyperandrogenemia 
and ovulation in PCOS (Legroetal2013). Pilot trials in PCOS with a short 10-day course of 
diazoxide, an inhibitor of insulin secretion, have shown significant reduction in circulating 
androgen levels (Nestler et al 1989). Metformin lowers insulin levels primarily by reducing 
hepatic glucose output and opposing glucagon-mediated signalling in the liver, and to a lesser 
extent by increasing glucose uptake in skeletal muscle (PernicovaandKorbonits2014). 
Randomized controlled trials with metformin in PCOS have shown an improvement in 
androgen measures of about 20% when compared to placebo (Harborneetal2003). 
Dapagliflozin, a sodium–glucose cotransporter (SGLT) 2inhibitor approved for T2D, is 
currently in a phase 3 clinical trial in PCOS, with and without metformin or exenatide to 
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(NCT02635386). There is a clear association between hyperinsulinism and hyperandrogenism 
in PCOS and clinical evidence that lowering insulin levels and/or increasing insulin sensitivity 
improve hyper androgenism and ovulation in these patients.
Sodium–glucose cotransporters (SGLT) 1 and 2 play an important role in glucose homeostasis 
with SGLT1 being the primary transporter responsible for absorption of glucose and galactose 
in the intestine, and SGLT 2 being the primary transporter responsible for renal glucose 
reabsorption (Kalra2014, Sandsetal2015). SGLT2 inhibitors are approved for the treatment 
of type 2 diabetes, acting primarily by increasing urinary glucose excretion (UGE) and 
improving glycemic control. Blockade of enteric SGLT1 results in glucose and galactose 
malabsorption (Sandsetal2015). There are no approved dual inhibitors of SGLT 1 and 2. 
Sotagliflozin, a dual inhibitor of SGLT1 and SGLT2, is in Phase III trials for diabetes, type2 
and type 1.
LIK066 is a highly selective, safe and potent dual SGLT1/2 inhibitor that is in development at 
Novartis for obesity. In humans, the pharmacodynamic effects of LIK066 include increased 
urinary glucose excretion (UGE), and inhibition of glucose absorption from the gut. Body 
weight loss has been demonstrated in a phase 2a trial in obesity. LIK066 significantly reduces 
post-prandial glucose and insulin excursions in 
, obese populations and 
T2D populations. This effect is observed with single dose and is acute, meaning that it is 
observed on the meal immediately following dosing and not 6 hours later, which suggests a 
direct lumenal effect on gut SGLT1 inhibition. This effect is also dose dependent, with 
maximal post-prandial insulin suppression at 50mg or higher. Fasting insulin and glucose 
levels arenot significantly affected by LIK066. To date, there are no data on the effect of 
LIK066 on androgen levels.
This is a mechanistic study that aims to evaluate whether cumulative post-prandial reduction 
in insulin levels with LIK066 over a short treatment period will improve circulating androgen 
levels in overweight and obese women with PCOS. This study could support the evaluation of 
PCOS in the development plans for the obesity indication.
The most relevant data for the present study are summarized in thesectionsbelow. 
Fordetailed information, please refer to the Investigator
's Brochure.
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1.4  
Study purpose
The purpose of the study is to evaluate whether LIK066 can be developed for the treatment of 
polycystic ovary syndrome (PCOS) in overweight and obese women.
2   
Objectives and endpoints
2.1  
Primary objective
Primary objective
Endpointsrelated to primary objective
To assess the treatment effect of LIK066 
on hyperandrogenism at Day 15 in 
overweight and obese subjects with PCOS 
Change in average morning fasting free 
testosterone blood concentrations from 
baseline to Day 15
2.2  
Secondary objectives
Secondary objectives
Endpoints related to secondary objectives
To assess the safety and tolerability of 
LIK066 in overweight and obese subjects 
with PCOS throughout the study.
Adverse events throughout the study, 
serum electrolytes and hematocrit on Day 
15
To evaluate the treatment effect of 
LIK066 on gonadotropins and sex steroid 
levels on Day 15
LH, FSH, SHBG, androstenedione, 
DHEA, DHEAS, Total testosterone, free 
androgen index (FAI)
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3  
Investigational plan
3.1  
Study design
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This is a randomized, subject-and investigator-blinded, placebo-controlled, parallel group, 
non-confirmatory study in overweight and obese PCOS subjects.
Approximately 24 subjects will be randomized in a 1:1 ratio to LIK066 or placebo 
(12subjects on LIK066; 12 on placebo). Discontinued subjects may be replaced. If more than 
2subjects experience menstrual bleeding during the study, additional subjects may be 
enrolled to account for those subjects in case they are excluded from the pharmacodynamic 
analysis set (if ovulation is confirmed based on progesterone assessment). The number of 
enrolled subjects; excluding replacements, should not exceed 30.
The treatment period is 2 weeks; dosing is oral, just before meals, 50 mg of LIK066 or 
matching placebo t.i.d. for 14 days and only one dose in the morning on Day 15.


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Figure 3-1  
Study design
Each subject will participate in a screening period of up to 6 weeks, a baseline period 
(including an optional overnight stay at the studysite), a treatment period of 2weeks 
(outpatient visits and one optional overnight stay at end of treatment), and a follow-up period 
of about 1week with an end of study visit on approximately Day 22. A subject
's duration of 
participation in the study is up to a total of 9 weeks inclusive of the 6-week screening window.
At screening, subjects should report to the study site after an overnight fast of at least 8hrs. 
Blood samples for eligibility criteria shouldbe collected during fasting preferablybefore8am. 
Subjects who meet all eligibility criteria at screening will be admitted for baseline evaluations. 


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The baseline visit (Day -1) includes an optional overnight stay (starting Day -2) and an 
8-10hour overnight fast. Serial blood samples for hormone levels will be collected between 
approximately 6am and 8amthe following morning (Day -1), followed by the test meal for 
breakfast (without drug administration) and serial post-prandial blood sampling over a 4hour 
period.No other food is allowed during this time.
If the time interval between the screening and baseline visits is more than 21daysor if there is 
any significant changes in the subject’s health condition reported during this interval, then 
baseline safety labs must be reviewed by the investigator to ensure eligibility criteria (related 
to safety)continue to be met and to then enablerandomization.The investigator must 
randomize eligible subjects on, or prior to, Day 1 (i.e. assign randomization numbers provided 
by Novartis as described in the Site Operation Manual; SOM). The site staff must provide 
subjects with study drug and instructions on drug administration immediately before meals, 
three times a day. The site staff should inform subjects that they are to avoid high 
carbohydrate meals in order to minimize GI discomfort with dosing (Details provided in the 
SOM). The site staff must also make the subjectsaware of the symptoms of hypotension, 
hypoglycemia and ketoacidosis during the dosing period as described in the informed consent 
form(ICF).
The site staff must also instruct subjects on proper hydration and proper genito urinary 
hygiene during dosing, as described in the SOM.
During the treatment period, a follow-up visit should be conducted on Day8 to check 
tolerability, safety and compliance. This visit may be conducted either by phone or in person 
at the site, at the discretion of the investigator.
On Day 14, subjects should return to the site for an optional overnight stay. The end of 
treatment assessment will take place on Day 15 after an overnight fast of at least 8 hours. 
OnDay15 morning, serial blood samples will be collected during fasting between 
approximately 6am and 8am. This will be followed by last dose administration and by a 
repeat breakfast test meal, similar in composition tothe baseline test meal. Serial blood 
samples will be collected over the 4 hour post-prandial period. No other food is allowed 
during this time.The investigator will discharge subjects after completing Day15 assessments.
The End-of-Study visit will occuron approximately Day 22, for study completion evaluations. 
This visit may be performed earlier in the case of early termination.
At baseline, the physical examination should include cutaneous manifestations of 
hyperandrogenism, e.g. hirsutism, acne, androgenic alopecia, as well as acanthosis nigricans 
and skin tags; baseline measures of body weight, waist circumference, hip circumference and 
waist/hip ratio. The medical history should include the approximate onset of the last menstrual 
period and prior history of gestational diabetes.
In this study, endocrine assessments include total testosterone, free testosterone, LH, FSH, 
SHBG, estradiol, progesterone, DHEAS, DHEA, androstenedione, insulin and glucose. Safety 
assessments throughout the study will include vital signs, physical examinations, ECGs, 
standard clinical laboratory evaluations (blood chemistry, hematology, urinalysis), adverse 
events and serious adverse events.


