Conditions: Diabetes Mellitus and Heart Failure
Keywords: Diabetes mellitus LIK066 Obesity Type 2 diabetes mellitus (T2DM) Heart Failure (HF) Hypertension Renal dysfunction Adult-onset diabetes Noninsulin-dependent diabetes mellitus (NIDDM) High blood sugar
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 125
Healthy volunteers: no

Brief summary:
This was a dose-finding study to evaluate the efficacy, safety and tolerability of 3 different doses of LIK066 compared to placebo or empagliflozin in T2DM patients with heart failure

Detailed description:
The study was prematurely discontinued on 04-May-2018 due to slow enrollment that would preclude obtaining study results in a timely manner.

Arms:
arm 1: Eligible participants randomized to this treatment arm received the LIK066 2.5mg dose regimen once daily for 36 weeks. arm 2: Eligible participants randomized to this treatment arm received the LIK066 10mg dose regimen once daily for 36 weeks. arm 3: Eligible participants randomized to this treatment arm received the LIK066 50mg dose regimen once daily for 36 weeks. arm 4: Participants randomized to this treatment arm received empagliflozin once daily for 36 weeks. arm 5: Participants randomized to this treatment arm received LIK066 matching placebo and empagliflozin matching placebo.

Interventions: intervention 1: LIK066 intervention 2: Placebo intervention 3: Empagliflozin
Intervention descriptions: intervention 1: LIK066 was supplied in different doses as tablets taken orally. intervention 2: Placebo was supplied as tablets and capsules taken orally. intervention 3: Empagliflozin was supplied as capsules taken orally.

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
LIK066 
Clinical Trial Protocol CLIK066B2204 / NCT03152552 
A multi-center, randomized, double-blind, parallel-group 
dose-finding study to assess the effect of 3 doses of 
LIK066 compared to placebo or empagliflozin in type 2 
diabetes mellitus patients with heart failure 
Document type: 
Clinical Trial Protocol Amendment 
EUDRACT number: 
2016-003084-19 
Version number: 
v02 (clean) 
Clinical trial phase: 
IIa 
Release date: 
04-Feb-2018
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.1 (February 2016) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Amendment 2 ........................................................................................................................... 10 
Amendment 1 ........................................................................................................................... 12 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 19 
1.1 
Background ............................................................................................................ 19 
1.2 
Purpose .................................................................................................................. 20 
2 
Study objectives and endpoints ......................................................................................... 20 
2.1 
Primary objective ................................................................................................... 20 
2.2 
Secondary objectives ............................................................................................. 20 
 
 21 
3 
Investigational plan ........................................................................................................... 21 
3.1 
Study design........................................................................................................... 21 
3.1.1 
Epoch 1 (screening) ............................................................................... 21 
3.1.2 
Epoch 2 (placebo run-in) ....................................................................... 22 
3.1.3 
Epoch 3 (treatment) ............................................................................... 22 
3.1.4 
Epoch 4 (treatment) ............................................................................... 23 
3.2 
Rationale for study design ..................................................................................... 23 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 24 
3.4 
Rationale for choice of comparator ....................................................................... 24 
3.5 
Purpose and timing of interim analysis ................................................................. 25 
3.6 
Risks and benefits .................................................................................................. 25 
4 
Population .......................................................................................................................... 27 
4.1 
Inclusion criteria .................................................................................................... 27 
4.2 
Exclusion criteria ................................................................................................... 27 
5 
Treatment ........................................................................................................................... 30 
5.1 
Study treatment ...................................................................................................... 30 
5.1.1 
Investigational and control drugs .......................................................... 30 
5.1.2 
Additional treatment .............................................................................. 31 
5.2 
Treatment arms ...................................................................................................... 31 
5.3 
Treatment assignment and randomization ............................................................. 31 


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5.4 
Treatment blinding ................................................................................................. 32 
5.5 
Treating the patient ................................................................................................ 33 
5.5.1 
Patient numbering ................................................................................. 33 
5.5.2 
Dispensing the study drug ..................................................................... 33 
5.5.3 
Handling of study and additional treatment .......................................... 33 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 34 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 34 
5.5.6 
Rescue medication ................................................................................ 34 
5.5.7 
Concomitant medication ....................................................................... 35 
5.5.8 
Prohibited medication ........................................................................... 35 
5.5.9 
Emergency breaking of assigned treatment code .................................. 36 
5.6 
Study completion and discontinuation ................................................................... 37 
5.6.1 
Study completion and post-study treatment .......................................... 37 
5.6.2 
Discontinuation of study treatment ....................................................... 37 
5.6.3 
Withdrawal of informed consent ........................................................... 38 
5.6.4 
Lost to follow-up ................................................................................... 38 
5.6.5 
Early study termination by the sponsor ................................................. 39 
6 
Visit schedule and assessments ......................................................................................... 39 
6.1 
Information to be collected on pre-screening failures or screening failures ......... 44 
6.2 
Patient demographics/other BL characteristics ..................................................... 44 
6.3 
Treatment exposure and compliance ..................................................................... 44 
6.4 
Efficacy .................................................................................................................. 45 
6.4.1 
Weight and height ................................................................................. 45 
6.4.2 
NT-proBNP ........................................................................................... 45 
6.4.3 
Body composition ................................................................................. 45 
 
 46 
6.4.5 
Echocardiography ................................................................................. 46 
6.4.6 
HbA1c ................................................................................................... 46 
6.4.7 
FPG ....................................................................................................... 46 
6.4.8 
Blood pressure (BP) .............................................................................. 47 
6.4.9 
Fasting lipid profile ............................................................................... 47 
6.4.10 
24h urine collection ............................................................................... 48 
6.4.11 
Appropriateness of efficacy assessments .............................................. 48 
6.5 
Safety ..................................................................................................................... 48 
6.5.1 
Physical examination ............................................................................ 48 
6.5.2 
Vital signs.............................................................................................. 49 


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6.5.3 
Laboratory evaluations .......................................................................... 49 
6.5.4 
ECG ....................................................................................................... 50 
6.5.5 
Bone mineral density (BMD) ................................................................ 51 
6.5.6 
Pregnancy and assessments of fertility ................................................. 51 
6.5.7 
Appropriateness of safety measurements .............................................. 51 
6.6 
Other assessments .................................................................................................. 51 
 
 51 
6.6.2 
Resource utilization ............................................................................... 53 
 
 53 
7 
Safety monitoring .............................................................................................................. 54 
7.1 
Adverse events ....................................................................................................... 54 
7.2 
Serious adverse events ........................................................................................... 56 
7.2.1 
Definition of SAE ................................................................................. 56 
7.2.2 
SAE reporting........................................................................................ 56 
7.3 
Liver safety monitoring ......................................................................................... 57 
7.4 
Renal safety monitoring ......................................................................................... 58 
7.5 
Reporting of study treatment errors including misuse/abuse ................................ 59 
7.6 
Pregnancy reporting ............................................................................................... 59 
7.7 
Prospective suicidality assessment ........................................................................ 59 
7.8 
AEs of special interest ........................................................................................... 60 
7.8.1 
Ketoacidosis .......................................................................................... 60 
7.8.2 
Hypoglycemia ....................................................................................... 60 
8 
Data review and database management ............................................................................. 61 
8.1 
Site monitoring ...................................................................................................... 61 
8.2 
Data collection ....................................................................................................... 62 
8.3 
Database management and quality control ............................................................ 62 
8.4 
Data Monitoring Committee .................................................................................. 63 
8.5 
Adjudication Committee ........................................................................................ 63 
9 
Data analysis ...................................................................................................................... 63 
9.1 
Analysis sets .......................................................................................................... 63 
9.2 
Patient demographics and other baseline characteristics ....................................... 64 
9.3 
Treatments ............................................................................................................. 64 
9.4 
Analysis of the primary variable(s) ....................................................................... 65 
9.4.1 
Variable(s) ............................................................................................. 65 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 65 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 67 


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9.4.4 
Supportive analyses ............................................................................... 67 
9.5 
Analysis of secondary variables ............................................................................ 68 
9.5.1 
Efficacy variables .................................................................................. 68 
9.5.2 
Safety variables ..................................................................................... 71 
 
 71 
9.5.4 
DNA ...................................................................................................... 71 
 
 71 
 
 72 
 
 72 
 
 72 
9.7 
Interim analyses ..................................................................................................... 74 
9.8 
Sample size calculation .......................................................................................... 74 
10 Ethical considerations ........................................................................................................ 75 
10.1 
Regulatory and ethical compliance ........................................................................ 75 
10.2 
Informed consent procedures ................................................................................. 75 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 76 
10.4 
Publication of study protocol and results............................................................... 76 
10.5 
Quality Control and Quality Assurance ................................................................. 76 
11 Protocol adherence ............................................................................................................ 77 
11.1 
Protocol amendments ............................................................................................. 77 
12 References ......................................................................................................................... 78 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 80 
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ..................................................................................................................... 81 
15 Appendix 3: Specific Renal Alert Criteria and Actions .................................................... 83 
 
List of tables 
Table 5-1 
Rescue criteria for FPG or HbA1c ........................................................ 35 
Table 5-2 
Prohibited medication ........................................................................... 36 
Table 6-1 
Assessment schedule ............................................................................. 40 
Table 6-2 
Fasting lipid profile & TG, hs-CRP ...................................................... 48 
Table 6-3 
Hematology evaluations ........................................................................ 49 
Table 6-4 
Clinical chemistry ................................................................................. 49 
Table 6-5 
Urinalysis .............................................................................................. 50 
Table 6-6 
Biomarkers ............................................................................................ 50 


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Table 7-1  
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 59 
Table 9-1 
Power for detecting a significant dose response signal* ....................... 74 
Table 9-2 
Comparison of LIK versus placebo (at 2-sided alpha of 0.05) ............. 75 
Table 9-3 
Comparison of LIK versus empagliflozin ............................................. 75 
Table 13-1 
Vital signs notable range deviations ..................................................... 80 
Table 14-1 
Liver Event and Laboratory Trigger Definitions .................................. 81 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 81 
Table 15-1 
Specific Renal Alert Criteria and Actions ............................................. 83 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 22 
Figure 9-1 
Dose-response curve of candidate models ............................................ 66 
 


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List of abbreviations 
ACE(i) 
Angiotensin converting enzyme (inhibitor) 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin II receptor blocker 
ARNi 
Angiotensin receptor/neprilysin inhibitor 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BL 
Baseline 
BMI 
Body-mass index 
BMD 
Bone mineral density 
BP 
Blood pressure 
CFR 
US Code of Federal Regulations  
CHF 
Chronic heart failure 
CRF 
Case report/record form (paper or electronic) 
CPO 
Country pharma organization 
CRO 
Contract research organization 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBP 
Diastolic blood pressure 
DXA 
Dual-energy x-ray absorptiometry 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
 
 
FAS 
Full analysis set 
FDA 
Food & Drug Administration 
FPG 
Fasting plasma glucose 
GCP 
Good clinical practice 
(e)GFR 
(Estimated) glomerular filtration rate 
GI 
Gastrointestinal 
HbA1c 
Glycated hemoglobin  
HDL 
High-density lipoprotein 
HF 
Heart failure 
HFpEF 
Heart failure with preserved ejection fraction 
HFrEF 
Heart failure with reduced ejection fraction 
IB 
Investigator brochure 
ICD 
Implantable cardioverter defibrillator 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IN 
Investigator notification 


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IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
 
 
(V)LDL 
(Very) low-density lipoprotein 
LFT 
Liver function test  
LVEF 
Left ventricular ejection fraction 
MACE 
Major cardiovascular events 
MAR 
Missing at random 
MI 
Myocardial infarction 
MMRM 
Model of repeated measures 
MRA 
Mineralcorticoid receptor antagonist 
NOAEL 
No observed adverse effect level 
NYHA 
New York Heart Association 
OAD 
Anti-diabetic drug 
OC/RDC 
Oracle Clinical/Remote Data Capture  
PCI 
Percutaneous coronary intervention 
 
 
 
 
PPD 
Premature patient discontinuation 
PPS 
Per protocol set 
(e)PRO 
(Electronic) patient reported outcomes 
 
 
RAN 
Randomized set 
RBC 
Red blood cell (count) 
RR 
Relative reduction 
SAE 
Serious adverse event 
SAF 
Safety set 
SBP 
Systolic blood pressure 
SCR 
Screened set 
SD 
Standard deviation 
SGLT(i) 
Sodium-glucose co-transporter (inhibitor) 
SU 
Sulfonylurea 
T2DM 
Type 2 diabetes mellitus 
TG 
Triglyceride 
TD 
Study treatment discontinuation 
TSH 
Thyroid-stimulating hormone 
UACR 
Urine albumin-to-creatinine ratio 
UGE 
Urinary glucose excretion 
ULN 
Upper limit of normal 
UTI 
Urinary tract infection 
WBC 
White blood cell (count) 
WHO 
World Health Organization  


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Glossary of terms 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of patient entry into the study at which study informed 
consent must be obtained (e.g. prior to starting any of the procedures 
described in the protocol) 
Epoch 
 
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Medication pack number 
A unique identifier on the label of each investigational drug package 
Patient ID  
A unique number assigned to each patient upon signing the informed 
consent  
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation (TD) 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study 
Withdrawal of consent  
Withdrawal of consent from the study is defined as when a patient 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
biologic material 
 
 
 


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Amendment 2 
Amendment rationale 
The protocol is being amended to provide the option for patients to be pre-screened for certain 
laboratory parameters (NT-proBNP, HbA1c, eGFR, serum potassium) assessed by the central 
laboratory before patients enter the study at screening (Visit 1). This measure is expected to 
significantly decrease the number of screen failure patients which will reduce the burden on 
many patients, who otherwise have to undergo the full range of screening assessments but do 
not qualify for the study.  
In addition, sites are allowed to use their own weight scales in case where patients exceed the 
weight limits of the bio-impedance/weight scales provided by the sponsor. 
It was clarified that if an echocardiography LVEF result from Visit 101 (placebo run-in) 
assessed by central reading is not available in time for randomization and stratification at V201, 
the echocardiography from Visit 101 can also be read locally by a cardiologist so the most 
recent LVEF result can be used for stratification. 
It was also clarified that, as different calibrated models of the bio-impedance scales are being 
provided by the sponsor (according to availability in different countries), not all body 
composition parameters can be assessed by all bio-impedance scale models.  
Changes to the protocol 
In Section 3.1 the option for pre-screening was added and the process explained. 
Figure 3-1 was updated to include the optional pre-screening into the study design. 
In Section 3.1.3 local reading of the V101 echocardiography by a local cardiologist was allowed 
to obtain LVEF result for stratification.  
In Section 4 the expected number of participating centers was updated. 
In Section 4.2 it was clarified that the time point for excluding atrial fibrillation is Visit 1. 
Section 5.5.1 , Table 6-1  and Section 6.1 were updated to reflect optional pre-screening. 
In Section 6.4.1 it was clarified that in exceptional cases sites can use their own scales for weight 
measurements.  
In Section 6.4.2 it was clarified that NT-proBNP measurements do not require fasting blood 
samples. 
In Section 6.4.3 it was clarified that not all body composition parameters can be assessed by all 
models of bio-impedance scales used in this study. 
In Section 6.4.8 it was clarified that the mean of the three sitting BP readings at V201 will be 
used to assess eligibility for the study. 
Section 7.1 and Section 7.2.2 were updated to clarify that from patients attending the pre-
screening, certain SAEs will be collected after the patients have signed the pre-screening 
informed consent form. 


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Throughout the protocol amendment it was clarified whether the term “informed consent/ICF” 
refers to the pre-screening informed consent, to the study informed consent or to both. 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
Changes described in this amended protocol are substantial and require IRB/IEC approval prior 
to implementation. 
 


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Amendment 1 
Amendment rationale 
The protocol was amended to provide information related to a new risk identified from data of 
the SGLT-2 inhibitor canagliflozin where more cases of lower limb amputations (mainly of the 
toe) have been observed in the canagliflozin group compared to the placebo group. No lower 
limb amputations have been seen in LIK066 studies, but this risk could constitute a possible 
class-effect. Patients with a history of lower limb amputation or with diabetic foot ulcer are 
excluded from enrollment into the study.   
In addition, the inclusion criterion for NT-proBNP has been lowered from >400 to >300 pg/mL.  
When designing initially the study protocol, a NT-proBNP value of >400 pg/mL was selected 
to make a patient eligible for the study. This was based on the experience and results from the 
PARAMOUNT study, which included patients with chronic HF and preserved left ventricular 
ejection fraction (LVEF) (Solomon et al, 2012). Based on more recent guidelines defining 
patients with preserved LVEF by NT-proBNP >125 pg/mL, (Ponikowski et al, 2016), the NT-
proBNP value to qualify patients for this study was changed to >300 pg/mL, as this cut-off has 
a robust predictive value to identify chronic HF patients with preserved LVEF (Bay et al, 2003). 
The inclusion criterion for serum potassium has been changed from ≤ 5.2mM to ≤ 5.3mM in 
order to be in line with the reference range used by the Central laboratory in this study. 
The HbA1c inclusion criterion has been modified from 7.0% - 10.0% to 6.5% - 10.0% in order 
to allow for exploration of LIK066 effects in the group of patients with HbA1c 6.5% - 7.0%.   
For safety reasons, patients with any history of ketoacidosis, lactic acidosis, or hyperosmolar 
coma are excluded from enrollment into the study.   
Furthermore, some minor changes and corrections of inconsistencies and typographical errors 
have been done. 
Changes to the protocol 
Section 3.1 has been amended regarding the duration of Epoch 1 and Epoch 2, as these epochs 
are now approximately 2 weeks. Also clarification with regards to missing LVEF results at 
randomization has been added, to also allow previous LVEF results for stratification; this was 
also updated in several other sections of the protocol. In addition, examples have been provided 
under which circumstances laboratory re-tests can be done. 
Section 3.6 has been updated to add a newly identified risk (lower limb amputation) observed 
with the SGLT-2 inhibitor canagliflozin and preventive measures are provided; this was also 
updated in other sections of the protocol (e.g. Section 6.5.1). 
In Section 4 the number of expected study centers was updated. 
In Section 4.1 the inclusion criterion for NT-proBNP was changed from 400 to 300 pg/mL, for 
serum potassium from ≤ 5.2mM to ≤ 5.3mM and for HbA1c from 7.0% - 10.0% to 6.5% - 
10.0%. 
Section 4.2 was changed to also exclude any history of ketoacidosis, lactic acidosis or 
hyperosmolar coma. Furthermore, a typo was corrected with regards to the units for 


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hemoglobin, and in addition history of lower limb amputation and diabetic foot ulcer were 
added to the exclusion criteria. 
Section 5.5.4 was updated to clarify the time point when patients should take their medication 
on study visit days. 
In Section 5.6.2 diabetic foot ulcer and lower limb amputation were added as conditions when 
study treatment has to be discontinued. It was also clarified, that patients who discontinue study 
medication during Epoch 3 should be followed-up until they discontinue the study at the end of 
Epoch 3. 
Table 6-1 was revised to clarify the time when the first glycemia diary has to be dispensed to 
the patients and also to clarify when the diaries will be reviewed. 
In Section 6.4.1 it is explained, that indoor clothing is also acceptable for weight measurements. 
Section 6.4.2 was corrected to state that NT-proBNP results will be blinded after randomization. 
In Section 6.4.7 the definition of overnight fast was updated.  
Section 6.4.8 has been amended to clarify that also BP devices can be used, which are not 
automated electronic BP devices and also to clarify the order of assessments. 
Sections 6.4.10 and Table 6-6 have been amended to update the renal biomarker parameters 
measured by the central laboratory.   
In Section 6.5.3.3 it was explained that urine dipstick for hematuria can be re-tested. 
In Section 6.5.5 it was clarified that 3 DXA scans are needed for BMD.  
In Section 7.8.2 some corrections and explanations for the use and the dispensation of the 
glycemia study diary were provided. 
In Section 9 some minor clarifications and corrections were done with regards to the data 
analysis. 
 
 


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Protocol summary 
Protocol number 
CLIK066B2204 
Title 
A multi-center, randomized, double-blind, parallel-group dose-
finding study to assess the effect of 3 doses of LIK066 compared to 
placebo or empagliflozin in type 2 diabetes mellitus patients with 
heart failure 
Brief title 
 
A dose finding study to assess the effect of LIK066 compared to 
placebo or empagliflozin in patients with type 2 diabetes mellitus 
and  heart failure  
Sponsor and Clinical 
Phase 
Novartis, Phase 2a  
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale Evaluate the efficacy, safety and tolerability of LIK066 in T2DM 
patients with cardiac disease and HF to help inform decisions on 
further development of LIK066 
Primary Objective(s)  
To determine the dose-response signal and assess the dose-response 
relationship of three dose regimens of LIK066 as measured by the 
change from baseline (BL) in NT-proBNP relative to placebo after 
12 weeks of treatment in T2DM patients with HF 
Secondary Objectives 
1. To evaluate the effect of all LIK066 doses vs placebo at 12 weeks 
and 36 weeks on: 
• Change from BL in glycated hemoglobin (HbA1c) 
• Change from BL in fasting plasma glucose (FPG) 
• Change from BL in weight 
• Change from BL in body composition (bio-impedance in 
all patients where appropriate and dual-energy x-ray 
absorptiometry (DXA) in a subset of patients) 
• Change from BL in sitting systolic blood pressure (SBP) 
and diastolic blood pressure (DBP) 
• Change from BL in the fasting lipid profile and hsCRP 
• Change from BL in 24h urinary glucose and sodium 
excretion,in a subset of patients 
• Change from BL in left atrial size and volume assessed by 
echocardiography  
• Change from BL in NYHA class 
2. To evaluate the effect of all LIK066 doses vs empagliflozin at 12 
weeks and 36 weeks on: 
• Change from BL in HbA1c 


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• Change from BL in FPG  
• Change from BL in weight 
• Change from BL in body composition (bio-impedance in 
all patients where appropriate and DXA in a subset of 
patients) 
• Change from BL in sitting SBP and DBP 
• Change from BL in the fasting lipid profile and hsCRP 
• Change from BL in 24h urinary glucose and sodium 
excretion, in a subset of patients 
3. To evaluate the change from BL to 36 weeks in all LIK066 doses 
vs placebo on NT-proBNP. 
4. To evaluate safety (adverse events (AEs) and lab parameters) 
and tolerability of LIK066 over 12 weeks and over 36 weeks for 
all patients 
5. To evaluate 24h urinary calcium and phosphate excretion after 
12 weeks and after 36 weeks in a subset of patients 
6. To evaluate bone mineral density in a subset of patients  
Study design 
Multi-center, randomized, double-blind, double-dummy, parallel-
group dose-finding study to assess efficacy, tolerability and safety 
of LIK066 versus placebo or empagliflozin. Patients can be pre-
screened for certain laboratory parameters. Following a screening 
visit, eligible subjects will enter the run-in. After the run-in period, 
eligible subjects will be randomized and treated for 36 weeks. The 
total duration of the study is up to 40 weeks 
Population 
Approximately 496 female and male patients ≥ 18 years old 
Key Inclusion criteria 
• Male or female outpatients, ≥ 18 years of age  
• BMI ≥ 22kg/m2  
• Type 2 diabetes with HbA1c between 6.5% and 10.0% 
• Documented symptomatic chronic heart failure (NYHA II-
IV)  
• Plasma NT-proBNP > 300pg/ml  
• Patients receiving ACEi, ARBs, MRAs, ARNi and/or β-
blockers must be on a stable dose of these medications  
• eGFR ≥ 45ml/min/1.73m2 (calculated by MDRD) 
Key Exclusion criteria 
• Type 1 diabetes, monogenic diabetes, diabetes resulting from 
pancreatic injury, or secondary forms of diabetes 


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• History of ketoacidosis, lactic acidosis, or hyperosmolar 
coma , or if occurring prior to randomization 
• Symptomatic genital infection or UTI within 4 weeks of 
screening 
• Myocardial infarction, stroke, surgery for heart disease, 
percutaneous coronary intervention within 3 months of 
randomization 
• Unstable angina within 3 months of screening 
• Isolated right HF due to pulmonary disease 
• Patients with a mean sitting systolic blood pressure ≤ 
100mmHg, at randomization  
• History 
of 
lower 
limb 
amputation 
(including 
toe 
amputation), or if occurring prior to randomization 
• Diabetic foot ulcer at screening, or before randomization 
Study treatment 
• LIK066 
• Placebo 
• Empagliflozin 
Efficacy assessments 
• NT-proBNP 
• glycated hemoglobin (HbA1c) 
• fasting plasma glucose (FPG) 
• body weight 
• body composition (bio-impedance/dual-energy x-ray 
absorptiometry) 
• systolic blood pressure and diastolic blood pressure 
• fasting lipid profile and hsCRP 
• 24h urinary glucose and sodium excretion 
• left atrial size and volume assessed by echocardiography  
• NYHA class 
Key safety 
assessments 
• Physical examinations 
• Vital signs 
• Monitoring of laboratory markers in blood and urine 
• Electrocardiogram 
• Bone mineral density 
• AE monitoring 
• Liver & renal safety monitoring 
Other assessments 
 
 


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• AEs of special interest (hypoglycemia & ketoacidosis) 
 
 
Data analysis 
The primary efficacy variable is the log-transformed ratio of NT-
proBNP (pg/mL) collected at Week 12 to BL (i.e., change from BL 
in log-transformed NT-proBNP at Week 12). It will be analyzed 
using the Multiple Comparison Procedure-Modeling (MCP-MOD) 
method (Pinheiro et al, 2006 & Pinheiro et al, 2014).  
In the MCP step, the following hypotheses will be used to test the 
dose response signal: 
• H01: There is no dose-response relationship or there is a dose 
response in the wrong direction for LIK066 after 12 weeks of 
treatment (i.e. the dose response relationship is flat, or as dose 
increases, there is less reduction in NT-proBNP from baseline). 
• H11: There is a dose-response relationship in the right direction 
for LIK066 after 12 weeks of treatment (i.e. as dose increases, 
there is more reduction in NT-proBNP from baseline). 
A set of the dose-response candidate models will be defined. In order 
to preserve the family-wise error rate at one-sided significance level 
of 2.5 %, the optimal contrasts derived from the model candidate set 
will be individually compared to the critical value derived using a 
multiplicity adjustment accounts for all tests of comparing LIK066 
doses to placebo with the candidate models simultaneously. The 
rejection of the null hypothesis will be achieved using the maximum 
test statistic from each estimated contrast test in the candidate set. 
The analysis to derive the test statistics is based on an analysis of 
covariance (ANCOVA) model with the log-transformed ratio of NT-
proBNP (pg/mL) at Week 12 to baseline as a response variable, 
treatment (placebo and all LIK066 doses), stratification variables 
geographical region and LVEF (< 45% versus ≥ 45%) as factors, and 
the baseline in log-transformed NT-proBNP as a covariate. 
In the MOD step, model averaging will be used to obtain the dose 
response estimates.  
Missing Week 12 values will be imputed using a multiple imputation 
approach under the assumption of missing at random. 
As a secondary endpoint, the dose-response of LIK doses versus 
placebo in the log-transformed ratio of NT-proBNP (pg/mL) at 


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Week 36 will be analyzed similarly using the method described 
above for the primary endpoint.  
Other secondary endpoints, including the changes from BL in 
HBA1c, FPG, weight, left atrial size and volume (assessed by 
echocardiography) etc. at both Weeks 12 and 36 will be analyzed 
using a mixed effect model of repeated measures (MMRM) as 
appropriate. 
 
Key words 
T2DM, heart failure, dose-finding, interventional study 


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1 
Introduction 
1.1 
Background  
Type 2 diabetes (T2DM) is a serious condition associated with high risk of cardio-vascular 
disease (CVD), and its complications, such as heart failure (HF). In patients with T2DM, both 
the incidence rate of HF and hospitalizations/mortality are higher than in patients without 
diabetes (Nichols et al, 2004; Kazsnicki et al, 2014). The poor prognosis in patients with T2DM 
and HF has been attributed to increased myocardial hypertrophy, myocardial fibrosis and 
abnormal cardiac metabolism (Kazsnicki et al, 2014), which may contribute to the development 
of myocardial ischemia, worsening of ventricular dysfunction, and arrhythmias (Taegtmeyer et 
al, 2002). HF is associated with recurrent hospitalizations and increased mortality rates (Chun 
et al, 2012). The risk of hospitalization and mortality associated with heart failure was 
significantly reduced with standard treatments, such as mineralocorticoid receptor antagonists 
(MRAs), β-blockers, angiotensin converting enzyme-inhibitors (ACEi) and angiotensin II 
receptor blockers (ARBs), as well as the recently studied sacubitril/valsartan treatment (Yancy 
et al, 2013; Solomon et al, 2016 ).   
Sodium-glucose co-transporter (SGLT) 2 inhibitors are approved for the treatment of type 2 
diabetes. In addition, long-term treatment with the SGLT2 inhibitor empagliflozin in the EMPA 
REG Outcome study resulted in 14% relative reduction (RR) in major adverse cardiovascular 
events (MACE) vs placebo driven by a statistically significant 38% RR in cardiovascluar (CV) 
death. The risk of hospitalizations for HF was also reduced (Zinman et al, 2015). In this study, 
patients with eGFR down to 30 ml/min/1.73m2 were included. In a subgroup analysis by renal 
function categories, the risk of CV death or HF hospitalization was significantly reduced in the 
groups with mild and moderate renal impairment. This composite endpoint was also 
significantly reduced in patients without previously diagnosed HF, and was numerically lower 
in patients with HF at baseline, who comprised approximately 10% of the study population 
(Fitchett et al, 2016). It is hypothesized that the observed benefit may have derived from the 
specific effects of SGLT2 inhibition on renal sodium and glucose handling, leading to both 
diuresis and improvements in diabetes-related maladaptive renal arteriolar responses (Sattar et 
al, 2016), from the switch of free fatty acids oxidation in the heart to the more efficient beta-
hydroxybutyrate oxidation, as well as from the enhanced oxygen supply due to 
hemoconcentration (Ferrannini et al, 2016). 
LIK066 is an inhibitor of SGLT1 and SGLT2. Via inhibition of both SGLT1 and SGLT2 in the 
proximal renal tubule, the drug may further enhance the effects on renal sodium and glucose 
handling compared with the selective SGLT2 inhibitors. In addition, SGLT1 is expressed in the 
small intestine where it is required for glucose and galactose absorption. Inhibition of enteric 
SGLT1 results in glucose and galactose malabsorption (Turk et al, 1991) which leads to calorie 
wasting and other potential endocrine-based weight loss mechanisms. Considering its dual 
mode of action (renal and intestinal) on re-absorption/absorption of glucose, LIK066 is planned 
for investigation in obese and overweight patients as a weight loss drug (calorie-loss enhancer). 
In a phase I study with normo- and dysglycemic adults with body-mass index (BMI)  ≥35kg/m2, 
treatment with LIK066 150mg qd resulted in a mean 5.7% placebo subtracted weight loss at 12 
weeks [Data on file]. 


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SGLT1 receptors are also expressed in the heart, however their role is not fully understood. The 
current study is planned to explore the effect of the dual SGLT1/2 inhibitor LIK066 on the HF 
biomarker NT-proBNP in a T2DM population with compromised cardiac function, along with 
exploration of its glucose-lowering potential. 
1.2 
Purpose  
The purpose of the study is to evaluate the efficacy, safety and tolerability of LIK066 in T2DM 
patients with cardiac disease and HF to help inform decisions on further development of 
LIK066. 
2 
Study objectives and endpoints 
2.1 
Primary objective 
To determine the dose-response signal and assess the dose-response relationship of LIK066  
2.5mg, 10mg, and 50mg qd as measured by the change from baseline (BL) in NT-proBNP 
relative to placebo after 12 weeks of treatment in T2DM patients with HF. 
2.2 
Secondary objectives 
1. To evaluate the effect of all LIK066 doses vs placebo at 12 weeks and 36 weeks on: 
• Change from BL in glycated hemoglobin (HbA1c), see Section 6.4.6. 
• Change from BL in fasting plasma glucose (FPG), see Section 6.4.7. 
• Change from BL in weight, see Section 6.4.1. 
• Change from BL in body composition (bio-impedance in all patients where appropriate 
and dual-energy x-ray absorptiometry (DXA) in a subset of patients, see Section 6.4.3) 
• Change from BL in sitting systolic blood pressure (SBP) and diastolic blood pressure 
(DBP), see Section 6.4.8. 
• Change from BL in the fasting lipid profile and hsCRP, see Section 6.4.9. 
• Change from BL in 24h urinary glucose and sodium excretion, in a subset of patients, 
see Section 6.4.10. 
• Change from BL in left atrial size and volume assessed by echocardiography, see 
Section 6.4.5.  
• Change from BL in NYHA class, see Section 6.4.4. 
2. To evaluate the effect of all LIK066 doses vs empagliflozin at 12 weeks and 36 weeks on: 
• Change from BL in HbA1c, see Section 6.4.6. 
• Change from BL in FPG, see Section 6.4.7.  
• Change from BL in weight, see Section 6.4.1. 
• Change from BL in body composition (bio-impedance in all patients where appropriate 
and DXA in a subset of patients, see Section 6.4.3) 
• Change from BL in sitting SBP and diastolic blood pressure (DBP), see Section 6.4.8. 
• Change from BL in the fasting lipid profile and hsCRP, see Section 6.4.9. 