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The test meal consists of a glucosedrink containing a total of 75grams of glucose and food 
containing fat and protein (meal composition: approximately 50% kcal carbohydrates, 30% 
kcal fat and 20% kcal protein-approximately 600 kcal in total).
The assessments schedule and the SOM provide additional details.
3.2  
Rationale of study design
Randomizationreduces the risk of imbalances in baseline subject characteristics between 
groups, and reduces the risk of bias in the interpretation of pharmacodynamic, safety and 
tolerability endpoints.
Subject-and investigator-blindingminimizes bias in adverse event reporting by subjects 
and investigators and in causality assessments by investigators.
Parallel treatment arms:Acrossover design would be impractically long due to the need 
of a prolonged wash-out period to enable the pituitary-gonadal functionto get back to 
baseline.
Placebo comparator supports the analysis of the treatment effect of LIK066 on 
pharmacodynamic markers, especially given the risk of confounding effects due to 
biologic and analytic variability of androgen levels in women.  Including a placebo arm 
also helps for causality evaluation of adverse events in relation to study drug, study 
procedures and/or underlying disease.
Domiciling controls for confounders that influence the circadian rise in testosterone levels, 
such as overnight fast; enables serial sampling of fasting testosterone over the time period 
of peak secretion (between about 6 am and 8 am); and ensures an adequate fasting period 
prior to the breakfast meal, which is important for assessing the treatment effect of 
LIK066 oninsulin secretion.
Free testosterone (T)as primary end-point: 
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Free T and not total T, is considered to be 
more sensitive as a diagnostic marker of hyperandrogenism in women with PCOS.  Total 
testosterone has inadequate sensitivity to differentiate between normal and PCOS women.  
Free T is also the biologically active form of testosterone and, unlike total T, free T may
 
significantly change in response to treatment effects on SHBG. 


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3.3  
Rationale for dose/regimen, route of administration and duration 
of treatment
Thedosing regimen for LIK066 in this study is 50 mg orally (or matching placebo), t.i.d. 
before each main meal (Quaque ante cibum, q.a.c.) (before breakfast, lunch and dinner) for 
14days. The last dose will be administered on Day 15 morning before the test meal.
LIK066 regimens of either 50 mg or 150mg once a day are approximately ≥ ED80 for 
maximal urine glucose excretion (UGE), and are predicted to be ≥ ED90 for body weight loss, 
reflecting dual SGLT1 and SGLT2 inhibition (internal data analysis). At these doses, LIK066 
has been shown to reduce post-prandial incrementalinsulin and plasma glucose in a 
dose-dependent manner in clinical studies in healthy, obese and T2D subjects.
Dose level: Gut inhibition of SGLT1 by LIK066 is expected to inhibit absorption of prandial 
glucose, resulting in lower post-prandial serum glucose excursions and lower post-prandial 
insulin release. 
 
 
 
In patients with PCOS, reduction of insulin levels by about 
25%, e.g. with metformin, has been associated with improved hyperandrogenism and 
subsequent ovulation (Harborneetal2003). 
 
 
Dosing regimen of t.i.d. and q.a.c (before each meal): The post-prandial effect of LIK066 
on glucose and insulin is observed on the meal that immediately follows dosing, and not 
significantly with later meals, possibly due to limited lumenalexposure time to LIK066. 
Forexample, an LIK066 dose of 150 mg induced acute reduction of post-prandial glucose and 
insulin but had no apparent effect on a test meal given approximately 6 hours post-dose as
reported in the IB. For this reason, LIK066 will be administered immediately before each of 
the main meals; breakfast, lunch and dinner, i.e. t.i.d. and q.a.c. to ensure repeated 
pharmacologic reduction in insulin response per meal. This regimen is expected to induce a 
more sustained reduction in cumulative insulin levels at least during the daytime.
Safety and tolerability: The local gut lumenal exposure to LIK066 has been associated with 
GI symptoms, notably diarrhea and flatulence that are temporally related to meal intake with 
dosing.  This has been reported with 50 mg, 75 mg and 150mg and may be mitigated with 
reduced carbohydrates in the meal. There is no indication of gender specific difference on this 
tolerability profile to date.
The daily systemic exposure from the 50mg t.i.d. regimen in the PCOS population is 
expected to maintain a ≥ 10-fold exposure multiple relative to the NOEL AUC threshold for 
aneugenicity.
Rationale for treatment duration: A 14 day treatment period is expected to support an
effect of LIK066 on androgen levels in this population given the expected magnitude of 
reduction in overall insulin levels with t.i.d. dosing. A similar treatment duration with insulin 
inhibitors, such as diazoxide, were shown to reduce hyperandrogenism (Nestleretal1990;
Nestleretal1989
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Overall, a dosing regimen of LIK066 at 50 mg p.o. t.i.d. and q.a.c. ×14 days is anticipated to 
be safe and effective for pharmacodynamic evaluation of treatment effect on the androgen and 
insulin profile in this population.
3.4  
Rationale for choice of comparator
A placebo will be used as a comparator to ensure blinding and to determine any study effect.
3.6  
Risks and benefits
There is no anticipated therapeutic benefit expected for subjects participating in this study. 
The risk to subjects in this trial will be minimized by adherence to the inclusion/exclusion 
criteria, close clinical monitoring during the treatment periods, and stopping rules outlined in 
Section7.5.
In clinical studies, LIK066 was generally safe and well tolerated up to 350 mg daily dose.
Adverse drug reactions (ADR) that have been observed with LIK066 to date include 
gastrointestinal events, most commonly diarrhea (> 50% of subjects) (Investigator’s 
Brochure-Section6). Vulvovaginal infections (~ 5%) and headaches (~ 5%) have also been 
the most commonly reported ADRs. These adverse events have been mild-to-moderate and 
none resulted in study drug discontinuation. One subject elected to withdraw from a study 
(at50mg po t.i.d.) for GI tolerability issues. Subjects will be monitored clinically by 
symptoms, adverse event reporting and clinical labs such as chemistry. The investigator will 
also instruct subjects on prevention measures such as avoiding high carbohydrate meals with 
dosing, and good genital hygiene.
Potential risks
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with LIK066 that are known class effects or related to the mechanism of 
action include postural hypotension, urinary tract infection, hypoglycemia and ketoacidosis.
An increase in cases of lower limb amputation (primarily of the toe) were observed in T2DM 
patients with cardiovascular disease treated with canagliflozin in long-term clinical studies.
No lower limb amputations have been seen in LIK066 studies. This study excludespatients 
with T2DM. These risks will be monitored as described above. Additional prevention 
measures will include adequate hydrationamong other instructions to subjects as described in 
the ICF. 
The investigator should use his/herclinical judgment and treat any adverse events according 
to the standardof care.
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The aneugenicity risk with LIK066 for this study is considered to be minimal at the proposed 
dosing regimen (Section1.3.2). LIK066 is not anticipated to increase the risk of adverse 
developmental or reproductive outcomes in humans atthe proposed dosing regimen. 
Theinvestigator must instruct subjects to avoid pregnancy for the duration of trial because
there may be unknown risks of LIK066 to the fetus. Subjects must commit to abiding by the 
required methods of contraception (Section4.1). If there is any question that the subject will 
not reliably comply, they should not be enrolled in the study.
Blood samples will be collected frequently during the study either via venipuncture or cannula. 
Risks associated with blood collection include pain, swelling and/or bruising at the insertion 
site of the needle. Although rare, localized clot formation, infections and nerve damage may 
occur. Lightheadednessand/or fainting such as a vaso-vagal reaction may also occur during or 
shortly after the blood draw.
There may be unknown risks to LIK066 which may be serious and unforeseen.
3.6.1 
Bloodsample volumes
A maximum of 500 mL of blood is planned to be collected over a period of 6-9 weeks from 
each subject as part of the study. Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessmentschedule(Section 8.1).
A summary blood log is provided in the SOM. Instructions for all sample collection, 
processing, storage and shipment information is also available in the SOM and Laboratory 
Manual.
See Section8.9regarding the potential use of residual samples. 
4  
Population
4.1  
Inclusion criteria
Subjectswith polycystic ovary syndrome (PCOS) eligible for inclusion in this study must 
fulfill allofthe following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Overweight/obese women with PCOS aged 18 to 40 years, inclusive
3. PCOS diagnosed as
Hyperandrogenism, clinical OR biochemical, AND
Amenorrhea or oligomenorrhea (less than 8 menses within the last 12 months), AND
Exclusion of other causes of hyperandrogenism (see exclusion criteria)
NOTE:
Clinical hyperandrogenismis defined as 
moderate to severe hirsutism with a Ferriman-Gallway score equal to or >8
(FerrimanandGallwey1961) AND 
a free testosterone level that is approximately equal to or >1.4x  the ULNrange 
of the assay usedOR
calculated free androgen indexequal to or >7