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• Change from BL in 24h urinary glucose and sodium excretion, in a subset of patients 
(see Section 6.4.10). 
3. To evaluate the change from BL to 36 weeks in all LIK066 doses vs placebo on NT-proBNP. 
4. To evaluate safety (adverse events (AEs) and lab parameters) and tolerability of LIK066 
over 12 weeks and over 36 weeks for all patients (see Section 6.5) 
5. To evaluate 24h urinary calcium and phosphate excretion after 12 weeks and after 36 weeks 
in a subset of patients (see Section 6.4.10). 
6. To evaluate bone mineral density in a subset of patients (see Section 6.5.5)  
3 
Investigational plan 
3.1 
Study design 
This is a multi-center, randomized, double-blind, double-dummy, parallel-group study 
evaluating the efficacy, safety and tolerability of 3 doses of LIK066 vs placebo and vs 
empagliflozin.  
Pre-Screening: Pre-screening for some blood tests is possible (it is optional) and can be used 
to identify appropriate patients to be screened for this clinical study. The pre-screening visit 
includes blood tests for NT-proBNP, HbA1c, eGFR and serum potassium, which will be 
analyzed at the central laboratory. At Visit 1, these laboratory parameters will be assessed by 
the central laboratory, independently whether or not pre-screening was done for the patient.  
3.1.1 
Epoch 1 (screening) 
Patients will be screened at Visit 1 (see Figure 3-1). The screening period (Epoch1) takes 
approximately 2 weeks. Patients meeting all eligibility criteria will enter the run-in Epoch 2 at 
Visit 101. If patients fail to meet one or more inclusion/exclusion criteria, they can be re-
screened once. If for technical reasons (e.g. hemolyzed blood sample, broken or lost tube) 
laboratory results are not definable, such parameters can be re-tested. 


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Figure 3-1 
Study design 
 
3.1.2 
Epoch 2 (placebo run-in) 
Patients meeting the eligibility criteria defined in Section 4 will enter the placebo run-in (Epoch 
2). During the approximately 2 weeks duration of Epoch 2, patients will receive single-blind 
placebo run-in medication as described in Section 5.2. 
At Visit 101, the patients’ volume status must be assessed based on physical examination and 
laboratory values and, if hypovolemic, corrected during the run-in. 
3.1.3 
Epoch 3 (treatment) 
After the placebo run-in Epoch 2, eligible patients will be randomized in a 1:1:2:2:2 ratio to one 
of the following regimens at Visit 201 (randomization), see Section 5.2: 
• LIK066 2.5mg qd at bedtime 
• LIK066 10mg qd at bedtime 
• LIK066 50mg qd at bedtime 
• Empagliflozin (up-titrated from 10mg qd to 25mg qd after 2 weeks); in the morning  
• Placebo LIK066 at bedtime/Placebo Empagliflozin in the morning  
At randomization, patients must be stratified based on geographical region and the left 
ventricular ejection fraction (LVEF) measurement at Visit 101: < 45% versus ≥ 45%. Only if 
the LVEF results from the central reading vendor are not available in time for randomization, 
the LVEF result from Visit 101 read locally by a cardiologist or from the last measurement 
(echocardiogram, nuclear study, or left ventricular angiography) done locally prior to 
enrollment into the study can be used for stratification. 
LIK066 10mg qd
LIK066 2.5mg qd
LIK066 50mg qd
Empagliflozin 25mg qd
Placebo qd
Epoch 2
Epoch 3 Randomization (n = 496)
Epoch 4
2 w ks
12 w eeks
24 w eeks
2 w ks
Screening (n = ~1000)
V1
V101
V199/201 V202
V203
V204
V299/301
V302
V399
LIK066 10mg qd
Empagliflozin 25mg qd
Placebo qd
LIK066 50mg qd
LIK066 2.5mg qd
Placebo qd  run-in
10
mg
Epoch 1
A
(n=62)
B
(n=62)
C
(n=124)
D
(n=124)
E
(n=124)
Pre-Screening (optional)


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Following randomization, patients will attend study visits in Epoch 3 (12 weeks) for the 
evaluation of the short-term efficacy (change in NT-proBNP), tolerability and safety parameters 
as defined in Table 6-1. During Epoch 3, patients will take the study medication as described 
in Section 5.5.4. 
Treatment of T2DM 
Patients will continue their usual T2DM treatment. Patients taking sulfonylureas (SU) or insulin 
may be at an increased risk of hypoglycemia when LIK066 or empagliflozin is added, therefore 
reduction of the dose of the SU or insulin should be considered: 
• A reduction by 50%, or as close to 50% as possible based on dose options available locally, 
of the dose of SUs for patients (see Section 5.5.3) using such medication (either as 
monotherapy or in combination with other oral anti-diabetic drugs (OADs)) should be 
considered. In case of persistent deterioration in glycemic control, the concomitant 
background OAD should be initially escalated to the maximal approved dose, followed by 
addition of rescue medication when required (see Section 5.5.6). To limit the number of 
patients with early deterioration of glycemic control who would meet the FPG rescue 
criteria early after randomization (see Section 5.5.6) an FPG randomization criterion is 
included in Section 4.2.  
• For patients on insulin, initial dose reduction of the total daily insulin dose by 10% or more 
should be considered at the investigator’s discretion based on patient’s total daily dose and 
glycemic control. Due to the potential risk of ketoacidosis with SGLT2i, dose reduction in 
patients with HbA1c ≥ 8% may not be appropriate. In case of deterioration in glycemic 
control (see Section 5.5.6), insulin can be up-titrated. 
3.1.4 
Epoch 4 (treatment) 
After completing the procedures required at the last study visit of Epoch 3 (Visit 301) patients 
will continue in Epoch 4 the treatment they were allocated to in Epoch 3 for 24 weeks. Long-
term efficacy (assessed by HbA1c, echocardiography and NT-proBNP), tolerability and safety 
parameters as defined in Table 6-1 will be evaluated. 
3.2 
Rationale for study design 
The study is designed as a standard randomized, controlled, parallel-group study. A single-blind 
placebo run-in epoch (Epoch 2) is included to familiarize patients with the study drug intake 
schedule and correct hypovolemia (if diagnosed at Visit 101). The effect on NT-proBNP will 
be evaluated after 12 weeks of treatment in Epoch 3, as well as after 36 weeks of the study 
(Epoch 4) to provide information about the longer-term effect of LIK066 on NT-proBNP, and 
on clinical and echocardiography parameters. Glycemic control will also be assessed after 12 
and 36 weeks of treatment.   
The patient population is described in more detail in Section 4 below. 


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3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
LIK066 has been studied in multiple clinical trials with a variety of dosing regimens using either 
single or multiple daily doses at durations of up to 12 week in healthy subjects, patients with 
T2DM and obese patients. 
 
 
 
 
 
 
 
 
Since the objective is to find a dose with sub-optimal to optimal effect on SGLT1 and SGLT2 
inhibition in the kidney, but with no or minimal gut effect to minimize the risk of diarrhea, 
LIK066 50mg qd is selected as the highest dose for this study.
 
 
 
To minimize the risk of GI adverse 
effects of the SGLT1 inhibition in the gut such as diarrhea, the LIK066 dose will not be taken 
around mealtime; hence dose administration is recommended at bedtime. The 10mg dose is 
selected between the low and top dose in the study and to enable exploration of the shape of the 
dose-response curve. 
Based on results from previous exploratory phase II studies in HF comparing 
sacubitril/valsartan with valsartan (e.g. LCZ696B2214; Solomon et al, 2012), treatment with 
LIK066 for a duration of 12 weeks would be expected to be sufficient in order to reveal a 
significant change in NT-proBNP. Twelve weeks after introducing an anti-diabetic treatment is 
an accepted time point for initial evaluation of drugs’ effect on glycemic control (HbA1c).The 
full duration of exposure of 36 weeks will provide data for parameters requiring longer follow-
up to be evaluated (echocardiography) as well as safety data. 
3.4 
Rationale for choice of comparator 
A placebo group is included to obtain efficacy, tolerability and safety data in an unbiased 
manner and to determine the dose-response characteristics of the investigational drug. An active 
comparator empagliflozin, which is approved in the treatment of T2DM to improve glycemic 
control, is included as a reference drug (Zinman et al, 2015). Empagliflozin has also shown CV 
benefit in T2DM patients in the EMPA-REG Outcome study. Considering that the mechanism 
leading to the CV benefit with empagliflozin currently remains unclear, the higher of the two 
approved doses in patients with T2DM, empagliflozin 25mg qd, was chosen as a comparator to 
potentially achieve a maximum effect on NT-proBNP. Choosing the higher of the two doses 
should not pose a safety concern, as  no difference in the safety profile of empagliflozin 10 mg 
and 25 mg was reported in the EMPA REG Outcome study in patients with eGFR ≥ 30 
ml/min/1.73m2 (Fitchett et al, 2016), a cut-off value lower than the 45 ml/min/1.73m2 in 
CLIK066B2204. In order to minimize potential adverse effects empagliflozin will be up-titrated 
from 10mg qd to 25mg qd after 2 weeks of treatment. 


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3.5 
Purpose and timing of interim analysis 
No interim analysis is planned.  
3.6 
Risks and benefits  
The risk to patients in this study will be minimized by compliance with the eligibility criteria 
and study procedures, and close clinical monitoring. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 Further information is provided in the Investigator Brochure (IB). 


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Publications on SGLT2 inhibition in subjects with T2DM treated with selective SGLT2 
inhibitors reported higher incidences of urinary tract infections (UTIs) and genital mycotic 
infections compared with placebo (Bailey et al, 2010; Nauck et al, 2011; Nyirjesy et al, 2012) 
and some genital infections have been seen in healthy volunteers and patients treated with 
LIK066. SGLT2 inhibition may result in hypotension in elderly subjects, in subjects with low 
blood systolic pressure, or if on diuretics, ACE inhibitors, or ARBs. Patients with T2DM treated 
with antidiabetic agents, especially with sulphonylurea or insulin, may be at an increased risk 
of hypoglycemia. In rare cases treatment with SGLT2 inhibitors may be complicated by 
ketoacidosis (Rosenstock et al, 2015). However, this has not been seen to date in clinical studies 
with LIK066. In long-term clinical studies in patients with T2DM with CVD or at high risk for 
CVD, an increase in cases of lower limb amputation (primarily of the toe) has been observed 
with the SGLT-2 inhibitor canagliflozin (Neal et al, 2017). No lower limb amputations have 
been seen in LIK066 studies to date, but since this risk may constitute a possible class effect, 
patients with a higher risk for amputation events should be instructed on routine preventative 
foot care and maintaining adequate hydration. The only preclinical/class safety issues which 
have been seen in clinical studies with LIK066 are the GI side effects and vulvovaginal 
infections. A detailed description of safety in humans with LIK066 is found in the LIK066 IB. 
Hematology and biochemistry tests will be monitored at each study visit after randomization 
and study drug can be discontinued for clinically significant laboratory change or abnormality 
as per investigator’s judgment. Detailed criteria for follow-up in case of a liver event are defined 
in Appendix 2. To prevent UTIs and genital infections, patients will be instructed to pay 
attention to genital hygiene and have appropriate hydration. If UTI and/or genital infections 
occur, treatment will be initiated as appropriate at the investigator’s discretion. 
Strict criteria for deterioration of glycemic control and initiation of rescue anti-diabetic 
medication are provided (Section 5.5.6). To minimize the risk of hypoglycemia when study 
drug is added to patients treated with SUs or insulin, guidance is provided in Section 3.1.3. 
Considering the potential benefit patients with T2DM and mild and moderate renal impairment 
may have on their risk of CV death and HF hospitalization (Section 1.1) patients with eGFR 
down to 45 ml/min/1.73m2 are included in this study. No safety concern in addition to the known 
adverse effects of SGLT2i has been reported in the EMPA REG Outcome study which included 
patients with T2DM with eGFR down to 30 ml/min/1.73m2  (Zinmann et al, 2015). 
This clinical study involves exposure to radiation from DXA total body and bone scans in a 
subset of patients. The total amount of radiation exposure per patient from these scans will be 
equivalent to less than 30 days of exposure to natural background radiation. For effective 
radiation doses at this level the risk for the patient is considered to be minimal. Therefore, the 
radiation exposure in this study involves minimal risk and is necessary to obtain the research 
information desired (Stabin, 2016). 
Benefits to participation in the study may include blood glucose reduction, weight reduction 
and, potentially, improvement in HF signs and symptoms, as well as in some cardio-metabolic 
markers such as NT-proBNP, blood pressure or lipids. 


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4 
Population 
The study population will consist of male and female patients (≥18 years old) with type 2 
diabetes and heart failure (heart failure with preserved ejection fraction (HFpEF) and heart 
failure with reduced ejection fraction (HFrEF)). The goal is to randomize a total of 
approximately 496 patients in approximately 140 centers worldwide. Since a 25% screening 
failure rate and a 33% run-in failure rate is expected, approximately 1000 patients will be 
screened. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed.  
2. Male or female outpatients, ≥ 18 years of age at Visit 1. 
3. BMI ≥ 22kg/m2 at Visit 1. 
4. Type 2 diabetes with HbA1c between 6.5% and 10.0% at Visit 1. 
5. Documented symptomatic chronic heart failure (NYHA II-IV) with at least one of the 
following symptoms at the time of Visit 1: 
• Dyspnea on exertion 
• Orthopnea 
• Paroxysmal nocturnal dyspnea 
• Peripheral edema 
6. Plasma NT-proBNP > 300pg/ml at Visit 1. 
7. Patients receiving ACEi, ARBs, MRAs, ARNi and/or β-blockers must be on a stable dose 
of these medications during the 1 month period prior to Visit 1.  
8. Patients must be on diuretic therapy prior to Visit 1 (flexible dosing is permitted). 
9. Controlled systolic BP defined as a target systolic BP less than 140mmHg; systolic BP up 
to and including 160mmHg if patient is on three or more medications to control BP, at 
randomization (Visit 201).  
10. eGFR ≥ 45ml/min/1.73m2 at Visit 1 (calculated by the Modification of Diet in Renal 
Disease formula (MDRD)). 
11. Serum potassium ≤ 5.3mM at Visit 1. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. 
Use of other investigational drugs within 5 half-lives of Visit 1, or within 30 days, 
whichever is longer. 


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2. 
History of hypersensitivity to any of the study drugs or their excipients or to drugs of 
similar chemical classes. 
3. 
Diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety 
for patients participating in the study such as: 
• Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV -block without a 
pacemaker.  
• History of familial long QT syndrome or known family history of torsades de pointes. 
• Atrial fibrillation with a resting heart rate >100 beats per minute (bpm) at Visit 1. 
4. 
Patients taking medications prohibited by the protocol (see Section 5.5.8) 
5. 
History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases. 
6. 
Pregnant or nursing (lactating) women. 
7. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient. 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository. 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS). 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential.  


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If the above wording is not in line with specific country regulations, exclusion criteria for 
women of child-bearing potential will be managed locally and in line with those regulations. 
 
8. Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or 
secondary forms of diabetes (e.g. Cushing’s syndrome or acromegaly-associated diabetes). 
9. Use of SGLT2 inhibitors within 2 months of Visit 1, or between Visit 1 and Visit 201 
(randomization). 
10. Self-measured FPG > 12.2mM (220mg/dL) on two occasions in the week prior to 
randomization (Visit 201). 
11. History of ketoacidosis, lactic acidosis, or hyperosmolar coma, or any of these occurring 
between Visit 1 and Visit 201 (randomization). 
12. Symptomatic genital infection or UTI in the 4 weeks prior to Visit 1, or between Visit 1 and 
Visit 201 (randomization). 
13. GI disorders associated with chronic diarrhea. 
14. Myocardial infarction (MI), stroke, surgery for heart disease, percutaneous coronary 
intervention (PCI) in the 3 months prior to Visit 201 (randomization). 
15. Unstable angina within 3 months of Visit 1, or between Visit 1 and Visit 201 
(randomization). 
16. Isolated right HF due to pulmonary disease. 
17. Dyspnea and/or edema from non-cardiac causes, such as lung disease, anemia, or severe 
obesity.  
18. Hemodynamically significant mitral and/or aortic valve disease.  
19. Hemodynamically significant obstructive lesions of left ventricular outflow tract, including 
aortic stenosis. 
20. Hypertrophic obstructive cardiomyopathy.  
21. Secondary forms of cardiomyopathy such as restrictive cardiomyopathy or infiltrative 
cardiomyopathy (e.g., amyloid disease). 
22. Patients with a history of any organ transplant or who were on a transplant list (life 
expectancy < 6 months at time of entry into the study). 
23. Patients with a mean sitting systolic blood pressure ≤ 100mmHg, at Visit 201 
(randomization).  
24. Patients with an implantable medical device (e.g. cardioverter defibrillator (ICD)) that has 
discharged in the month prior to Visit 1. 
25. Episode(s) of malignant ventricular tachycardia or any other types of severe arrhythmia 
producing significant hemodynamic consequences or considered life-threatening within 3 
months of Visit 1.  


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26. Acute or chronic liver disease (except liver steatosis), such as hepatitis, cirrhosis or portal 
hypertension at Visit 1 or Visit 201 (randomization). 
27. History of hepatitis B or C, or Hepatitis A or B vaccination in the last 3 months prior to 
Visit 1, or between Visit 1 and Visit 201 (randomization).  
28. Active substance abuse, alcohol abuse (as defined by consumption of more than 24 alcohol 
units per week) and alcohol related history of disease within the past 2 years.  
29. Chronic treatment with medication which has a hepatotoxic potential. 
30. Chronic use of anti-retroviral therapies. 
31. Chronic use of strong CYP3A4 inhibitors (e.g. clarithromycin, telithromycin, itraconazole, 
ketoconazole, voriconazole or posaconazole) or chronic use of strong uridine-5’-
diphosphoglucoronosyltransferase (UGT) inhibitors (e.g. probenecid, valproic acid or 
mefenamic acid). 
32. Concurrent medical condition that may interfere with the interpretation of efficacy and 
safety data. 
33. Clinically significant thyroid stimulation hormone (TSH) level outside of the normal range 
at Visit 1. 
34. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) more than three-fold 
above upper limit of normal (>3 x ULN), or total bilirubin/direct bilirubin > 1.5 x ULN) at 
Visit 1, confirmed by repeat measurement within 5 working days of the respective visit. 
35. Hemoglobin < 11g/dL in men, < 10g/dL in women at Visit 1 (screening). 
36. Platelet count < 100,000/μl and/or white blood cell (WBC) count < 4000/μl at Visit 1 
(screening). 
37. Hematuria determined by dipstick measurement at Visit 1 (screening). 
38. Elevated fasting triglycerides (TG) > 5.6mM (500mg/dl), at Visit 1 (screening), confirmed 
by repeat measurement within 3 working days of the respective visit. 
39. Clinically significant laboratory abnormalities which, in the opinion of the investigator, 
cause the patient to be considered inappropriate for inclusion in the study. 
40. History of lower limb amputation (including toe amputation), or if occurring between Visit 
1 and Visit 201 (randomization). 
41. Diabetic foot ulcer at Visit 1, or between Visit 1 and Visit 201 (randomization). 
5 
Treatment 
5.1 
 Study treatment 
5.1.1 
Investigational and control drugs 
The sponsor will provide single-blind study medication for Epoch 2: 
• LIK066-matching placebo tablets 


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• Empagliflozin-matching placebo capsules (tablets over-encapsulated) 
The sponsor will provide double-blind study medication for Epoch 3 and Epoch 4: 
• LIK066 2.5mg film-coated tablets 
• LIK066 10mg film-coated tablets 
• LIK066 50mg film-coated tablets 
• LIK066-matching placebo tablets 
• Empagliflozin 10mg film-coated tablets (over-encapsulated) 
• Empagliflozin 25mg film-coated tablets (over-encapsulated) 
• Empagliflozin-matching placebo capsules (tablets over-encapsulated) 
For each treatment arm (see Section 5.2), patients will receive a combination of one tablet and 
one capsule as described above. All patients will take the study medication as explained in 
Section 5.5.4, and the dose regimens will be prepared for each treatment arm in medication 
wallets. 
No other drugs will be supplied. Sufficient medication will be supplied for treatment according 
to the study protocol. 
5.1.2 
Additional treatment 
No additional treatment beyond investigational drug and control drug are included in this study. 
5.2 
Treatment arms 
All patients entering Epoch 2 (run-in) will receive single-blind placebo (see Section 3.1.2& 
Section 5.5.4). 
At visit 201 (randomization), patients eligible for randomization will be assigned to one of the 
following 5 treatment arms in Epoch 3 (see 3.1.3 Epoch 3 (treatment)) in a ratio of 1:1:2:2:2: 
• 2.5mg qd LIK066 
• 10mg qd LIK066 
• 50mg qd LIK066 
• 10mg qd empagliflozin up-titrated to 25mg qd after 2 weeks 
• Placebo qd 
In Epoch 4 (see 3.1.4 Epoch 4 (treatment)), patients will continue to receive the treatment they 
were assigned to in Epoch 3. 
5.3 
Treatment assignment and randomization  
At Visit 201 (randomization) all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT 


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will assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. The randomization number will not be communicated to the user 
of the IRT system. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
drug supply management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).  
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis randomization group. 
Randomization will be stratified according to geographical region and LVEF (< 45% versus ≥ 
45%), see Section 3.1.3. 
5.4 
Treatment blinding 
Patients, investigator staff, Novartis study team, persons performing the assessments, and data 
analysts will remain blind to the identity of the treatment from the time of randomization until 
database lock, using the following methods: 
1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions: the 
randomization codes associated with patients from whom PK samples are taken will be 
disclosed to PK analysts who will keep the PK results confidential until database lock.   
2. The identity of the treatments will be concealed by the use of study drug that are all identical 
in packaging, labeling, schedule of administration, appearance, taste and odor. A double 
dummy design will be used as the identity of the study drugs cannot be disguised due to 
their different forms. 
Unmasking will only occur in the case of patient emergencies (see Section 5.5.9), at the time of 
the Week 12 analysis and at the conclusion of the study.  
The analysis group (statisticians/programmers), who will be unmasked to perform the Week 12 
analysis, will not be involved in any study conduct activities related to the study Week 12 to 
Week 36 period (Epoch 4) after the unmasking. A separate analysis group, who does not have 
access to the analysis results and the identity of treatments at Week 12 analysis, will perform 
the pre-planned final analysis at the end of the study. 
The core study team (including the study leader(s), study physician and data manager), who are 
directly involved in study conduct activities during the study Week 12 to Week 36 period 
(Epoch 4), will not have access to the patient level data with identity of treatments such as 
patient listings at Week 12 analysis. 
The Week 12 analysis results and the identity of treatments will not be shared with the study 
site personnel until after the final database lock at the end of study. 


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5.5 
Treating the patient  
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
5.5.1 
Patient numbering  
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the pre-screening or study informed consent form, the patient is assigned a patient 
number by the investigator. At each site, the first patient is assigned patient number 1, and 
subsequent patients/subjects are assigned consecutive numbers (e.g. the second patient is 
assigned patient number 2, the third patient is assigned patient number 3). At screening (Visit 
1) the investigator or his/her staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. For studies using eCRFs, only the 
assigned patient number must be entered in the field labeled “Patient ID” on the EDC data entry 
screen (e.g. enter ‘1’, ‘2’, etc.). Once assigned to a patient, the patient number will not be reused. 
If the patient fails to be randomized for any reason, the IRT must be notified within 2 days that 
the patient was not randomized. The reason for not being randomized will be entered on the 
Screening Log, and the Demography eCRF should also be completed. 
5.5.2 
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the treatment arms. Investigator staff will identify 
the study drug package(s) to dispense to the patient by contacting the IRT and obtaining the 
medication number(s). Immediately before dispensing the package to the patient, investigator 
staff will detach the outer part of the label from the packaging and affix it to the source 
document (Drug Label Form) for that patient’s unique patient number.  
5.5.3 
Handling of study and additional treatment  
5.5.3.1 
Handling of study treatment  
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis CPO Quality 
Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 


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to return all unused study treatment and packaging at each study visit and where applicable, at 
the time of discontinuation of study treatment.  
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
5.5.3.2 
Handling of additional treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment  
The patients have to take study medication, 1 capsule in the morning, with or without food, and 
1 tablet at bedtime. 
All prescribed dosages and all dose changes during the study must be recorded on the 
appropriate study drug Dosage Administration Record eCRF. All kits of study treatment 
assigned by the IRT will be recorded/databased in the IRT. 
During each study visit, the investigator should encourage compliance with study medication 
by instructing the patient to take the study drug exactly as prescribed to maintain the validity of 
the study and to optimize any potential effect of the study drug regimen. The patient should be 
instructed to contact the investigator if he/she is unable for any reason to take the study drug 
regimen as prescribed. 
On study visit days, the patients must take their study medication or their anti-diabetic treatment 
only after blood draws have been done. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Study drug dose adjustments and/or interruptions are not permitted, unless done for safety 
reasons (see Section 7.1). 
5.5.6 
Rescue medication 
During Epoch 3 and Epoch 4, rescue medication may be used in addition to ongoing study 
medication for those patients whose glycemic control is deteriorating. The patient must come 
in for an unscheduled visit to have a sample drawn for FPG and HbA1c measurement performed 
by the central laboratory if: 
• Self-measured FPG on three consecutive occasions exceeds the limits in Table 5-1. 
• The FPG result from a blood sample analyzed at the central laboratory exceeds the limits 
described in Table 5-1. 
 
 


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Table 5-1 
Rescue criteria for FPG or HbA1c  
Timeframe 
Parameter 
Value 
Action 
Between V201 (Randomization) 
and V204 (Week 8) 
FPG 
>240mg/dL 
(13.3mM) 
Unscheduled visit for central lab 
parameter measurement. 
If elevation confirmed by central lab: 
background OAD to escalate to the 
maximum approved dose, followed 
by addition of insulin as per the 
investigator’s discretion. 
Between V204 (Week 8) and 
V301 (Week 12) 
FPG 
>220mg/dL 
(12.2mM) 
Between V301 (Week 12) and 
V399 (Week 36) 
FPG 
>200mg/dL 
(11.1mM) 
Between V301 (Week 12) and 
V399 (Week 36) 
HbA1c 
>8% 
If the results confirm the exceeded limits, the background OAD should be initially escalated to 
the maximal approved dose, followed by addition of rescue medication.  
Rescue medication, preferably insulin, should be used according to the local label and must be 
provided locally. 
Rescued patients will continue to participate in the study to allow for assessment of exposure 
and safety of LIK066. 
Use of rescue medication must be recorded on the Rescue Medication eCRF. 
5.5.7 
Concomitant medication  
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the Concomitant Medications 
/ Surgical and Medical Procedures eCRF. 
Every effort should be made by the Investigator to keep the dose level of each patient’s allowed 
background heart failure medications stable throughout the entire study duration.  However; if 
the clinical condition of the patient warrants a change in any of these medications, it is allowed 
at the discretion of the study Investigator. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. 
5.5.8 
Prohibited medication 
Use of the treatments displayed in Table 5-2 is not allowed after patients have become eligible 
for participation into the study. At the latest, patients should stop using the medications listed 
in Table 5-2 at the start of Epoch 2. 
 


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Table 5-2 
Prohibited medication 
Medication/product 
Prohibition 
period 
Action taken 
St. John’s wort (strong CYP3A inducer) 
Entire study (from 
V1 until end-of-
study) 
Discontinue treatment during the 
screening period once patient is 
eligible for participation in the study. 
SGLT inhibitors other than study 
medication 
Entire study (and 
up to 2 months 
before Visit 1) 
SGLTi has to be stopped 
immediately, otherwise the patients 
has to be discontinued from study 
medication 
Some medications or products must be used with caution: 
• Use of grapefruit juice (strong inhibitor of CYP3A4) should be discouraged and its 
consumption must not happen within 2h of study medication intake. 
• Use of antibiotic or antifungal medications that are strong inhibitors of CYP3A4 should be 
limited to 10 days during the study and must not be used at the time of randomization. 
Examples of such medications are clarithromycin, telithromycin, itraconazole, 
ketoconazole, voriconazole or posaconazole. 
• Use of UGT inhibitors such as probenecid, valproic acid or mefenamic acid should be 
limited to 10 days during the study and must not be used at the time of randomization. 
5.5.9 
Emergency breaking of assigned treatment code  
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 
for the patient. The investigator will then receive details of the investigational drug treatment 
for the specified patient and communication confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Study Team that the code has 
been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT system at any time in case of emergency. The investigator will provide 
the protocol number, the study drug name (if available) and the patient number. 
In addition, oral and written information to the patient must be provided on how to contact the 
investigator`s backup in cases of emergency, or when the investigator is unavailable, to ensure 
that un-blinding can be performed at any time.  
Patients whose treatment has been unmasked must be discontinued from study treatment (see 
Section 5.6.2). 


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5.6 
Study completion and discontinuation  
5.6.1 
Study completion and post-study treatment  
A patient will be considered to have completed the study when the patient has completed the 
last planned visit (see Table 6-1). The study as a whole will be considered completed when all 
randomized subjects have completed the last visit planned in the protocol or have discontinued 
the study prematurely. 
For subjects who are lost to follow-up, see Section 5.6.4. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.6.2 
Discontinuation of study treatment  
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator.  
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances:  
• Patient wish  
• Pregnancy (see Section 6.5.6 and Section 7.6) 
• Use of prohibited treatment see Table 5-2 
• Any situation in which study participation might result in a safety risk to the patient 
• Emergence of the following adverse event: Ketoacidosis, diabetic foot ulcer or lower limb 
amputation (including toe amputation)  
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing participation 
in the study 
• Patients whose study treatment has been unmasked (see Section 5.5.9) 
• Withdrawal of consent (see Section 5.6.3) 
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after discontinuation 
of study drug, for a study treatment discontinuation visit (see Table 6-1). Treatment 
discontinuation visit assessments detailed in Table 6-1 should be completed and recorded in the 
eCRF. The investigator must determine the primary reason for the patient’s premature 
discontinuation of study treatment and record this information on the appropriate eCRF.  
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits:  
• new / concomitant treatments 
• adverse events/Serious Adverse Events 


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If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.  
Patients who discontinue study medication during Epoch 3 should be followed-up until they 
discontinue the study at the end of Epoch 3 (V299). 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9 
5.6.3 
Withdrawal of informed consent  
Patients 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 all of the following applies: 
• A patient does not want to participate in the study anymore 
and 
• does not want any further visits or assessments 
and 
• does not want any further study related contacts 
and 
• does not allow analysis of already obtained biologic material  
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal.  
A final evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1. 
5.6.4 
Lost to follow-up  
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit has passed. 


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5.6.5 
Early study termination by the sponsor  
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the study visits and assessments and indicates with an “X” when the 
assessments are performed. 
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at which 
time all of the assessments listed for the final visit will be performed. At this final visit, all 
dispensed investigational product should be reconciled and the adverse event and concomitant 
medications reconciled on the eCRF. 
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.  