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Biochemical hyperandrogenismis defined as free testosterone level that is 
approximately equal to or >1.75xthe ULNrange of the assay used.
The screening labs for free T can be repeated once for borderline levels; the highest level 
of free T must be considered for eligibility.
4.Indicators of insulin resistance at screening defined as:
Sex hormone binding globulin, SHBG < LLN OR
Fasting insulin above the median of normal range of assay used
5. Overweight/obese subjects with BMI equal to or>27  kg/m2and stable weight +/-3kg 
over previous 3 month (by history)
6. At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be 
assessed in the sitting position and again in the standing position as outlined in the SOM. 
Subjects with mild hypertension and those with treated hypertension are allowed. Sitting 
vital signs should be within the following ranges:
oral body temperature between 35.0-37.5 °C
systolic blood pressure, 90-150mmHg
diastolic blood pressure, 50-90mmHg
pulse rate, 40-90bpm
If vital signs are outside these ranges, the Investigator should obtain two additional 
readings,so that up to three consecutive assessments are made, following the procedure in 
the SOM.
At least the lastreading must be within the ranges provided above in order for the 
subjectto qualify.
Subjects should be excluded if their standing vital signs (relative to sitting) show findings 
which, in the opinion of the Investigator, are associated with clinical manifestations (such 
as lightheadness or palpitations) of postural hypotension (i.e. absence of any other cause). 
Postural hypotension is defined as either a > 20 mmHg decrease in systolic or a 
>10mmHg decrease in diastolic blood pressure, accompanied by a > 20bpm increase in 
heart-rate (from sitting to standing).
7. Subjects must use non-hormonal methods of contraception from enrollment until one 
week after last dose. Non-hormonal 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.
Hysterectomy or tubal ligation at least six weeks before the treatment period.
Placement of a non-hormonal intrauterine device (IUD).
Male partner sterilization (at least 6 months prior to screening). The vasectomized 
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.
8. Able to communicate well with the Investigator, to understand and comply with the 
requirements of the study.


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4.2  
Exclusion criteria
Subjects with polycystic ovary syndrome (PCOS) fulfilling any of the following criteria are 
noteligible for inclusion in this study:
1. Subjectswith pre-existing type 1 or type 2 diabetes mellitus, Cushing’s syndrome, 
congenital adrenal hyperplasia, ovarian or adrenal androgen-secreting tumor, uncontrolled 
thyroid disease, untreated obstructive sleepapnea.
2. Oophorectomy.
3. Exogenous causes of hirsutism (such as drug-induced).
4. Menstruation in the 30 days prior to screening or prior to the initiation of treatment 
(Day1).
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test
6. Abnormal screening labs defined as:
Early morning total testosterone levels => 2.5×ULN or => 200ng/dl
DHEAS > 2×ULN or > 700 mcg/dl
Prolactin > ULN on early AM sample (allow repeat ×1 for borderline levels, enroll 
based on 1 normal level)
17-OHP levels (early AM sample) > 200ng/dl
TSHlevels > 10 uUI/ml and clinical symptoms of hypothyroidism.  Subjects with sub 
clinical hypothyroidism do not need to be excluded.  Subjects well controlled on 
thyroid medication can be enrolled.
7. Symptomatic genital or urinary tract infection (UTI) in the 4 weeks prior to screeningor 
the presence of active UTI at screening
8. Ongoing participationin a weight loss program such as with exercise, diet or drugs.
9. 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); active gastrointestinal disorders such as irritable 
bowel syndrome and inflammatory bowel disease.
10.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)
11.History of hypersensitivity to the study drug(active orplacebo), or to drugs of similar 
chemical classes.Ingredients of the study drug are described in Section3.2.1 of the 
Investigators’ Brochure.
12.Use of prohibited medications, including:
antidiabetic medications or weight loss drugswithin 3 months of screening.
hormonal therapy including but not limited to estrogen/progesteronecontraceptives, 
estrogens, androgens, gonadotropin-releasing hormone within 3 monthsof screening, 
orprogesterone contraceptives within 1 month of screening.Thyroid replacement 
therapy is allowed; subjects must be on a stable dose for at least 3 months prior to 
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Infertility treatment e.g. letrozole and clomiphene citrate within 1 monthof screening
muscle anabolic agents/drugs within 3 monthsof screening.
Systemic glucocorticosteroid treatment for > 7 consecutive days for worsening of an 
underlying condition within 4 weeks of screening. Use of topical or inhaled 
glucocorticosteroids 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 at least 7 days prior to the study treatment.
Strong CYP3A inducers including avasimibe, carbamazepine, phenytoin, rifampin, 
St.John’s wort at least 7 days prior to the study treatment,
General UGT inhibitors including probenecid, valproic acid at least 7 days prior to the 
study treatment.
other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives 
of enrollment, or longer if required by local regulations. Any other limitation of 
participation in an investigational trial based on local regulations.
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, 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 ibuprofenis acceptable for incidental 
and limited use.
13.Malignancy including leukemia and lymphoma (not including basal cell skin cancer which 
has been adequately treated) within1 year prior to screening.
14.History of autonomic dysfunction (e.g. historyof fainting,clinically significant orthostatic 
hypotension, clinically significant sinus arrhythmia).
15.Significant cardiovascular disease. active or within 6 months of screening such as 
myocardial infarct (MI), unstable angina, or clinically significant ECG abnormalities at 
screening
16.Evidence of clinically significant  abnormal liver function tests for any of the labs at 
screening, confirmed by a repeat assessment:
ALT, AST, GGT, alkaline phosphatase > 3 ×ULN.
serum bilirubin > 1.5 ×ULN .
17.Any history of ketoacidosis,lactic acidosis, or hyperosmolar coma.
18.Significant blood loss equaling at least one unit of blood (500 ml) or a blood transfusion 
within 3 months prior to screening.
19.History of drug or alcohol abuse within the 12 months prior to screening or evidence of 
such abuse as indicated by the laboratory assays conducted at screening.
20.Evidence of immunodeficiency diseases, including a positive HIV (ELISA and Western 
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21.Any finding during screening assessments (vital signs, physical examination, ECG or 
clinical lab assessments), surgical or medical condition which may significantly alter the 
absorption, distribution, metabolism, or excretion of drugs, or in the investigator’s 
judgment, which may jeopardize the subject in case of participation in the study, or would 
interfere with interpretation of the study results.
The investigator must ensure that all subjects meet the study eligibility criteria before they are 
enrolled in the study. The investigator must not apply any eligibility criteria other thanthose 
listed in the protocol. Deviation from any of the protocol eligibility criteria excludes a subject 
from enrollment into the study.
A relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5  
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1  
Contraception requirements
Women of child-bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement outlined 
in Section4.1(Inclusion Criteria). If there is any question that the subject will not reliably 
comply, they should not be entered or continue in the study.
5.2  
Prohibited treatment
The medications listed under the exclusion criteria (Section4.2) are not allowed to be used 
during the study. The investigator may discontinue subjects if treated with prohibited 
medications during the study. The investigator should discuss such cases with the Sponsor.
Antihypertensive, dyslipidemia and GERD medications are allowed but subjects must be on a 
stable regimen for 3 months or more prior to randomization.
Concomitant and prior medications (dose, regimen, indication and treatment duration) must 
be recorded in the CRF.
5.3  
Dietary restrictions and smoking
Subjects will be asked to fast for at least 8hours overnight on certain days, when blood 
samples will be collected early morning to measure various biomarkers under fasting state, as 
described in Section3and the SOM.
Smoking/use of nicotineproducts should be avoided for 8 hours before the study visits as 
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Grapefruit andgrapefruit juice shouldbe avoidedfor approximately 7 days prior to dosing 
until the end of the study.
Subjects will be instructed to use a low carbohydrate diet during the study treatment. 
Detailswill be provided in the SOM. A test meal will be served at baseline and end of 
treatment as described in Section3and the SOM.
5.4  
Other restrictions
No strenuous physical exercise (e.g. weight training, aerobics) at least 24hours before each 
study visit, and during the visit.
6  
Treatment
6.1  
Study treatment
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.
6.1.1 
Investigational treatment and control drug
The investigational drug, LIK066 50 mg tablets and matching placebo tablets in blisters will 
be prepared by Novartis in single blind patient specific packs to be dispensed by the 
unblinded pharmacist at the investigator site according to the randomization schedule as 
described in the SOM.
6.1.2 
Additional study treatment
No additional treatment beyond investigational drug is included in this trial.
6.2  
Treatment arms
Subjects will be assigned to one of the following 2 treatment arms in a ratio of 1:1
LIK066 50mg three times daily; before breakfast, lunch and dinner (12 subjects).
Matching placebo tablets three times daily; before breakfast, lunch and dinner 
(12subjects).
6.3  
Treatment assignment and randomization
Randomized treatment will be assigned to individual subjects by way of a randomization 
number, which will be in the range of 5101-5130.
The randomization number is only used to identify which treatment the subjects have been 
randomized to receive. The Subject number assigned to a subject at screening remains the 
unique identifier for the subject throughout the study.  For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.


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Replacement randomization numbers will be in the range of 6101-6130. If a subject requires a 
replacement, the replacement subject will be assigned a randomization number corresponding 
to the original subject (e.g. Subject 6103 would replace Subject 5103). Anyadditional 
subjects enrolled will use sequential subject numbering.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
Treatmentallocation cards (noting the randomization numbers) will be produced by or under 
the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of treatment arms to randomization numbers in the 
specified ratio.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
The investigator will enter the randomization number on theCRF (eCRF). If more than one 
study center recruits subjects simultaneously, the CTL or designee will coordinate assigning 
randomization numbers across sites as described in the SOM.
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
6.4  
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain 
blinded to studytreatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, and schedule of administration, appearance, and odor.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study
.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section6.7).
Drug product will be supplied in bulk, so an unblinded pharmacist who is independent of the 
study team will be required in order to maintain the blind. This unblinded pharmacist 
(ordelegate) will receive treatment allocation cards from Drug Supply Management with the 
appropriate treatment allocation numbers. Appropriate measures must be taken by the 
unblinded pharmacist to ensure that the treatment assignments are concealed from the rest of 
the site staff.
Sponsor staff
The following unblinded sponsor roles are required for this study:
Unblinded field monitor(s)
Unblinded clinical staff managing drug re-supply to site
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The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be 
unblinded through review of source documentation compiled by the unblinded pharmacist, 
which details treatment allocation to individual subjects. The unblinded monitors will also be 
able to review the treatment allocation cards provided to the unblinded pharmacist. The names 
of the unblinded monitor(s) are detailed in the Monitoring Plan.
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly, but may be 
unblinded through communication of drug re-supply needs via the unblinded site pharmacists.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in the SOM. For example,unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. biomarker 
expert) are allowed to access treatment assignment information for the purpose of conducting 
interim analyses.
The clinical trialteam is allowed to share unblinded results with other sponsor staff 
(e.g.decision boards) as required for internal decision making on the study or the project at 
the time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
6.5  
Treating the subject
LIK066 or matchingplacebo tablets will be administered orally just before meals mostly at 
home by the subject. See the SOM for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.6  
Emergencybreaking of assigned treatment code
Emergency unblinding must only be undertaken when it is essential to treat the subject safely 
and efficaciously. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. A complete set of emergency code break cards will be provided to the investigator 
site(s) and a complete set will be available at Novartis. All code break cards must be retained 
until the end of the study and returned to Novartis. They must be stored in a secure place but 
be accessible to the investigator 24hours per day in case of emergency. The investigator will 
receive a blinded code break card for each subject, with the details of study treatment covered 
by a removable, scratch-off cover. In an emergency, the scratch-off cover can be removed to 