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Table 6-1 
Assessment schedule 
Epoch  
 
1 
2 
3  
4 
Visit  
Pre-
screen 
1       
Screen 
101    
Run-in 
199 
TD/ 
PPD 
201       
RND/ BL  
202 
203 
204 
299 
TDA/ PPD 
301 
302 
 
399 
TDA/ 
PPD/ 
EOS 
Week 
 
-4 
-2 
0 
2 
4 
8 
12 
24 
36 
 
Screening assessments 
Pre-screening informed consent 
SP 
 
 
 
 
 
 
 
 
 
 
 
Study informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion (Section 4) 
 
X 
 
X* 
X* 
 
 
 
 
 
 
 
Patient demographics (Section 
6.2) 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical history: protocol solicited 
& Heart Failure/Diabetes 
 
X 
 
 
 
 
 
 
 
 
 
 
Smoking & alcohol history (Section 
6.2) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Height (Section 6.4.1) 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight / BMI (Section 6.4.1) 
 
XC 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure (Section 6.4.8) 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
NYHA classification (see 
Section 6.4.4) 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Body composition: bio-impedance 
(see Section 6.4.3) 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
Echocardiography (see Section 
6.4.5) 
 
 
X 
 
 
 
 
 
 
XD 
 
XD 
NT-ProBNP (Section 6.4.2) 
SP 
X 
 
 
X 
 
XB 
 
XB 
XB 
 
XB 


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Epoch  
 
1 
2 
3  
4 
Visit  
Pre-
screen 
1       
Screen 
101    
Run-in 
199 
TD/ 
PPD 
201       
RND/ BL  
202 
203 
204 
299 
TDA/ PPD 
301 
302 
 
399 
TDA/ 
PPD/ 
EOS 
Week 
 
-4 
-2 
0 
2 
4 
8 
12 
24 
36 
HbA1c (Section 6.4.6) 
SP 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
FPG (Section 6.4.7) 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Fasting lipid profile, hsCRP 
(Section 6.4.9) 
 
XT 
 
 
X 
 
 
 
X 
X 
 
X 
  
Patient reported outcomes 
 
Safety 
Complete physical examination 
(Section 6.5.1) 
 
S 
 
 
 
 
 
 
S 
 
 
S 
Short physical examination  
(Section 6.5.1) 
 
 
S 
S 
S 
S 
S 
S 
 
S 
S 
 
Vital signs (Section 6.5.2) 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (Section 6.5.4) 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
Hematology (Section 6.5.3) 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Biochemistry  
(Section 6.5.3 & Section 7.3) 
SP 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
TSH (Section 6.5.3) 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum, Section 
6.5.3 & Section 6.5.6) 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine dipstick, 
Section 6.5.3 & Section 6.5.6) 
 
 
 
X 
X 
 
 
 
X 
X 
 
X 
Hematuria (urine dipstick, Section 
6.5.3) 
 
X 
 
 
 
 
 
 
 
 
 
 


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Epoch  
 
1 
2 
3  
4 
Visit  
Pre-
screen 
1       
Screen 
101    
Run-in 
199 
TD/ 
PPD 
201       
RND/ BL  
202 
203 
204 
299 
TDA/ PPD 
301 
302 
 
399 
TDA/ 
PPD/ 
EOS 
Week 
 
-4 
-2 
0 
2 
4 
8 
12 
24 
36 
Urinalysis (Section 6.5.3) 
 
 
 
 
X 
 
 
 
XG 
XG 
 
XG 
Urine albumin to creatinine ratio 
(spot UACR, Section 6.5.3) 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
AEs (Section 7.1) 
 
S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAEs (Section 7.2) 
 
(XP) 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
Ketoacidosis AEs (Section 7.8.1) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypoglycemia AEs (Section 7.8.2) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medication records & procedures 
Prior & concomitant medications, 
rescue medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Surgical and medical procedures 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose administration record 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administrative procedures 
Contact IRT system 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense glucometer and first 
glycemia study diary 
 
 
S 
 
 
 
 
 
 
 
 
 
Patient returns glycemia study 
diary for review 
 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Drug dispensing 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Study drug accountability 
 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Screening phase disposition 
 
X 
 
 
 
 
 
 
 
 
 
 
Run-in phase disposition 
 
 
 
X 
 
 
 
 
 
 
 
 


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Epoch  
 
1 
2 
3  
4 
Visit  
Pre-
screen 
1       
Screen 
101    
Run-in 
199 
TD/ 
PPD 
201       
RND/ BL  
202 
203 
204 
299 
TDA/ PPD 
301 
302 
 
399 
TDA/ 
PPD/ 
EOS 
Week 
 
-4 
-2 
0 
2 
4 
8 
12 
24 
36 
Epoch 3 phase disposition 
 
 
 
 
 
 
 
 
X 
 
 
 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
X 
Sub-studies (subset of patients) 
Sub-study 1: DXA (Section 6.4.3 & 
Section 6.5.5): Body 
composition/BMD 
 
 
 
 
X 
 
 
 
 
XD 
 
XD 
Sub-study 2: 24h urine collection 
(Section 6.4.10)  
Bone biomarkers (Section 6.5.3.4) 
Renal biomarkers (Section 6.5.3.4) 
 
 
 
 
X 
 
 
 
XG 
XG 
 
XG 
 
RND = Randomization visit;  
EOS = End of Study;  
TD = study treatment discontinuation;  
PPD = premature patient discontinuation;   
X = assessment to be recorded on clinical data base;  
S = assessment to be recorded on source documentation only;  
* = reassessed prior to randomization;  
A = patients only discontinuing study medication need to have such assessments done per unplanned assessment eCRF; 
B = laboratory values will be blinded;  
C = BMI will be calculated at Visit 1; 
D = no echocardiography/DXA assessment for patients <12 weeks after Visit 201 with PPD/TD. If week 12 echocardiography/DXA done before PPD/TD, no repeat 
echocardiography/DXA needed for patients < 24 weeks after Visit 201; 
G = urinary glucose values will be blinded;  
T = only triglycerides 
P = pre-screening for NT-proBNP, HbA1c, eGFR and serum potassium is optional (the pre-screening data will be handled as source documentation only). These laboratory 
parameters will be assessed from all patients by the central laboratory at Visit 1, independently whether or not pre-screening was done. At Visit 1, SAEs are to be collected from 
pre-screened patients only if the SAE is reported to be causally related with study procedures (i.e. blood sampling). 
 
 


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6.1 
Information to be collected on pre-screening failures or 
screening failures  
For all patients who have signed the pre-screening informed consent but fail the pre-screening, 
only SAE data will be collected if the SAE is reported to be causally related with study 
procedures (i.e. blood sampling). Adverse events that are not meeting this criterion will be 
followed by the investigator and collected only in the source data. 
All patients who have signed the study informed consent but fail the screening will have the 
Screening Phase Disposition eCRF for the screening epoch, demographics, inclusion/exclusion, 
and serious adverse event (SAE) data collected. Adverse events that are not serious will be 
followed by the investigator and collected only in the source data. 
6.2 
Patient demographics/other BL characteristics  
Demographic and BL characteristics data to be collected on all randomized patients include: 
year of birth, age, sex, race, ethnicity, relevant medical history/current medical conditions 
present before signing the study informed consent including smoking and alcohol history. 
Where possible, diagnoses and notable symptoms will be recorded.  
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the study informed 
consent form (ICF) signature. 
6.3 
Treatment exposure and compliance  
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. This information should be captured in the 
source documents at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. The site will also be required to complete the appropriate Dosage 
Administration Record eCRF to record any study drug regimen changes or interruptions. 
On-treatment medication 
For all medications (other than the study drug regimen) initiated after the start of study, the 
reason for prescribing the medication, and the start and, where applicable, end dates will be 
recorded on the Concomitant Medications eCRF. 
Rescue medication 
Information regarding the administration of rescue medication as per Section 5.5.6 will be 
recorded on the appropriate Rescue Medication eCRF. 


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6.4 
Efficacy 
6.4.1 
Weight and height 
Body weight will be measured to the nearest 0.1kg at visits indicated in Table 6-1 on a calibrated 
scale (weight and bio-impedance measurements, Section 6.4.3), provided by the sponsor. 
Exceptionally (e.g. if the body weight exceeds the limits of the provided scale) sites can use 
another scale for weight measurement as available, but during the study the same scale should 
be used for the same patient. The measurement will be performed with the study patient in 
underwear and without shoes. Indoor clothing is also acceptable, but measurements should be 
done consistently (either with underwear or with indoor clothing) throughout the study. Voiding 
before weight measurement is required. 
Height will be measured at Visit 1 and will be used to automatically calculate BMI. 
6.4.2 
NT-proBNP 
NT-proBNP will be measured from a blood sample at visits indicated in Table 6-1 and analyzed 
at a central laboratory. NT-proBNP measured at Visit 1 will be used for assessing an inclusion 
criterion (see Section 4.1) and will not be masked. The results of all NT-proBNP measurements 
after randomization (V201) will remain masked until final database lock, except that they will 
be extracted to a restricted area for the statistical/programming team to perform the analysis for 
the Week 12 analysis. 
6.4.3 
Body composition 
Body composition will be measured in all patients using bio-impedance, except in patients 
where it is contra-indicated, e.g. those using an implantable cardioverter-defibrillator, at visits 
indicated in Table 6-1. Body composition parameters will be assessed as available for the 
different models of calibrated bio-impedance scales. 
In about 25% of patients at participating sites, a DXA scan will be performed at visits indicated 
in Table 6-1. A whole body DXA scan will be acquired to assess body composition (lean body 
mass, fat mass, visceral fat mass, body water (calculated); in addition bone mineral density 
(BMD) will be assessed (Section 6.5.5). The exam takes approximately 10-15 minutes and is 
non-invasive.  
In order to assure quality throughout the study, the DXA instrument manufacturer and model 
should remain consistent at a site and its calibration should be monitored. Use of a standardized 
scan acquisition protocol and appropriate and unchanging scan acquisition and analysis 
software is essential to achieve consistent results. In order to reduce variability in interpretation 
of the scans, centralized scan analysis will be done by experienced staff. 
DXA will be performed according to the procedures described in the Imaging Manual. Prior to 
the examination, the patient will be checked for absence of removable metal objects on his/her 
body, such as snaps, belts, underwire bras, jewelry, and so on. The patient will then be 
positioned so that his/her body is straight on the mat and the site personnel must ensure that the 
positioning is consistent from scan to scan. A whole body array scan will then be initiated on 
the patient. 


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Immediately after the whole body scan, a DXA scan will be acquired to measure lumbar spine, 
hip and distal forearm bone mineral density. More details can be found in Section 6.5.5. 
DXA data will be transferred to a central reading vendor for independent review and analysis. 
 
 
 
 
 
 NYHA classification will be assessed and scored at each visit, and the results will be 
entered in the appropriate eCRF. 
6.4.5 
Echocardiography 
Echocardiography will be performed at visits indicated in Table 6-1. A subset of a standard 
echocardiographic two-dimensional and doppler examination will be performed. The images 
will be sent to a central reading vendor for independent review and analysis. An 
Echocardiography Manual with detailed instructions and data transfer procedures will be 
provided to the study sites.  
The following echocardiographic assessments will be performed: 
 
 
 
 
 
 
• Left atrial size and volume 
 
 
 
 
 
 
 
  
6.4.6 
HbA1c 
HbA1c will be measured from a blood sample obtained at visits indicated in Table 6-1 and 
analyzed using a National Glycohemoglobin Standardization Program (NGSP) certified method 
at a central laboratory. 
6.4.7 
FPG 
FPG will be measured from a blood sample obtained after an overnight fast (patients should not 
eat or drink anything (except water) at least for 8h before each study visit.) at visits indicated 
in Table 6-1 and analyzed at a central laboratory.  


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6.4.8 
Blood pressure (BP) 
Arterial BP, pulse rate readings and signs and symptoms of orthostasis will be assessed with an 
automated electronic BP device (if available at the study site). Alternatively, another BP device 
will be used.  
Three sitting BP measurements and one standing BP measurement will be performed at visits 
indicated in Table 6-1. Every effort should be made to have the same staff member obtain BP 
measurements for a given patient, at the same time of day, using the same equipment, at each 
visit. 
Sitting BP and standing measurements must be performed after completing the ePRO 
questionnaires (as applicable) and the ECG, and prior to blood draws and study medication and 
anti-diabetic medication intake. At Visit 1 (screening) BP must be measured at both arms. The 
arm with the higher SBP reading must be used for the BP measurements at Visit 1 and the same 
arm must be used at all subsequent visits. The arm used at each visit must be documented in the 
source documentation. 
The patient should be in a relaxed setting and measurements should not be taken immediately 
after exertion or the consumption of coffee. At each study visit, after the patient has been sitting 
for 5 minutes with the back supported and both feet placed on the floor, SBP and DBP will be 
measured three times using the BP device and an appropriate size cuff. The bladder of the cuff 
should be large enough to encircle 80% of the arm. The cuff should be placed so its bottom is 
1 to 2cm above the elbow and the arm should be supported so that the bottom of the cuff is at 
the level of the heart. The tube should run down the center of the arm, approximately in line 
with the middle finger. The patient should be asked to relax his/her arm and turn the palm 
upward. The patient should not speak or move their arm during the measurement deflation of 
the cuff. Three separate sitting BP should be obtained with a full two-minute interval between 
measurements and with the cuff fully deflated between measurements. The patient will then 
stand, and after standing for two minutes, one BP measurement will be taken (see also Section 
6.5.2).  
All 3 sitting BP measurements and the single standing measurement will be recorded and 
documented in the eCRF and in the patient’s source documents. All 3 sitting BP readings will 
be used for evaluation of sitting BP. The mean of the three sitting BP readings at randomization 
(Visit 201) will be used to assess eligibility for the study (see Inclusion/Exclusion Criteria in 
Section 4).  
6.4.9 
Fasting lipid profile 
Fasting lipid profile and TGs as described in Table 6-2 will be measured on blood samples 
obtained after an overnight fast at visits indicated in Table 6-1 and analyzed at a central 
laboratory. 


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Table 6-2 
Fasting lipid profile & TG, hs-CRP 
Category 
Parameter(s) 
Fasting lipid 
profile & TGs  
 
 
Inflammation 
biomarker 
TG, total cholesterol, HDL cholesterol, LDL cholesterol, calculated VLDL 
cholesterol and non-HDL cholesterol, lipoproteins (apolipoprotein A-I, 
apolipoprotein B) 
LDL cholesterol will be calculated if TG ≤400 mg/dL, if TG >400 mg/dL then 
direct LDL cholesterol measurement will be done.  
hs-CRP 
6.4.10 
24h urine collection 
UGE, albumin, creatinine and sodium excretion will be measured from a 24h urine collection 
from about 25% of randomized patients at visits indicated in Table 6-1 and analyzed at a central 
laboratory. UGE results after the baseline assessment will be kept blinded until the final 
analysis, except that they will be extracted to a restricted area for the statistical/programming 
team to perform the Week 12 analysis. 
Bone biomarkers (urinary calcium and phosphate excretion) and renal biomarkers (cystatin C, 
albumin and creatinine) will be measured from the same urine collection (see Section 6.5.3.4).  
Detailed instructions for urine collection will be provided to patients, and handling of the urine 
sample will be described in the laboratory manual. 24h urine collection will be done by the 
patients at home, therefore no overnight stay at the site is required.  
6.4.11 
Appropriateness of efficacy assessments  
N-terminal pro-brain natriuretic peptide (NT-proBNP) is a stable, biologically inert fragment 
cleaved from proBNP along with BNP. NT-proBNP is a marker of left ventricular wall stress. 
Elevated NT-proBNP levels are associated with adverse outcomes and reductions in NT-
proBNP levels have been associated with better outcomes in patients with HF (Masson et al 
2006; Komajda et al 2011).  
Echocardiography, weight and body composition, BP and fasting lipids are standard measures 
to assess the efficacy of a drug used in HF patients. HbA1c and FPG will inform about the 
glucose lowering effect of the drug. UGE measurement allows for evaluation of LIK066’s 
primary mode of action’s contribution to potential improvement in glycemic control and HF 
parameters. 
6.5 
Safety  
6.5.1 
Physical examination 
A complete physical examination will be performed at visits indicated in Table 6-1 and includes 
the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities (including feet), vascular status, volume 
status (see Section 3.1.2 ) and neurological status. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic examinations will be performed. 
A short physical exam will be performed at all scheduled visits indicated in Table 6-1 and at 
unscheduled study visits. This exam will include the examination of general appearance, feet, 


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vital signs (SBP and DBP, see Section 6.4.8), pulse rate, respiratory rate and assessment of heart 
failure signs and symptoms.  
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing IC must be included in 
the medical history part of the eCRF. Significant findings made after first administration of 
investigational drug which meet the definition of an AE must be recorded on the AE section of 
the eCRF. 
6.5.2 
Vital signs  
BP will be measured as described in Section 6.4.8. The pulse rate from the last sitting BP 
measurement will be recorded. Respiratory rate will also be measured. Clinically notable vital 
signs are defined in Appendix 1. 
6.5.3 
Laboratory evaluations 
Laboratory evaluations for safety will be performed at visits indicated in Table 6-1 and all 
specimens collected will be analyzed at a central laboratory. Details on the collection, shipment 
of samples, reporting of results by the central laboratory as well as laboratory notable range 
deviations are provided in the laboratory manual. 
6.5.3.1 
Hematology 
Samples for analysis of hematology (see Table 6-3) will be collected at visits indicated in Table 
6-1. 
Table 6-3 
Hematology evaluations 
Category 
Parameter(s) 
Hematology 
RBC (total), WBC (total), platelet count (direct), hemoglobin, hematocrit, 
basophils (absolute, %), eosinophils (absolute, %), lymphocytes 
(absolute, %), monocytes (absolute, %), neutrophils (absolute, %) 
6.5.3.2 
Clinical chemistry 
Samples for analysis of clinical chemistry (see Table 6-4) will be collected at visits indicated in 
Table 6-1.  
Table 6-4 
Clinical chemistry 
Category 
Parameter(s) 
Biochemistry 
ALT, albumin, alkaline phosphatase (ALP), AST, bicarbonates, bilirubin 
(direct, total), blood urea nitrogen (BUN), calcium (total), chloride (Cl-), 
creatinine, cystatin C, eGFR (MDRD), magnesium (Mg2+), phosphates, 
potassium (K+), protein (total), sodium (Na+), uric acid, γ-GT, amylase, 
lipase, serum ketones and beta hydroxybutyrate 
Chemistry (TSH) 
TSH (only at screening visit (Visit 1)) 
Chemistry (pregnancy) 
Serum β-HCG (only at screening visit (Visit 1)) 


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6.5.3.3 
Urinalysis 
Urine samples will be collected for analysis of parameters listed in Table 6-5 at visits indicated 
in Table 6-1.  Urine will be used to assess pregnancy and hematuria (dipstick) at visits indicated 
in Table 6-1 as well. Urine dipstick for hematuria can be re-tested in pre-menopausal women 
having their period (documented) at the time of the previous hematuria test. Urinary glucose 
results after the baseline assessment will be kept blinded until the final analysis, except that 
they will be extracted to a restricted area for the statistical/programming team to perform the 
Week 12 analysis. 
Table 6-5 
Urinalysis 
Category 
Parameter(s) 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, nitrites, blood, leucocytes 
Urinalysis 
UACR Urine albumin to creatinine ratio (spot urine), cystatin 
C/creatinine ratio (spot urine) 
Urine (dipstick) 
Hematuria, only at screening visit (Visit 1) 
Urine (dipstick) 
Pregnancy test (β-hCG) 
6.5.3.4 
Bone and renal biomarkers 
Serum samples for bone and renal biomarkers (see Table 6-6) will be collected from the patients 
participating in sub-study 2 at visits indicated in Table 6-1.   
Urine samples for bone and renal biomarkers from the patients participating in the sub-study 
will be assessed from 24h urine collection (Section 6.4.10). 
Table 6-6 
Biomarkers 
Category 
Parameter(s) 
Bone biomarkers 
β-c-terminal telopeptide (β-CTX1), serum procollagen type 1 N-
propeptide (sP1NP), intact parathyroid hormone (iPTH), 25-hydroxy 
vitamin D, 1,25 dihydroxy vitamin D, osteocalcin, oestradiol, Ca2+, Mg2+, 
phosphates (see also Table 6-4) 
Renal biomarkers 
Serum cystatin C, urinary cystatin C (24h urine sample), urinary 
creatinine (24h urine sample), urinary albumin (24h urine sample),  
6.5.4 
ECG 
Twelve-lead ECGs must be performed at visits described in Table 6-1. ECG equipment will be 
provided to the sites to ensure standardized output allowing for interpretation of the ECGs at a 
central reading facility. 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable ECG 
baseline. The preferred sequence of cardiovascular data collection during study visits is ECG 
collection first, followed by vital signs, and blood sampling. 
Each ECG tracing must be labeled with study number, patient initials, patient number, date and 
time, and filed in the study site source documents. For any ECGs with patient safety concerns, 
two additional ECGs must be performed to confirm the safety. 


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Clinically significant abnormalities must be recorded on the relevant section of the Medical 
History/Current Medical Conditions/AE eCRF(s) as appropriate. 
6.5.5 
Bone mineral density (BMD) 
In about 25% of patients at participating sites, DXA scans will be performed at visits indicated 
in Table 6-1.   
Immediately after DXA whole body scan to measure body composition (see Section 6.4.3), 
lumbar spine, hip and distal forearm DXA scans will be acquired to measure BMD. Optimum 
patient positioning will be described in the Imaging Manual.  
6.5.6 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing (see 
Section 6.5.3.2 & Section 6.5.3.3). Additional pregnancy testing may be performed if requested 
by local requirements. 
A positive urine pregnancy test requires immediate interruption of study drug until serum β-
human chorionic gonadotropin (β-hCG) is performed and found to be negative. If positive, the 
patient must be discontinued from the study treatment (see Section 5.6.2). 
6.5.7 
Appropriateness of safety measurements 
The safety assessments are standard for this indication/subject population. The following 
additional assessments are included to document and evaluate risks identified with SGLT2 
inhibitors or during the LIK066 clinical program: 
• Bone biomarkers will evaluate the effect of LIK066 on bone re-modeling  
• Renal biomarkers will evaluate whether LIK066 may cause kidney injury due to its dual 
SGLT1/2 inhibition. 
6.6 
Other assessments 


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6.6.2 
Resource utilization  
Not applicable. 


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7 
Safety monitoring  
7.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign including abnormal laboratory findings, symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study (or for participation in the pre-screening, as applicable) until the end of study visit. 
For patients who sign the pre-screening ICF, AEs which occur after signature of this consent 
will only be captured if they meet the definition of serious as outlined in Section 7.2.1 and are 
reported to be causally related with study procedures (i.e. blood sampling). Once the study ICF 
is signed, all AEs per the descriptions below will be captured as adverse events. 
An AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy  
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
• the severity grade 
• Mild: usually transient in nature and generally not interfering with normal activities 
• Moderate: sufficiently discomforting to interfere with normal activities 
• Severe: prevents normal activities 
• its relationship to the study treatment  
• “No Relationship to study treatment or other investigational treatment” or 
• “Relationship to study treatment” or 
• “Relationship to other investigational treatment” or  


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• “Relationship to both study treatment and other investigational treatment or 
indistinguishable“ 
• its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
• whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met. 
• action taken regarding investigational treatment  
 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:  
• no action taken (e.g. further observation only)  
• investigational treatment dosage increased/reduced 
• investigational treatment interrupted/withdrawn 
• concomitant medication given  
• non-drug therapy given  
• patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient study 
ICF and should be discussed with the patient during the study as needed. Any new information 
regarding the safety profile of the medicinal product that is identified between IB updates will 
be communicated as appropriate, for example, via an Investigator Notification (IN) or an 
aggregate safety finding. New information might require an update to the study informed 
consent and has then to be discussed with the patient. 
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 


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7.2 
Serious adverse events  
7.2.1 
Definition of SAE  
An SAE is defined as any adverse event appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the study informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
SAE reporting  
For patients who sign the pre-screening informed consent form, SAEs which occur after 
signature of this consent will only be captured if they are reported to be causally related with 
study procedures (i.e. blood sampling).  


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Every SAE, regardless of causality, occurring after the patient has provided study informed 
consent and until 30 days after the last study visit must be reported to Novartis within 24 hours 
of learning of its occurrence.  
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis if the investigator suspects a causal relationship to study treatment.  
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the SAE Report Form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report. The 
investigator must assess the relationship of each SAE to each specific component of study 
treatment, complete the SAE Report Form in English, and submit the completed form within 
24 hours to Novartis. Detailed instructions regarding the submission process and requirements 
for signature are to be found in the investigator folder provided to each site.  
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Novartis Chief Medical Office 
and Patient Safety associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
7.3 
Liver safety monitoring  
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified or reported as serious): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and completion of 
the standard base liver eCRF pages 


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Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.  
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2. 
For the liver laboratory trigger: 
• Repeat the liver function test (LFT) within the next week to confirm elevation. 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats must then be performed at the central laboratory as soon as possible. If a liver 
event is subsequently reported, any local LFTs previously conducted that are associated with 
this event must be reported on the Liver CRF pages. 
• If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
• Repeat the LFT to confirm elevation as appropriate 
• Discontinue the investigational drug if appropriate 
• Hospitalize the patient if appropriate 
• A causality assessment of the liver event should be made via exclusion of alternative causes 
(e.g., disease, co-medications) 
• Perform an investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate eCRF pages, including the liver 
event overview eCRF pages. 
7.4 
Renal safety monitoring  
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 
• Serum event: 
• confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status 
• Urine event 
• new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (UACR)  
• new onset (≥1+), hematuria  
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 3.  


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7.5 
Reporting of study treatment errors including misuse/abuse  
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (European Medicines Agency definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE. 
Table 7-1  
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error 
type 
Document in Dose 
Administration 
(DAR) eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes  
Yes, even if not 
associated with a SAE 
7.6 
Pregnancy reporting  
To ensure patient safety, each pregnancy occurring after signing the study ICF must be reported 
to Novartis within 24 hours of learning of its occurrence. In such instance, study treatment 
should be handled as per Section 5.6.2. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.  
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
7.7 
Prospective suicidality assessment 
Not applicable. 


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7.8 
AEs of special interest 
7.8.1 
Ketoacidosis 
In rare cases, SGLT-2 inhibitors can lead to ketoacidosis. Therefore, investigators must pay 
close attention for any signs of ketoacidosis. Signs and symptoms of ketoacidosis may include 
deep and rapid breathing, nausea, vomiting, severe abdominal pain, confusion, unusual fatigue 
or sleepiness, and coma. All signs and/or symptoms and results from relevant laboratory tests 
must be reported on the AE eCRF. If ketoacidosis is confirmed, the study treatment should be 
handled as per Section 5.6.2 and appropriate measures must be taken to correct the acidosis and 
monitor glucose levels. 
Every case of ketoacidosis must be reported to the Ketoacidosis Adjudication Committee (see 
Section 8.5), and the Ketoacidosis Adjudication eCRF must be completed by the Adjudication 
Committee. 
7.8.2 
Hypoglycemia 
Patients with T2DM treated with anti-diabetic agents may be at an increased risk of 
hypoglycemia due to the expected weight loss. All patients must be educated regarding 
hypoglycemic symptoms and treatment. This education should include general review of 
hypoglycemia: 
• Explanation of possible triggers of hypoglycemia (e.g., strenuous exercise, delayed meals, 
changes in meal composition, illness, Ramadan-period, etc.). 
• Identification of the symptoms of hypoglycemia (e.g., central symptoms such as dizziness, 
lightheadedness; adrenergic symptoms such as fast heart rate, palpitations, heart 
racing/pounding, shakiness; cholinergic symptoms such as sweating, hunger, blurred vision, 
impairment of motor function, confusion or inappropriate behavior). 
• Review of appropriate treatment for events (oral glucose intake). 
A home glucose monitor will be provided with all appropriate supplies and its use will be 
explained to the patient. Blood glucose should be measured each time the patient experiences 
symptoms which may be suggestive of hypoglycemia, as well as other time points as 
recommended by the investigator to inform about the need for reducing or discontinuing anti-
diabetic treatment to prevent severe hypoglycemic events. 
Any time the patient experiences symptoms which they suspect are related to hypoglycemia, 
the patient should treat the event as appropriate. Patients should record the event in the glycemia 
study diary, including:  
• The glucose value. 
• Precipitating factors (strenuous exercise, delayed or missed meals, changes in meal 
composition, illness, Ramadan-period, etc.). 
• Time of occurrence in relation to the last medication and to the last meal intake. 
• The treatment used. 
• The response to the treatment used. 
• Need for assistance to treat the hypoglycemia event. 


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• Additionally, if a patient performs routine self-monitoring of blood glucose, any 
asymptomatic plasma glucose < 70 mg/dL (< 3.9 mmol/L) should be treated and recorded 
in the glycemia study diary. 
• The glycemia study diaries will be dispensed at run-in (V101) and at following visits. The 
patient must return the completed study diary at each following  visit. 
Data entry 
The glycemia study diary will be reviewed by the investigator at each visit and any 
hypoglycemia must be recorded on the Hypoglycemic Events eCRF. 
8 
Data review and database management  
8.1 
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (ie eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and good clinical practice (GCP) compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture/data entry, the adherence to the protocol and to GCP, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis Clinical Research Associate organization. Additionally, a central analytics 
organization may analyze data and identify risks and trends for site operational parameters, and 
provide reports to Novartis Clinical Teams to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on eCRFs must be traceable to these source documents in the patient's file. The 
investigator must also keep the ICF(s) signed by the patient (a signed copy is given to the 
patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 


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8.2 
Data collection  
The trial will be conducted in a fully validated Data Capture system which conforms to US CRF 
21 Part 11 requirements. Investigator site staff will not be given access to the system until they 
have been trained. Designated investigator staff will enter the data required by the protocol into 
the Data Capture system. Automatic validation programs within the system check for data 
discrepancies in the eCRFs and by generating appropriate error messages, allow the data to be 
confirmed or corrected by the investigator staff. The investigator staff must certify that the data 
entered are complete and accurate. After database lock, the investigator will receive copies of 
the patient data for archiving at the investigational site. 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the eCRFs are complete and accurate. After database lock, the investigator 
will receive copies of the patient data for archiving at the investigational site.  
 
8.3 
Database management and quality control  
Novartis staff (or CRO working on behalf of Novartis) review the data entered into the eCRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query Form 
will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back 
to Novartis staff that will make the correction to the database. The signed copy of the Data 
Query Form is kept at the investigator site. 
Concomitant medications entered into the database will be coded using the World Health 
organization WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
(ATC) classification system. Concomitant procedures, non-drug therapies and adverse events 
will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
ECG, echocardiography and DXA assessments will be processed centrally and the results will 
be sent electronically to Novartis (or a designated CRO). 
Patients using electronic PROs will fill in their PRO data in a site based tablet. The system will 
be supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis personnel (or designated CRO).  
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 


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supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of 
Novartis.  
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management. 
8.4 
Data Monitoring Committee  
Not required. 
8.5 
Adjudication Committee  
A Ketoacidosis Adjudication Committee will review cases suspected for ketoacidosis as defined 
in the adjudication charter (see also Section 7.8.1). 
9 
Data analysis  
The main analysis will be performed at the end of Epoch 3 when all patients complete their 
treatment and assessments for Epoch 3, and data collected up to and including week 12 (Visit 
301) are cleaned (referred to as “Week 12 analysis” in sections below). The study remains 
blinded (see Section 5.4). 
Data collected during Epoch 4 will be analyzed based on the secondary objectives requiring 
data collection beyond Week 12 and will complement the results from the Week 12 analysis. 
The analysis performed after study end is referred to as “End of study analysis” in sections 
below.  
For both Week 12 analysis and End of study analysis, treatment group refers to LIK066 2.5mg 
qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd unless 
specified otherwise.   
9.1 
Analysis sets  
The following analysis populations will be defined for statistical analysis. Subjects without 
valid written study informed consent will be excluded from all analysis sets.  
Screened set (SCR) – All patients who signed the study informed consent. The SCR includes 
only unique screened patients, i.e., in the case of re-screened subjects only the chronologically 
last screening data is counted.   
Randomized set (RAN) – All patients who received a randomization number, regardless of 
receiving trial medication.   


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Safety set (SAF) (double-blind phase) – All patients who received at least one dose of double-
blind study drug. Patients will be analyzed according to treatment received. Treatment received 
will be considered identical to the randomized treatment if the patient has received at least one 
dose of the randomized treatment.  
Full analysis set (FAS) – All patients in RAN who were not mis-randomized*. Following the 
intent-to-treat (ITT) principle, patients are analyzed according to the treatment they have been 
assigned to at the randomization.  
* Mis-randomized patients are those who have not been qualified for randomization and who 
have been inadvertently randomized into the study, but have not received double-blind study 
drug. Mis-randomized patients are defined as cases where IRT contacts were made by the site 
either prematurely or inappropriately prior to confirmation of the patient’s final randomization 
eligibility and double-blind medication was not administered to the patient. These patients were 
subsequently discontinued from the study.  
 
Per protocol set (PPS) – All patients in FAS who took at least one dose of study medication 
and had no major protocol deviations.  
Major protocol deviations are those ones affecting the primary endpoint analyses, and will be 
pre-specified prior to unblinding treatment codes for analyses. A list will be provided in the 
Clinical Study Report Statistical Analysis Plan.  
9.2 
Patient demographics and other baseline characteristics  
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including sex, age, race, weight, height, body mass index (BMI), systolic blood 
pressure, diastolic blood pressure, eGFR, LVEF, LVEF group (< 45% versus ≥ 45%), 
geographical region, NYHA class and medical history. These summaries will be performed for 
the FAS. 
Continuous variables will be summarized using n, mean, standard deviation (SD), median, Q1 
(25th percentile), Q3 (75th percentile), minimum, and maximum. Categorical variables will be 
summarized using frequency and percentage. 
9.3 
Treatments  
 
Week 12 analysis 
The duration of double-blind treatment exposure in Epoch 3 will be summarized descriptively 
by treatment group (using n, mean, standard deviation, median, Q1, Q3, minimum and 
maximum) for the SAF. In addition, the number and percentage of patients will be summarized 
by treatment group for duration category.   
Prior and concomitant medications/ non-drug therapies will be summarized in separate tables 
as appropriate for the safety population.  
The number and percentage of patients taking rescue medication, 
and duration of exposure to rescue medication during Epoch 3 will be summarized by treatment 
group for the SAF. The use of prohibited medication, if any, will also be summarized. 