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determine the treatment. The scratch-off covers are not to be removed for any reason other 
than an emergency. When the investigator removes the scratch-off cover he/she must note the 
date, time, and reason for removing it and retain this information with the case report form 
documentation. The unblinded treatment code must not be recorded on the CRF. The 
investigator must also immediately inform the study monitor that the code has beenbroken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the code break cards at any time in case of emergency. The investigator will 
need to provide: 
protocol number
study drug name (if available)
subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.
6.7  
Treatment exposure and compliance
The investigator must promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. The subject must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the subject. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log.
6.8  
Recommended treatment of adverse events
Based on prior clinical experience with LIK066, which was administered to more than 
200subjects at doses up to 350 mg single dose or up to 150 mg daily 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. 
Moreaggressive treatment, if required, will be performed at the discretion and direction of the 
investigator, with timely communication with the sponsor. Stopping rules (Section7.5) will 
be applied as appropriate.
Medication used totreat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.9  
Rescue medication
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6.10 
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administeredor taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation 
in the study.
7  
Study completion and discontinuation
7.1  
Study completion and post-study treatment
Eachsubject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All treated subjects should have a safety follow-up call conducted 30 days after last visit. 
Theinformation collected iskept as source documentation. All SAEs reported during this 
time period must be reported as described in Section 9.2and the Site Operations Manual. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation.
7.2  
Discontinuation of study treatment
Discontinuation of study treatment for any given subject is defined as study treatment being 
stopped earlier than defined in the protocol. 
Study treatment mustbe discontinued under the following circumstances:
Subject/guardian 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 his/her participation in the trial.
Any protocol deviation that results in a significant risk to the subject’s safety.
Pregnancy (see Section8.6Safetyand Section9.6Pregnancyreporting)
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Metabolic ketoacidosis CTCAE grade 3 or above 
Study treatment for an individual subject must be placed on hold until a joint review of the 
safety data occursfor any of the following events/findings if 1) deemed clinically moderate to 
severe, 2) puts the subject at a safety risk and 3) suspected related to study drug:
Diarrhea above grade 2 per CTCAE criteria(CTCAE 2010)anddeemed to put the subject 
at safety risk per investigator judgment
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.
SAEs
The decision to permanently discontinue treatment for any subject experiencing any of the 
above will be based on a joint full review of the clinical data by the investigator and the 
sponsor and a joint decision.
In the event a treatment code is inadvertently broken, site responsible and Novartis will 
jointly determine whether to discontinue dosing for that subject.
In the event of study drug discontinuation, the investigator must make every effort to 
determine the primary reason and record this information on the Dosage Administration CRF.
Subjects who discontinue study treatment or who no longer participate in the study should 
NOT be considered withdrawn UNLESS they withdraw their consent (Section7.3Withdraw 
of Informed Consent). Whenever possible, they should return for the EOS assessments. If they 
fail to return for these assessments for unknown reasons, the investigator should make every 
effort (e.g. telephone, e-mail, letter) to contact the subject/pre-designated contact (Section7.4, 
Lost to follow-up).
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 
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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 investigators and the sponsor will continually review adverse events and laboratory 
findings during the study.
The study must be halted, i.e. halting new enrollment and halting dosing for all subjects in 
case of hypoglycaemia CTCAE grade 3 or aboverequiring third party intervention and incase 
of grade 3 and aboveketoacidosis.
The study may be halted, i.e. halting new enrollment and halting dosing for all subjects in 
case of safety concerns that are suspected to be related to study drug, such as:
if 2 or more subjects develop diarrhea above grade 2 per CTCAE criteria and deemed to 
put the subject at safety risk per investigator judgment
if 2 or more subjects are discontinued from dosing due to safety concerns from similar 
laboratory abnormalities
one or more subjects develop a drug-relatedSAEs
The safety data will be jointly reviewed by the sponsor and investigators.  The study may be 
stopped if justifiable by the number and/or severity of adverse events, such as an increase in 
severity of known adverse events such as diarrhea (severity greater by 1 CTCAE category), or 
2or more subject develop study drug related SAE, or 1 or more subjects develop an 
unexpected and severe adverse event.The decision to stop the study must be jointly made by 
the sponsor and the investigators upon review of all available clinical data.Restart of this 
clinical trial in such case will bedocumented bya substantial amendmentand following 
approval by relevant health authorities. 
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 assoon as possible and treated as a prematurely discontinued subject. 
Theinvestigator 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 
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8  
Procedures and assessments
8.1  
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the Assessment schedule or as close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who prematurely discontinue the study for any reason should be 
scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed.At this final visit, all 
dispensed investigational product should be reconciled, and the adverse event and concomitant medications recorded on the CRF.
Table 8-1  
Assessment schedule
Epoch
Screening
Treatment
Visit Name Scre
ening
Baseline
Treatment
Visit Numbers1
1
213
10114 10214
10315
Days -44 
to -3
-1
1   8
15
Time (post-dose) -  -2h -1h  0h 0.5h 1h 1.5h 2h  3h  4h  -   -  -2h -1h  0h 0.5h 1h 1.5h 2h  3h  4h
Informed consent  
X
X
Demography
X
Alcohol Test and Drug 
Screen 2
X
Hepatitis screen2
X
HIV screen2
X
Pregnancy and 
assessments of fertility
X
X
X
Medical history/current 
medical conditions
X
X3
Concomitant medications
As needed
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Epoch
Screening
Treatment
Visit Name Scre
ening
Baseline
Treatment
Visit Numbers1
1
213
10114 10214
10315
Days -44 
to -3
-1
1   8
15
Time (post-dose) -  -2h -1h  0h 0.5h 1h 1.5h 2h  3h  4h  -   -  -2h -1h  0h 0.5h 1h 1.5h 2h  3h  4h
Physical Examination2
X4
X3
X
Blood Pressure
X5
X
X
X
Pulse rate
X5
X
X
X
Body Temperature  
X
X
X
X
Body Height
X
Body Weight
X   X
X   X
Electrocardiogram (ECG)  X
X
X
Hematology
X   X
X
Clinical Chemistry  
X6
X7
X
Urinalysis
X   X
X
Subjects domiciled2,8
X
X
Drug administration 
record
X   X
X
Drug dispensation2
X   X
X   X   X   X   X   X   X
X9
X9
X9
X10
X10
X9
X9
X9
X10
X10
X11
X12
X12
Glucose enriched test 
meal
X
X
Blood insulin and glucose
X   X   X   X   X   X   X
X   X   X   X   X   X   X
X
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Epoch
Screening
Treatment
Visit Name Scre
ening
Baseline
Treatment
Visit Numbers1
1
213
10114 10214
10315
Days -44 
to -3
-1
1   8
15
Time (post-dose) -  -2h -1h  0h 0.5h 1h 1.5h 2h  3h  4h  -   -  -2h -1h  0h 0.5h 1h 1.5h 2h  3h  4h
Adverse Events
As needed
Serious Adverse Events
As needed
Study completion 
information
Safety Follow up Call2
Comments
As needed


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Epoch  Treatment
Visit Name  
EOS
Post Study Safety 
Contact
Visit Numbers1
199
Days  
22  
Last Visit +30
Time (post-dose)  
-
-
Informed consent
Demography
Alcohol Test and Drug Screen 2
Hepatitis screen2
HIV screen2
Pregnancy and assessments of fertility
Medical history/current medical conditions
Concomitantmedications
As needed
Physical Examination2
X
Blood Pressure
X
Pulse rate
X
Body Temperature
Body Height
Body Weight
X
Electrocardiogram (ECG)
X
Hematology
Clinical Chemistry
Urinalysis
X
Subjects domiciled2,8
Drug administration record
Drug dispensation2
X11
Glucose enriched test meal
Blood insulin and glucose
Adverse Events
As needed
Serious Adverse Events
As needed
Study completion information
X
Safety Follow up Call2
X
Comments
As needed
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1Visit structure given for internal programming purpose only
2Will not be recorded in the CRF
3Should record the following in the CRF: hirsutism, acne, androgenic alopecia, acanthosis nigricans, skin tags, 
waist circumference, hip circumference, waist/hip ratio and prior history of gestational diabetes. Details in the 
SOM
4Includes Ferriman Gallwey score for hirsutism
5Sitting and standing
6Screening assessment include early morning measurement of total testosterone, free testosterone, SHBG, LH, 
FSH, prolactin, 17-OH progesterone, estradiol, DHEAS, DHEA, androstenedione, insulin and TSH
7Includes HbA1c measurement at baseline
8The night before this visit to ensure overnight fasting and early AM collection of blood samples
9Free testosterone, total testosterone, LH and FSH
10Total and free testosterone
11Progesterone
12SHBG, estradiol, progesterone, DHEAS, DHEA and androstenedione
13Baseline assessments may be completed within 7 days prior to Day 1. Some of the assessments scheduled at 
baseline may be completed when subjects are domiciled the night before as explained in the SOM.  
 
 
14
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8.2  
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject’s representative gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible 
given his/her understanding. If the subject is capable of doing so, he/she must indicate assent 
by personally signing and dating the written informed consent document or a separate assent 
form.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents.
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 relatedto optional future 
research which will require a separate signature if the subject agrees to future research.  
Theprocedures set out in the main consent form concerning the storage, maintenance of 
privacy, and release of the data or specimens for the main study will also be adhered to for 
any 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. 
Anynew 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 Section4.1
(Inclusion criteria) and in Section5.1
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(Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included 
in this study.


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8.3  
Subject screening
It is permissible to re-screen a subject if she fails the initial screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis.
All subjects will be screened for HIV, Hepatitis B and Cand substances of abuse. See the 
SOM for details.
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 will also be collected until signature 
of informed consent. Medical history should include the approximate onset of the last 
menstrual period and prior history of gestational diabetes.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
At baseline, the physical examination should includecutaneous manifestations of 
hyperandrogenism, e.g. hirsutism, acne, androgenic alopecia, as well as acanthosis nigricans 
and skin tags; baselinemeasures of body weight, waist circumference, hip circumference and 
waist/hip ratio. Detailsare outlined in the SOM.
8.6  
Safety
Safety assessments are specified below. Details,including methods for assessment and 
recording are specified in the SOM, with the Assessment schedule(Section8.1) detailing 
when each assessment is to be performed. 
Safety assessments include:
Vital signs (body temperature, blood pressure, pulse rate and body weight)
ECG evaluation
Laboratory assessments (hematology, blood chemistry and urinalysis)
Physical examination

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8.8  
Other assessments
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9  
Safety monitoring
9.1  
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject
afterproviding written informed consentfor 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 Section9.5for 
an overview of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
they induce clinical signs or symptoms,
they are considered clinically significant,
they require therapy.
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 Appendix1andAppendix2
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Adverse events should 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 Section9.2for 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 Section9.2
C
o
 
 
for definition of SA)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Information about common side effects already known about the investigational drug can be 
found in the Investigator
's Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. 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.
*Refer to the Site Operations Manual for data capture methodology regarding AE collection 
for subjects that fail screening.


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9.2  
Serious adverse event reporting
9.2.1 
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:
is fatal or life-threatening
results in persistent or significant disability/incapacity
constitutes a congenital anomaly/birth defect
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study and has not worsened since the start of study drug
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
social reasons and respite care in the absence of any deterioration in the subject’s general
condition
is medically significant, e.g. defined as an event that jeopardizes the 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 (please refer to ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to 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 
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9.2.2 
SAE reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis.
Randomized
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last 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.
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 theoriginal episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported
one must be reported separately as a new event.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure Reference Safety 
Information and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (CMO& PS) Department associate may urgently require further information 
from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN)to inform all investigators involved in any study with the same 
study treatment that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.Note: SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
9.3  
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix1for complete definitions of liver events.


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Follow-up of liver events:
Every liver event defined in Table 15-1-Appendix 1should 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-Appendix1.
Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and γ-GT) to confirm 
elevation within 48-72 hours. The central lab performing the standard blood chemistry 
assessments may alertthe investigator when such changes are observed. These liver 
chemistry repeats may be performed using the local laboratory used by the site if needed. 
Repeat laboratory test results must be reported as appropriate.
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 Section7.2(Discontinuation of study 
treatment), if appropriate
Hospitalization of the subject if appropriate
Causality assessment of the liver event
Thorough follow-up of the liver event should include
Repeating liver chemistry tests two or three times weekly. Testing should include ALT, 
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 ×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. Refer to the Site Operations Manual for additional details. 
9.4  
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2. The central lab performing the standard blood chemistry assessments may alert 
the investigator when such changes are observed. Repeats may also be performed using the 
local laboratory used by the site if needed.


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All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.5  
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF. If associated with an AE, the AE 
should be reported in the respective CRF page. Study treatment errors are only to be reported 
to Chief Medical Office and Patient Safety (CMO& PS) department if the treatment error is 
associated with an SAE.
All instances of misuse must be documented in the adverse event (AE) CRF irrespective of 
the misuse being associatedwith an AE/SAE. In addition, all instances of misuse must be 
reported to Novartis Chief Medical Office and Patient Safety (CMO& PS). As such, instances 
of misuse are also to be reported using the SAE form/CRF. 
For more information on AE and SAE definition and reporting requirements, please see 
Section9.1and Section9.2, respectively.
9.6  
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hoursof 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 (CMO& PS) 
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.


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9.7  
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Suchevaluations 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.
10  
Data review and database management
10.1 
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource or eCRFs) 
with the investigators and their staff. During the study Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
Themonitor will visit the site to check the completeness of subject records, the accuracy of 
data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and ensure that study drug is being stored, dispensed, and accounted 
for according to specifications. Key study personnel must be available to assist the monitor 
during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis or a CRO 
working on behalf of Novartis. Additionally, a central analytics organization may analyze data 
and identify risks & trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject
's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will be 
used for all primary and safety variables. Additional checks of the consistency of the source 
data with the CRFs are performed according to the study-specific monitoring plan. 
Noinformation in source documents about the identity of the subjects will be disclosed.


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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 
11requirements. 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. 
Afterdatabase 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 
Assessmentscheduleand 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.
10.3 
Database management and quality control
Corporate Confidential Information
Novartis or designated CRO staff review the data entered into the CRFs by investigational 
staff for completeness and accuracy and instruct the sitepersonnel 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 relevantprotocol 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.


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10.4 
Data Monitoring Committee
Not required.
10.5 
Adjudication Committee
Not required.
11  
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1 
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
11.2 
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group. Relevant medical history, 
current medical conditions, results of laboratory screens, drug tests and any other relevant 
information will be listed by treatment group and subject.
11.3 
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.
11.4 
Analysis of the primary variable(s)
11.4.1
Primary Variable(s)
Corporate Confidential Information
The primary efficacy endpoint will be the average of the three morning fasting free 
testosteroneconcentrations in blood.


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11.4.2
Statistical model, hypothesis, and method of analysis
The primary analysis will assess the treatment effect of LIK066 on free T at Day15. The ratio 
of Day 15 to baseline free T will be analyzed in an analysis of covariance model with 
treatment as a categorical factor and baseline free T as a covariate. Additional baseline 
characteristics that may be predictive of free T may be added to the model as covariates. 
Thelogarithm of the ratio and of baseline free T will be applied prior to the analysis.
The geometric mean of the ratio to baseline for free T will be estimated from the model for 
LIK066 and placebo, along with the treatment ratio and the associated p-value and two-sided 
90% confidence interval (CI). From these quantities, the following criteria will be assessed:
1. the upper confidence limit of the 90% CI is less than 1, and
2. the estimated treatment ratio is less than 0.75.
The first criterion addresses with high certainty whether the effect of LIK066 on free T 
reduction is superior to placebo. The second criterion addresses whether the observed 
treatment effect of LIK066 on free T reduction is at least 25%. An effect size of 20-25% on 
hyperandrogenism is considered to be clinically meaningful in PCOS as it correlates with 
improved ovulation and fertility (Harborneetal2003).
Subjects who are deemed to have hormonal evidence of ovulation during the study may be 
excluded from the primary analysis. 
11.4.3
Handling of missing values/censoring/discontinuations
The primary efficacy analysis will be based on all subjects with an evaluable baseline and 
Day 15 free T profile and that have no hormonal evidenceof ovulation during the study.
11.4.4
Sensitivity analyses
As a sensitivity analysis, the change from baseline in free T at Day 15 will be analyzed in an 
analysis of covariance model of the same form as the one specified for the primary analysis, 
except no logarithmic transformation will be applied. The least-squares mean change from 
baseline will be estimated from the model for LIK066 and placebo, along with the treatment 
difference and the associated p-value and two-sided 90% confidence interval.
11.5 
Analysis of secondary variable(s)
The secondary variables will be the gonadotropins (LH and FSH), the sex steroids (total 
testosterone, estradiol, progesterone, DHEAS, DHEA, androstenedione), SHBG, andfree 
androgen index. For LH, FSH, and total testosterone, the average of the three morning fasting 
concentrations will be additional secondary variables. 
11.5.1
Efficacy / Pharmacodynamics
Each of the secondary variables will be listed by treatment group, subject, and visit/time and 
summarized by treatment and visit/time. The change from baseline and % change from 
baseline will also be listed and summarized.