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End of study analysis 
The analyses for End of study analysis will be similar to the analyses performed for Week 12 
analysis as described above, except that the summaries of treatments will be provided for the  
overall study treatment duration: Epoch 3+Epoch 4. 
9.4 
Analysis of the primary variable(s) 
In general, NT-proBNP data follows a log-normal distribution. Therefore a log-transformation 
on the NT-proBNP data will be performed before all statistical analyses are carried out. The 
analysis results will then be back-transformed and displayed as percentages for ease of data 
interpretation. 
9.4.1 
Variable(s) 
The primary efficacy variable is log-transformed ratio of NT-proBNP (pg/mL) collected at 
Week 12 to BL (i.e., change from BL in log-transformed NT-proBNP at Week 12). Missing 
Week 12 values will be imputed using a multiple imputation approach as described in Section 
9.4.3. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The objective of determination of a dose-response signal and dose-response relationship in 
LIK066 doses compared to placebo will be evaluated using the Multiple Comparison 
Procedure-Modeling (MCP-MOD) method described in Pinheiro et al, 2006 & Pinheiro et al, 
2014.  
Test of the dose response signal 
The null hypothesis of a flat dose-response relationship for the reduction in NT-proBNP 
compared to placebo will be tested at a one-sided significance level of 2.5% against the 
alternative hypothesis of a dose-response relationship leading to a significant decrease in NT-
proBNP after 12 weeks of treatment.  
Hence, the following null and alternative hypotheses will be tested: 
• H01: there is no dose-response relationship or a dose response in the wrong direction for 
LIK066 after 12 weeks of treatment (i.e. the dose response relationship is flat, or as dose 
increases, there is less reduction in NT-proBNP from baseline). 
• H11: there is a dose-response relationship in the right direction for LIK066 after 12 weeks 
of treatment (i.e. as dose increases, there is more reduction in NT-proBNP from baseline). 
There are six candidate models to capture the shape of the dose response relationship for 
LIK066 at Week 12 endpoint, as depicted in Figure 9-1. The candidate models generate a set 
of six contrasts which will be evaluated using the data to test the above dose-response 
hypothesis. 
• Model 1: Emax with ED50 at 3mg. 
• Model 2: Emax with ED50 at 10mg. 


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• Model 3: Emax with ED50 at 25mg. 
• Model 4: linear. 
• Model 5: sigmoid Emax with ED50 at 15mg and hill parameter h=2. 
• Model 6: sigmoid Emax with ED50 at 25mg and hill parameter h=3. 
Figure 9-1 
Dose-response curve of candidate models 
 
The analysis to derive the test statistics is based on an analysis of covariance (ANCOVA) model 
with the log-transformed ratio of NT-proBNP (pg/mL) at Week 12 to baseline as a response 
variable, treatment (placebo and all LIK066 doses), stratification variables geographical region 
and LVEF (< 45% versus ≥ 45%) as factors, and the baseline in log-transformed NT-proBNP 
as a covariate. As needed, centers will be pooled according to country and region for the purpose 
of analysis.  
The response variable of log-transformed ratio of NT-proBNP (pg/mL) at Week 12 to baseline 
used in the above ANCOVA is from an imputed dataset, where the missing Week 12 NT-
proBNP is imputed using the multiple imputation method as described in Section 9.4.3. In order 
to account for the imputation uncertainty, this ANCOVA model will be repeated for each 
imputed dataset, which results in a set of least squares (LS) mean estimates for all dose groups 
and the related covariance matrices. Rubin’s rule will be used to combine the multiple sets of 
LS mean estimates and the related covariance matrices to a single set of LS mean estimates of 
log-transformed ratio of NT-proBNP (pg/mL) at Week 12 to baseline for all dose groups and 
the related covariance matrix.   


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The optimal contrasts derived from the candidate model sets will be applied to the combined 
estimated dose means and covariance matrix to obtain the t statistics for each candidate model 
and the common critical value C0.025. C0.025 is the common critical value derived from the 
reference multivariate t-distribution with the 6x6 correlation matrix induced by testing the 
candidate dose response models with respect to comparing all LIK doses to placebo group. 
The H01 will be rejected and the statistical significance of dose-response in NT-proBNP 
reduction is established if the max(t1, t2, t3, , …, t6) ≥ C0.025. 
Model averaging to obtain the dose response  
The response data in each imputed data set, including relevant covariates, will be used to fit the 
models in the candidate set.  The estimated dose-response will be derived by using model 
averaging methods on a subset of candidate models, for which the associated contrast tests are 
statistically significant. If there are more than three candidate models that are statistically 
significant, the top three models with largest t-statistics as calculated above will be selected as 
basis for the model averaging.  
Model averaging will be carried out for each imputed data set, and the resulting mean efficacy 
estimates and confidence intervals will be derived using the combination variance that accounts 
for the uncertainty of the imputed data using Rubin’s combination rules. Comparisons between 
LIK066 doses and placebo will be simultaneously derived for the model averaged estimates 
together with confidence intervals reflecting the imputation procedure applied. The model-
averaging-based estimates of mean changes in log-transformed NT-proBNP within each dose 
group, mean differences between LIK066 and placebo and their confidence intervals will then 
be back-transformed and displayed as ratios of NT-proBNP geometric mean at Week 12 to 
baseline within dose group, and relative rate of these ratios between LIK066 and placebo. 
Target dose selection will be based on the model averaged dose response estimates of mean 
NT-proBNP reduction efficacy of LIK066 over the dose range studied in the study. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Missing data for the primary endpoint will be imputed using a multiple imputation approach 
assuming that the missingness mechanism can be retrieved from observed data (missing at 
random (MAR)). The imputation model will include the longitudinal sequence of NT-proBNP 
data collected at baseline, Week 4 and Week 12 visits, stratification factors geographical region 
and LVEF (< 45% versus ≥ 45%), and other baseline covariates as appropriate.  
The full detailed information about the multiple imputation algorithms will be specified in a 
separate statistical analysis plan. 
9.4.4 
Supportive analyses  
As a sensitivity analysis, the dose-response modeling as described in Section 9.4.2 will be 
conducted for the PPS. Results based on the single best dose response model fit will also be 
reported. 
Summary statistics for NT-proBNP will be presented by visit (up to and including week 12 
visit) and treatment for observed and imputed values. The summary statistics (n, mean, standard 


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deviation (SD), median, Q1, Q3, minimum and maximum) will be presented by visit and 
treatment for NT-proBNP and change from BL in NT-proBNP. Figures will be produced to 
visually show the raw and the imputed mean changes by visit over 12 weeks of Epoch 3 for 
each treatment group, for all patients and by LVEF group (< 45% vs.  ≥ 45%).  
In addition, summary statistics for the NT-proBNP will be presented by visit (up to and 
including week 12 visit) and treatment for observed and imputed values, by the following 
subgroups: 
• LVEF at baseline: < 45% vs. ≥ 45% 
• NYHA class at baseline: II vs. III &IV 
• NT-proBNP at baseline: < median vs. ≥ median 
9.5 
Analysis of secondary variables 
The secondary efficacy variables will be analyzed in the FAS. Statistical testing of hypotheses 
on the secondary efficacy endpoints will be performed at the two-sided 0.05 significance level 
without adjustment for multiplicity. Safety variables will be analyzed in the SAF.   
9.5.1 
Efficacy variables 
9.5.1.1 
Variables 
For the comparison of LIK066 doses vs. placebo and LIK066 doses vs. empagliflozin (EMPA) 
at Week 12 and Week 36: 
• Change from BL in HbA1c  
• Change from BL in FPG  
• Change from BL in SBP and DBP  
• Change from BL in weight  
• Change from BL in body composition (assessed by bio-impedance)  
• Change from BL in body composition (assessed by DXA in a subset of patients)  
• Percentage change from BL in  fasting lipid profile (TG, total cholesterol, HDL 
cholesterol, LDL cholesterol, calculated VLDL cholesterol and non-HDL cholesterol, 
lipoproteins (apolipoprotein A-I, apolipoprotein B))  
• Change from BL in log-transformed hs-CRP  
• Change from BL in 24h urinary glucose and sodium excretion (in a subset of patients) 
For the comparison of LIK066 doses vs. placebo at Week 12 and Week 36: 
• Change from BL in left atrial size and volume assessed by echocardiography  
• Change from BL in NYHA class  
 
For the comparison of LIK066 doses vs. placebo at Week 36: 
• Change from BL in log-transformed NT-proBNP  
9.5.1.2 
Analysis method 
Analysis of change from BL in log-transformed NT-proBNP at Week 36 


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The same dose-response modeling approach using MCP-Mod on the primary endpoint of 
change from BL in NT-proBNP at week 12 will be used to evaluate the dose response in NT-
proBNP change at BL to Week 36 for the LIK066 doses as compared to placebo. 
Summary statistics for NT-proBNP will be presented by visit and treatment for observed and 
imputed values throughout the overall trial period. The summary statistics (n, mean, standard 
deviation (SD), median, Q1, Q3, minimum and maximum) will be presented by visit and 
treatment for the BL values, post-BL values and changes from BL in NT-proBNP. Figures will 
be produced to visually show the raw and the imputed mean changes by visit for each treatment 
group, for all patients and by LVEF group (< 45% vs. ≥ 45%).  
 
Analysis of other continuous outcome variables 
The following continuous variables will be analyzed using the methods described in this 
section: 
• Change from BL in HbA1c at Week 12 and Week 36 
• Change from BL in FPG at Week 12 and Week 36 
• Change from BL in SBP and DBP at Week 12 and Week 36 
• Change from BL in weight at Week 12 and Week 36 
• Change from BL in body composition (assessed by bio-impedance) at Week 12 and 
Week 36 
• Percentage change from BL in fasting lipid profile (TG, total cholesterol, HDL 
cholesterol, LDL cholesterol, calculated VLDL cholesterol and non-HDL cholesterol, 
lipoproteins (apolipoprotein A-I, apolipoprotein B)) at Week 12 and Week 36 
• Change from BL in log-transformed hs-CRP at Week 12 and Week 36 
• Change from BL in left atrial size and volume assessed by echocardiography at Week 
12 and Week 36 
The change from baseline in a continuous outcome at Week 12 (or Week 36) will be analyzed 
using a mixed effect model of repeated measures (MMRM) in which the stratification variables 
(geographical region and LVEF < 45% vs. ≥ 45%), treatment group, visit, and treatment group-
by-visit interaction will be included as fixed-effect factors and baseline outcome variable will 
be included as a covariate, with a common unstructured covariance matrix for all treatment 
groups. The analysis will be performed based on change from baseline in the outcome variable 
at all post-baseline scheduled visits up to Week 12 (or Week 36) and based on likelihood method 
with an assumption of MAR for missing data. Based on the MMRM model, the estimates and 
the 95% confidence intervals will be provided for the adjusted means of the change from 
baseline in the outcome variable at Week 12 (or Week 36) for each treatment group, and for the 
adjusted mean difference at Week 12 (or Week 36). 
For an outcome variable, the treatment effect (mean difference) of LIK066 doses vs. Placebo 
or LIK066 doses vs. empagliflozin will be analyzed using the MMRM model as described 
above including all treatment groups: LIK066 2.5mg qd, LIK066 10gm qd, LIK066 50mg qd, 
Empagliflozin 25mg qd and Placebo qd. For the comparison of LIK066 doses vs. Placebo, the 
treatment effects of LIK066 2.5mg qd vs. Placebo qd, LIK066 10mg qd vs. Placebo qd and 
LIK066 50mg qd vs. Placebo qd will be presented; For the comparison of LIK066 doses vs. 


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EMPA, the treatment effects of LIK066 2.5mg qd vs. Empagliflozin 25mg qd, LIK066 10gm 
qd vs. Empagliflozin 25mg qd and LIK066 50mg qd vs. Empagliflozin 25mg qd will be 
presented. 
In addition, summary statistics (n, mean, SD, median, Q1, Q3, minimum and maximum, and 
geometric mean for log-transformed variables) for these variables will be presented by visit and 
treatment. 
 
Analysis of ordinal outcome variable 
The change from BL in NYHA class at a given visit is a three-category ordinal variable 
(improved/unchanged/worsened) with the following definition: 1. Improved, if NYHA class 
decreases at least one level from BL; 2. Unchanged, if NYHA class is unchanged from BL; 3. 
Worsened, if NYHA class increases at least one level from BL.  
The NYHA class change from BL at Week 12 (or Week 36) will be analyzed using a repeated 
measures proportional odds cumulative logit model in which the stratification factors 
(geographical region and LVEF < 45% vs. ≥ 45%), treatment group, visit, and treatment group-
by-visit interaction will be included as fixed-effect factors, baseline NYHA class will be 
included as a covariate, and patient will be included as random effects. The analysis will be 
performed based on change from baseline in NYHA class at all post-baseline scheduled visits 
up to Week 12 (or Week 36) and based on likelihood method with an assumption of MAR for 
missing data. The estimate and the 95% confidence interval will be provided for the adjusted 
odds ratio at Week 12 (or Week 36) based on the longitudinal proportional odds cumulative 
logit model.  
The treatment effect (odds ratio) of LIK066 doses vs. placebo will be analyzed using the 
repeated measures proportional odds cumulative logit model as described above including all 
treatment groups: LIK066 2.5mg qd, LIK066 10mg qd, LIK066 50mg qd, Empagliflozin 25mg 
qd and Placebo qd. For the comparison of LIK066 doses vs. Placebo, the treatment effects of 
LIK066 2.5mg qd vs. Placebo qd, LIK066 10gm qd vs. Placebo qd and LIK066 50mg qd vs. 
Placebo qd will be presented. 
In addition, NYHA class will be summarized by visit and treatment group using frequency and 
percentage. A shift table will be provided to summarize the NYHA class shifting from BL to 
Week 12 (or Week 36) for Week 12 Analysis (or End of Study Analysis). 
 
Analysis of outcome variables from a sub-study 
Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be provided by visit and treatment for the outcome variables from a sub-study, for 
measurement at each visit and change from baseline values.  
The following outcome variables from sub-studies will be analyzed using the method as 
described above:  
• Change from BL in body composition (lean body mass, fat mass, visceral fat mass and 
body water (calculated) assessed by dual-energy x-ray absorptiometry (DXA)) at Week 
12 and Week 36 
• Change from BL in 24h urinary glucose and sodium excretion at Week 12 and Week 36 


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9.5.2 
Safety variables  
The safety assessments are listed below: 
• Identified and potential risks 
• AEs and SAEs 
• Vital signs 
• Laboratory evaluations 
• ECG  
• 24h urinary calcium and phosphate excretion (in a subset of patients) 
• BMD (in a subset of patients) 
The incidence of treatment emergent AEs (events started on or after the study treatment start 
date during Epoch 3 will be summarized by primary system organ class and preferred term. 
Summaries will also be provided by severity and relationship to study medication. The 
incidence of death, SAEs, and AEs leading to discontinuation will be summarized separately 
by primary system organ class and preferred term. The number and percentage of patients with 
AEs related to identified and potential risks will be summarized by treatment.  
Laboratory data will be summarized by presenting shift tables, summary statistics of raw data 
and change from baseline and by flagging of notable values in data listings.   
Other safety assessments (e.g., vital signs and ECG) will be summarized descriptively by 
treatment as appropriate. Data will be listed, notable values will be flagged, and other 
information collected will be listed as appropriate.   
Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be provided by visit and treatment for the 24h urinary calcium, phosphate excretion and 
BMD from the sub-study, for measurement at each visit and change from baseline values. 
The above analyses will be performed for the SAF for data collected during Epoch 3 for Week 
12 analysis. For End of study analysis, these analyses will be carried out for data collected 
during Epoch 3 + Epoch 4.  
9.5.4 
DNA  
Not applicable 


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9.7 
Interim analyses 
Not applicable 
9.8 
Sample size calculation 
The study planned to randomize approximately 496 patients in total, allocated in the ratio of 
1:1:2:2:2 to the LIK066 2.5mg qd, 10mg qd, 50mg qd, empagliflozin and placebo treatment 
groups, respectively.  
The following power calculations are based on the primary efficacy variable of log-transformed 
ratio of NT-proBNP at Week 12 to baseline. Due to the lack of available data in this patient 
population there is uncertainty on the standard deviation (SD) of the log-transformed ratio of 
week 12 to BL in NT-proBNP. Therefore calculations are provided for assumptions of SD in 
the range of 0.8, 0.85 to 0.9 to reflect the impact of this uncertainty on the power estimation. 
Based on the data from the PARAMOUNT HF study (data on file), a SD of 0.85 was considered 
a reasonable estimate. 
Assuming a one-sided 2.5% significance level (with adjustments for multiple comparisons 
using the MCP-MOD), a sample size of approximately 496 patients (124 each in placebo and 
LIK high dose; 62 each in LIK low doses; 124 in empagliflozin that is not included in the dose-
response modeling)  will provide a mean power (over all candidate models) of 75%(or 90%) to 
detect a dose response signal, assuming that the underlying true maximum NT-proBNP 
reduction on LIK066 vs placebo is 25% (or 30%), and the standard deviation (on the log scale) 
is 0.85. 
Table 9-1 
Power for detecting a significant dose response signal* 
Effect size for best dose 
SD 
Average power 
Minimum power† 
20% 
0.8 
58% 
54% 
20% 
0.85 
53% 
49% 
20% 
0.9 
48% 
45% 
25% 
0.8 
80% 
76% 
25% 
0.85 
75% 
71% 
25% 
0.9 
70% 
66% 
30% 
0.8 
93% 
91% 
30% 
0.85 
90% 
88% 
30% 
0.9 
87% 
84% 
* Assumes 372 patients in LIK066 and placebo arms with effective sample size of 336 patients due to an 
effect of missing data equivalent to 10% fewer patients. Calculations were performed using the DoseFinding 
package in R. 
† Power for a significant dose-response contrast test across all scenarios in Figure 9-1. The candidate model 
Emax with ED50 of 3mg has the lowest power. 
 