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11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
Corporate Confidential Information
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a bodysystem is only counted once towards the total of this body system.
Corporate Confidential Information


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11.5.5
Other assessments
Corporate Confidential Information
Not Applicable.
Corporate Confidential Information


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11.7 
Sample size calculation
The sample size for this study has been based on a relevant interventional study in a similar 
population ofadults with PCOS (Georgeetal2016). The mean and standard deviation of free 
T by LC-MS/MS in this study, as a pooled estimate across all treatment arms at baseline, is 
79pmol/L and 40 pmol/L, respectively. The study reported a decrease in free T of 19% after 
7days of treatment with AZD4901, a neurokinin B receptor antagonist.
The sample size calculation assumes similar baseline characteristics of free T, a 2% reduction 
in free T in the placebo arm, and a correlation between baseline and Day 14 free T of 0.5. 
Theassumption also is that the true treatment effect ofLIK066 is 35% over placebo. 
We choose to assume a correlation between baseline and Day 15 of 0.5 because, based on 
results of freeT in a published study of metformin in women with PCOS 
(Kurzthaleretal2014), we believe it to be smaller than the true correlation, and hence it is 
likely that the power for achieving the primary study criteria is conservative.
Based on these assumptions, a sample size of 24 subjects in a 1:1 treatment allocation (12 on 
LIK066; 12 on placebo) will provide 80% probability of achieving the dual criteria specified 
in the previous section. The probability of a type I error (achieving the criteria when in fact 
there is no true treatment effect on free T) is 5%. These results are based on 10,000 
simulations of the primary analysis.
11.8 
Power for analysis of key secondary variables
Not Applicable.
12  
Ethical considerations
12.1 
Regulatory and ethical compliance
Corporate Confidential Information
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.


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12.2 
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatoryfor 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.
12.4 
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignmentof roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.


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13  
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
13.1 
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding theneed 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 Section9(Safety Monitoring) must be followed and the Study Lead 
informed.


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14  
References
References are available upon request.
BarthJH,FieldHP,YasminE,et al(2009) Defining hyperandrogenism in polycystic ovary 
syndrome: measurement of testosterone and androstenedione by liquid chromatography–
tandem mass spectrometry and analysis by receiver operator characteristic plots. Eur J 
Endocrinol;162:611-615.
CTCAE (2010) Common Terminology Criteria for Adverse Events v4.03 (Internet). Available 
from: http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 31 March 2017).
DeMedeiros SF, Yamamoto MMW, de-Medeiros MAS, et al (2017)Should Subclinical 
Hypothyroidism Be an Exclusion Criterion for the Diagnosis of Polycystic Ovary 
Syndrome?Journal of Reproduction & Infertility;18(2):242-250.
Dunaif A, Segal KR, Futterweit W, et al (1989) Profound peripheral insulin resistance, 
independent of obesity, in polycystic ovary syndrome. Diabetes;1165-74.
Escobar-Morreale HF, Carmina E, Dewailly D,et al (2012)Epidemiology, diagnosis and 
management of hirsutism: a consensus statement by the Androgen Excess and Polycystic 
Ovary Syndrome Society,Human Reproduction Update;18(2):146–170.
FerrimanD, GallweyJD (1961) Clinical assessment of body hair growth in women. J Clin 
Endocrinol Metab;1440-7.
George JT, Kakkar R, Marshall J, et al (2016) Neurokinin B Receptor antagonism in women 
with Polycystic Ovary Syndrome: A randomized, placebo-controlled trial. J Clin Endocrinol 
Metab;4313-4321.
Harborne L, Fleming R, Lyall H, et al (2003) Descriptive review of the evidence for the use of 
metformin in polycystic ovary syndrome. Lancet; 1894-901.
Kalra S (2014) Sodium Glucose Co-Transporter-2 (SGLT2) inhibitors: A review of their basic 
and clinical pharmacology. Diabetes Ther;355-66.
Kurzthaler D, Hadziomerovic-Pekic D, Wildt L, et al (2014) Metformin induces a prompt 
decrease in LH-stimulated testosterone response in women with PCOS independent ofits 
insulin-sensitizing effects. Reprod Biol Endocrinol;98.
Legro RS, Arslanian SA, Ehrmann DA, et al (2013) Diagnosis and treatment of polycystic 
ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab;
4565-92.
NCT02635386: DAPA, EQW, DAPA/MET ER and PHEN/TPM ER in obese women with
PolycysticOvary Syndrome (PCOS).Available from: 
https://www.clinicaltrials.gov/ct2/show/NCT02635386?term=PCOS&type=Intr&intr=dapagli
flozin&rank=1 (Accessed 31 March 2017).
Nestler JE, Barlascini CO, Matt DW, et al (1989) Suppression of serum insulin by diazoxide 
reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin 
Endocrinol Metab;1027-32.


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Nestler JE, Singh R, Matt DW, et al (1990) Suppression of serum insulin level by diazoxide 
does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese 
women. Am J Obstet Gynecol;1243-6.
Pernicova I, Korbonits M (2014) Metformin-mode of action and clinical implications for 
diabetes and cancer. Nat Rev Endocrinol;143-56.
Rosenfield RL, Ehrmann DA (2016) The pathogenesis ofPolycystic Ovary Syndrome 
(PCOS): The Hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr 
Rev; 467-520.
Sands AT, Zambrowicz BP,Rosenstock J, et al (2015) Sotagliflozin, a dual SGLT1 and 
SGLT2 inhibitor, as adjunct therapy to insulin in Type 1 diabetes. Diabetes Care;1181-8.
Sirmans SM, Pate KA (2013) Epidemiology, diagnosis, and management of Polycystic Ovary 
Syndrome. Clin Epidemiol;1-13.


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


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Table 15-2  
Actions required for Liver Events
Criteria
Action required
Potential Hy’s Law case
Discontinue the study treatment immediately
Hospitalize, if clinically appropriate
Establish causality
Complete CRFs per liver event guidance*
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 × 
ULN
If confirmed, consider interruption or discontinuation of 
study drug 
If elevation persists for more than 2 weeks, 
discontinue the study drug
Establish causality
Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to ≤ 5 × 
ULN (patient is asymptomatic)
Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation
Repeat liver chemistry tests within 48-72 hours
If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality
Complete CRFs per liver event guidance*
Any AE potentially indicative of liver toxicity
Consider study treatment interruption or 
discontinuation 
Hospitalize if clinically appropriate
Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual
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 orMRI
Hypoxic/ischemic hepatopathy  
Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease
Caeruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin deficiency  
Alpha-1-antitrypsin


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


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

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LIK066
CLIK066X2205
A randomized, subject-and investigator-blinded,
placebo-controlledpharmacodynamic study of oral LIK066
in overweight and obese women with polycystic ovary 
syndrome
Statistical Analysis Plan (SAP)
Document type:  
SAP Documentation –NIBR 
Document status: Final
Release date:   
03-October-2017
Number of pages: 14
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May not be used, divulged, published or otherwise disclosed
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Table of contents
Table of contents.................................................................................................................3
List of tables........................................................................................................................4
List of figures......................................................................................................................4
1 Introduction.........................................................................................................................5
1.1 Scope of document..................................................................................................5
1.2 Study reference documentation...............................................................................5
1.3 Study objectives.......................................................................................................5
1.3.1. Primary objective(s).......................................................................................5
1.3.2. Secondary objective(s)...................................................................................5
1.4 Study design and treatment......................................................................................6
2 First interpretable results (FIR)...........................................................................................7
4 Statistical methods: Analysis sets........................................................................................8
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
6.2 Secondary objectives.............................................................................................11
6.2.1 
Variables...............................................................................................11
6.2.2 
Descriptive analyses..............................................................................11
6.2.3 
Statistical model, assumptions and hypotheses.....................................12
7 Statistical methods for safety and tolerability data............................................................13
7.1 Variables................................................................................................................13
7.2 Descriptive analyses..............................................................................................
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10 Reference list.....................................................................................................................14
List of tables
Table 4-1   
Protocol deviation codes and analysis sets..............................................9
List of figures
Figure 1-1                   Study design............................................................................................7


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1  
Introduction 
1.1  
Scopeof document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLIK066X2205”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2  
Study reference documentation
Draft amended study protocol (v01) is available at the time of finalization of Statistical 
Analysis Plan.
1.3  
Study objectives
The purpose of the study is to evaluate whether LIK066 can be developed for the treatment of 
polycystic ovary syndrome (PCOS) in overweight and obese women.
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives
To assess the treatment effect of 
LIK066 on hyperandrogenism at 
Day 15 in overweight and obese 
subjects with PCOS
Change in average morning fasting free 
testosterone blood concentrations from 
baseline to Day 15
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objectives
To assess the safety and tolerability 
of LIK066 in overweight and obese 
subjects with PCOS throughout the 
study.
Adverse events throughout the study, 
serum electrolytes and hematocrit on 
Day 15
To evaluate the treatment effect of 
LIK066 on gonadotropins and sex 
steroid levels on Day 15
LH, FSH, SHBG, androstenedione, 
DHEA, DHEAS, Total testosterone, 
free androgen index (FAI)


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1.4  
Study design and treatment
This is a randomized, subject-and investigator-blinded, placebo-controlled, parallel group, 
non-confirmatory study in overweight and obese polycystic ovary syndrome (PCOS) subjects.
Approximately 24 subjects will be randomized in a 1:1 ratio to LIK066 or placeboand be 
assigned to one of the following 2 treatment arms:
LIK066 50 mg three times daily; before breakfast, lunch and dinner (12 subjects).

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Matching placebo tablets three times daily; before breakfast, lunch and dinner (12 
subjects).
Discontinued subjects may be replaced. If more than 2 subjects experience menstrual bleeding 
during the study, additional subjects may be enrolled to account for those subjects in case they 
are excluded from the pharmacodynamic analysis set (if ovulation is confirmed based on 


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progesterone assessment). The number of enrolled subjects; excluding replacements, should 
not exceed 30.
As it can be seen fromFigure 1-1, the treatment period is 2 weeks; dosing is oral, just before 
meals, 50 mg of LIK066 or matching placebo t.i.d. for 14 days and only one dose in the 
morning on Day 15.
Figure 1-1Study design
2  
First interpretable results (FIR)
First interpretable results (FIR) willbe provided for this trial.
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4  
Statistical methods: Analysis sets
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For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
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 with relevant impact on PK data.


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The PD analysis set will include all subjects with any availablePD data, who received any 
study drugand 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 analysis in case of these PDs:
Exclude subject from PD 
analysis set
Subjects are excluded from      PD analysis in case of these 
Protocol deviations:
Exclude subject from   
 PD analysis sets
INCL03
Deviation from inclusion criterion 2
EXCL04
Deviation from exclusion criterion 4
EXCL06
Deviation from exclusion criterion 6
COMD01   
Use of prohibited medication during the study
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If updates to this table are needed,anamendment tothe SAP needs tobe implemented priorto
DBL.
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6  
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the primary PD analysis set will be included in the PD data analysis, 
unless otherwise stated.
6.1  
Primary objective
The primary aim of this study is to assess the treatment effect of LIK066 on 
hyperandrogenism at Day 15 in overweight and obese subjects with PCOS.
6.1.1 
Variables 
The primary efficacy endpoint will be the average of the three-morning fasting free 
testosterone concentrations in blood from baseline to Day 15.
6.1.2 
Descriptive analyses
The average of the three-morning fasting free testosterone concentrations in blood will be 
listed by treatmentgroup, patient and visit/timeand descriptive statistics will be provided by 
treatment and visit/time. Summary statistics will include mean (arithmetic and geometric), SD, 
CV (arithmetic and geometric), median, minimum and maximum as appropriate. Summary 
statistics will be also provided for the two post dose measurements of the free testosterone 
concentrations (at 2h and 4h).
Graphical methods will be employed to show group and individual summary plots over time 
by treatment.
6.1.3 
Statistical model, assumptions and hypotheses
The primary analysis will assess the treatment effect of LIK066 on free testosterone (T) at 
Day 15. 
The ratio of Day 15 to baseline free T will be analyzed in an analysis of covariancemodel,
with treatment as a categorical factor, baseline body weightand baseline free T as a covariate. 
Additional baseline characteristics that may be predictive of free T may be added to the model 
as covariates. The logarithm of the ratio and of baseline free T will be applied prior to the 
analysis.
The geometric mean of the ratio to baseline for free T will be estimated from the model for 
LIK066 and placebo, along with the treatment ratio and the associated p-value and two-sided 
90% confidence interval (CI). From these quantities, the following criteria will be assessed:
1. the upper confidence limit of the 90% CI is less than 1, and
2. the estimated treatment ratio is less than 0.75.
The first criterion addresses with high certainty whether the effect of LIK066 on free T 
reduction is superior to placebo. The second criterion addresses whether the observed 
treatment effect of LIK066 on free T reduction is at least 25%. An effect size of 20-25% on 
hyperandrogenism is considered to be clinically meaningful in PCOS as it correlates with 
improved ovulation and fertility (Harborne et al 2003).


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Subjects who are deemed to have hormonal evidence of ovulation during the study may be 
excluded from the primary analysis.
6.1.3.1 Handling of missing values/censoring/discontinuations
The primary efficacy analysis will be based on all subjects with an evaluable baseline and 
Day 15 free T profile whohave no hormonal evidence of ovulation during the study.If one or 
two of the three morning measurement are missing, the average of observed measurements 
will be used. If all are missing, there will be no imputation of the missing data. 
6.1.3.2 Sensitivity analyses
As a sensitivity analysis, the change from baseline in free T at Day 15 will be analyzed in an 
analysis of covariance model of the same form as the one specified for the primary analysis, 
except no logarithmic transformation will be applied. The least-squares mean change from 
baseline will be estimated from the model for LIK066 and placebo, along with the treatment 
difference and the associated p-value and two-sided 90% confidence interval.
6.2  
Secondary objectives
6.2.1 
Variables 
The secondary PD variables of this study are:
gonadotropins (LH and FSH)
the sex steroids (total testosterone, estradiol, progesterone, DHEAS, DHEA, 
androstenedione)
SHBG
Free androgen index
For LH, FSH, and total testosterone, the average of the three morning fasting 
concentrations at baseline and day 15 will be used assecondary variables.
Baseline for all secondary parameters is defined asthelast pre-dosing measurement at 
baseline or screening if baseline measurement is missing.
6.2.2 
Descriptive analyses
Secondaryvariables will be listed by treatment group, subject, and visit/time and summarized 
by treatment and visit/time. The change from baseline and percentage(%) change from 
baseline will also be listed and summarized.Summary statistics will be provided by treatment 
and visit/time and will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, maximum asappropriate. In the summary tables, the 
frequency (n, %) of values below the LLOQ and above the ULOQ, respectively, will be 
included. To ensure that each biomarker only has numerical values, censored values will be 
imputed as:
Values below LLOQ will be replaced by LLOQ/2.
Values above the ULOQ will be replaced by ULOQ.
Imputed values will be used in descriptive summary, inferential analyses and plots.


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6.2.3 
Statistical model, assumptions and hypotheses
Theratio of Day 15 to baseline will be analyzed in an analysis of covariance model with 
treatment as a categorical factor and baseline as a covariate. The logarithm of the ratio and of 
baseline will be applied prior to the analysis. The geometric mean of the ratio to baseline will 
be estimated from the model for LIK066 and placebo, along with the treatment ratio and the 
associated p-value and two-sided 90% confidence interval.
6.2.3.1 Graphical presentation of results
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Graphical methods will be employed to show group summary plots over time by treatment as 
required.


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7  
Statistical methods for safety and tolerability data
All subjects within the Safety analysis set will be included in the safety data analysis.
7.1  
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.2  
Descriptive analyses
Subject demographics and other baseline characteristics
All data forbackground and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed bytreatment group and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group andsubject.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
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All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.


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Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment andsubject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body systemand treatment.
Immunogenicity
Not applicable.
10  
Reference list
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Harborne L, Fleming R, Lyall H, et al. (2003) Descriptive review of the evidence for the use 
of metformin in polycystic ovary syndrome. Lancet; 1894-901.