Power consideration for assessing the glucose-lowering potential at Week 12 
To explore the glucose-lowering potential of LIK066 vs. placebo or empagliflozin (EMPA), the 
treatment difference in HbA1c change from BL to Week 12 will be considered. 


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Table 9-2 
Comparison of LIK versus placebo (at 2-sided alpha of 0.05) 
 
Expected 
treatment 
difference  
SD 
Power 
LIK high dose (n=124) versus placebo 
(n=124)* 
0.5% 
1 
96% 
Any LIK low dose (n=62) versus 
placebo (n=124)* 
0.5% 
1 
85% 
*assuming 10% information loss due to drop-out. 
Table 9-3 
Comparison of LIK versus empagliflozin  
 
Expected 
treatment 
difference 
SD 
Probability 
of 
the 
95% 
confidence 
interval upper bound 
< 0.4% 
LIK high dose (n=124) versus EMPA 
(n=124) 
0 
1 
84% 
Any LIK low dose (n=62) versus 
EMPA (n=124) 
0 
1 
68% 
*assuming 10% information loss due to drop-out. 
The calculations in Table 9-2 and 9-3 were performed using nQuery 7.0. No multiple testing 
adjustment was applied. 
10 
Ethical considerations  
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
10.2 
Informed consent procedures  
Eligible patients may only be included in the pre-screening or in the study after providing 
written (witnessed, where required by law or regulation), IRB/IEC-approved informed consent, 
or, if incapable of doing so, after such consent has been provided by a legally acceptable 
representative(s) of the patient. In cases where the patient’s representative gives consent, the 
patient must be informed about the pre-screening and/or the study, as applicable, to the extent 
possible given his/her understanding. If the patient is capable of doing so, he/she must indicate 
assent by personally signing and dating the written informed consent document or a separate 


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assent form. Informed consent must be obtained before conducting any pre-screening or study-
specific procedures (e.g. pre-screening assessments/all of the procedures described in the 
protocol). The process of obtaining informed consent must be documented in the patient source 
documents.  
Novartis will provide to investigators in separate documents proposed pre-screening and study 
informed consent forms that comply with the ICH GCP guideline and regulatory requirements 
and are considered appropriate for pre-screening and for participation in the study. Any changes 
to the proposed consent forms suggested by the investigator must be agreed to by Novartis 
before submission to the IRB/IEC, and a copy of the approved version must be provided to the 
Novartis monitor after IRB/IEC approval. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study. 
10.3 
Responsibilities of the investigator and IRB/IEC  
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
informed consent form(s), consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. 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. 
10.4 
Publication of study protocol and results  
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
10.5 
Quality Control and Quality Assurance  
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Global 
Development Quality Audit, a group independent from those involved in conducting, 


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monitoring or performing quality control of the clinical trial. The clinical audit process uses a 
knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
11 
Protocol adherence  
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.  
11.1 
Protocol amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients may be implemented immediately provided the health authorities are subsequently 
notified by protocol amendment and the reviewing IRB/IEC is notified. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any patient included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring must be followed. 
 
 


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12 
References  
Bailey CJ, Gross JL, Pieters A, et al (2010) Effect of dapagliflozin in patients with type 2 
diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, 
placebo-controlled trial. Lancet; 375: 2223-33. 
Bay M, Kirk V, Parner J, et al (2003) NT-proBNP: a new diagnostic screening tool to 
differentiate between patients with normal and reduced left ventricular systolic function. Heart 
2003; 89:150–154.Chun S, Tu J, Wijeysundera H et al, (2012). Lifetime analysis of 
hospitalizations and survival of patients newly admitted with heart failure. Circ Heart Fail; 5: 
414-421 
Ferrannini E, Mark M et Mayoux E (2016) CV Protection in the EMPA-REG OUTCOME Trial: 
A“Thrifty Substrate” Hypothesis. Diabetes Care DOI: 10.2337/dc16-0330; published ahead of 
print 
Fitchett D, Zinman B, Wanner C et al, (2016) Heart failure outcomes with empagliflozin in 
patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME 
trial. Eur Heart J; doi:10.1093/eurheartj/ehv728 (published ahead of print) 
Green CP, Porter CB, Bresnahan DR, Spertus JA (2000). Development and evaluation of the 
Kansas City cardiomyopathy questionnaire: a new health status measure for heart failure. 
Journal of the American College of Cardiology; 35 (5):1245-55. 
Herdman M, et al (2011) Development and preliminary testing of the new five-level version of 
the EQ-5D (EQ-5D-5L). Qual Life Res; 20 (10): 1727-1736. 
Kazsnick J, Drzewoski M (2014) Heart failure in the diabetic population – pathophysiology, 
diagnosis and management. Arch Med Sci; 10, 3: 546–556 
Komajda M, Carson PE, Hetzel S, et al (2011) Factors associated with outcome in heart failure 
with preserved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved 
Ejection Fraction Study (I-PRESERVE). Circ Heart Fail; 4: 27–35. 
Masson S, Latini R, Anand IS, et al. (2006). Direct Comparison of B-Type Natriuertic Peptide 
(BNP) and Amino-Terminal proBNP in a Large Population of Patients with Chronic and 
Symptomatic Heart Failure: The Valsartan Heart Failure (Val-HeFT) Data. Clinical Chemistry; 
52: 1528-1538 
Nauck MA, Del Prato S, Meier JJ, et al (2011) Dapagliflozin vs glipizide as add-on therapy in 
patients with type 2 diabetes who have inadequate glycemic control with metformin. Diabetes 
Care; 34(9): 2015-22. 
Neal B, Prekovic V, Mahaffey KW, et al. (2017) Canagliflozin and Cardiovascular and Renal 
Events in Type 2 Diabetes. NEJM; doi: 10.1056/NEJMoa1611925. 
Nichols GA, Gullion CM, Koro CE et al, (2004). The incidence of congestive heart failure in 
Type 2 Diabetes. Diabetes Care 27:1879–1884 
Nyirjesy P, Zhao Y, Ways K, et al (2012) Evaluation of vulvovaginal symptoms and Candida 
colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium 
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Pinheiro J, Bornkamp B, Bretz F (2006) Design and analysis of dose finding studies combining 
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639-56. 
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Statistics in Medicine; 33: 1646-661 
Ponikowski P, Voors AA, Anker SD, et al (2016) 2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of 
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the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 
Jul 14;37(27): 2129-200. doi: 10.1093/eurheartj/ehw128. Epub 2016 May 20 
RosenstockJ and Ele Ferrannini (2015) Euglycemic diabetic ketoacidosis: a predictable, 
detectable, and preventable safety concern with SGLT2 inhibitors. Diabete Care; 38:1638–1642 
Sattar N, McLaren J, Kristensen S et al, 2016 SGLT2 Inhibition and cardiovascular events: why 
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59:1333–1339 
Solomon SD, Zile M, Pieske B, et al (2012) The angiotensin receptor neprilysin inhibitor 
LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized 
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Solomon SD, Claggett B, Desai AS, et al (2016) Influence of Ejection Fraction on Outcomes 
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Circulation; 105:1727-1733 
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Conceptual framework and item selection. Medical Care, 30 (6): 473-483. 
Yancy CW, Jessup M, Bozkurt B et al, (2013) 2013 ACCF/AHA Guideline for the Management 
of Heart Failure: Executive Summary. Circulation;128:1810-1852 
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Mortality in Type 2 Diabetes. NEJM; 373:2117-28 
 


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


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


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Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN 
accompanied by 
symptomsb 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks  
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
bone pathology) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish causality 
• 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, discontinue the 
study drug immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient  
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
Jaundice 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Consider study treatment interruption or 
discontinuation  
• 
Hospitalization if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death. 


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

SAP_001.pdf: 
Clinical Development
LIK066
CLIK066B2204 / NCT03152552
A multi-center, randomized, double-blind, parallel-group 
dose-finding study to assess the effect of 3 doses of 
LIK066 compared to placebo or empagliflozin in type 2 
diabetes mellitus patients with heart failure
Statistical Analysis Plan (SAP) Amendment 1
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
3-Aug-2018
Number of pages:
36
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CLIK066B2204
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
May, 
2018
Before 
DBL
Changes in 
planned 
analyses 
due to the 
decision of 
early study 
termination
Removed the definition of per-protocol 
set and its relevant content 
Sections 2.2, 
2.3.1, 2.5.4, 
2.6.1, 
Tables 5-2, 5-3
Updated subgroup analyses
Sections 2.2.1, 
2.3.2, 2.5.4, 
2.6.1.2
Removed “Week 12 Analysis” and 
“End of Study Analysis” as defined in 
the study protocol
Throughout the 
document, 
wherever 
applicable
Updated efficacy analyses
Sections 2.5, 
2.6.1.2, 2.7.1.2, 
2.8.2
Removed “on-treatment” safety 
analyses
Sections 2.6.2.1, 
2.6.2.2
Removed analyses for treatment 
interruption
Section 2.4.1
 
11-
Jul-
2018
Before 
DBL
To 
align 
with 
project 
standard
Updated the definitions of prior and 
concomitant medications and non-drug 
therapies
Section 2.4.2


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Updated the definition of Enrolled Set
Section 2.2


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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.3.2
Demographics and baseline characteristics...........................................14
2.3.3
Medical history......................................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies...................................................16
2.5
Analysis of primary objective................................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................18
2.5.3
Handling of missing values/censoring/discontinuations.......................18
2.5.4
Supportive analyses...............................................................................19
2.6
Analysis of secondary objectives...........................................................................19
2.6.1
Efficacy variables..................................................................................19
2.6.2
Safety analyses......................................................................................20
28
28
29
 
29
29
29
2.9
Interim analysis......................................................................................................29
3
Sample size calculation .....................................................................................................29
4
Change to protocol specified analyses ..............................................................................31


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5
Appendix ...........................................................................................................................31
5.1.1
Study drug.............................................................................................31
5.1.2
AE date imputation ...............................................................................31
5.1.3
Concomitant medication date imputation .............................................32
5.2
AEs coding/grading ...............................................................................................33
5.3
Laboratory parameters derivations ........................................................................34
5.4
Rule of exclusion criteria of analysis sets..............................................................34
5.5
Search criteria for the anti-diabetic medications by type: .....................................35
6
Reference...........................................................................................................................36


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Chemical classification system
bid
bis in diem/twice a day
BMD
Bone Mineral Density
BMI
Body Mass Index
CSR
Clinical Study Report
DMC
Data Monitoring Committee 
ECHO
Echocardiography
eCRF
Electronic Case Report Form
ENR
Enrolled Set
FAS
Full Analysis Set
FPG
Fasting plasma glucose
Hb1Ac
Glycated hemoglobin
HF
Heart failure
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
LVEF
Left Ventricular Ejection Fraction
NCI
National Cancer Institute
OAD
Oral Antidiabetic Drug
o.d.
Once Daily
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
PT
Preferred Term
qd
Qua’que di’e / once a day
RAN
Randomized Set
RAP
Report and Analysis Process
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SCR
Screened Set
SOC
System Organ Class
T2DM
Type 2 Diabetes Mellitus
TFLs
Tables, Figures, Listings
TZD
Thiazolidinedione
WHO
World Health Organization


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1
Introduction
Due to the early termination of the study, the planned analyses for a full/complete CSR (as 
outlined in the study protocol) may not provide clinically and/or statistically meaningful results. 
Therefore, an abbreviated CSR was planned for the study CLIK066B2204. This document
provides details of the statistical analyses to support the completion of the abbreviated Clinical 
Study Report (CSR) for the study CLIK066B2204. 
1.1
Study design
This is a multi-center, randomized, double-blind, double-dummy, parallel-group study 
evaluating the efficacy, safety and tolerability of 3 doses of LIK066 vs placebo and vs
empagliflozin in type 2 diabetes mellitus (T2DM) patients with heart failure (HF). 
Pre-Screening: Pre-screening for some blood tests is possible (it is optional) and can be used to 
identify appropriate patients to be screened for this clinical study. The pre-screening visit 
includes blood tests for NT-proBNP, HbA1c, eGFR and serum potassium, which will be 
analyzed at the central laboratory. At Visit 1, these laboratory parameters will be assessed by 
the central laboratory, independently whether or not pre-screening was done for the patient. 
Patients will be screened at Visit 1. The screening period (Epoch 1) takes approximately 2 
weeks. Patients meeting all eligibility criteria will enter the run-in Epoch 2 at Visit 101. If 
patients fail to meet one or more inclusion/exclusion criteria, they can be re-screened once.
Patients meeting the eligibility criteria will enter the placebo run-in (Epoch 2). During the 
approximately 2 weeks duration of Epoch 2, patients will receive single-blind placebo run-in 
medication. 
After the placebo run-in Epoch 2, eligible patients will be randomized in a 1:1:2:2:2 ratio to one 
of the following regimens at Visit 201 (randomization):

LIK066 2.5mg qd at bedtime

LIK066 10mg qd at bedtime

LIK066 50mg qd at bedtime

Empagliflozin (up-titrated from 10mg qd to 25mg qd after 2 weeks); in the morning

Placebo LIK066 at bedtime/Placebo Empagliflozin in the morning
At randomization, patients will be stratified based on geographical region (defined as: North 
America (Canada, United States), Latin America (Argentina, Guatemala, Mexico), Europe 
(Austria, Belgium, Bulgaria, Croatia, Czech Republic, Denmark, Germany, Hungary, Ireland, 
Italy, Netherlands, Norway, Poland, Spain, United Kingdom), Asia Pacific and Others (South 
Korea, Singapore, South Africa, Taiwan)) and the left ventricular ejection fraction (LVEF)
measurement at Visit 101: < 45% versus ≥ 45%. Only if the LVEF results from the central 
reading vendor are not available in time for randomization, the LVEF result from Visit 101 read 
locally by a cardiologist or from the last measurement (echocardiogram, nuclear study, or left 
ventricular angiography) done locally prior to enrollment into the study can be used for 
stratification. The study plans to randomize approximately 496 patients. 


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Following randomization, patients will attend study visits in Epoch 3 (12 weeks) for the 
evaluation of the short-term efficacy (change in NT-proBNP), tolerability and safety parameters 
as defined in Table 6-1 of the study protocol. During Epoch 3, patients will take the study 
medication as described in Section 5.5.4 of the study protocol.
After completing the procedures required at the last study visit of Epoch 3 (Visit 301), patients 
will continue in Epoch 4 the treatment they were allocated to in Epoch 3 for another 24 weeks
to assess long-term efficacy (by HbA1c, echocardiography and NT-proBNP), tolerability and 
safety. 
The analyses for the abbreviated CSR will be carried out after the completion of the study. 
There will be no interim analysis.
Figure 1-1 Study Design
1.2
Study objectives and endpoints
Table 1-1
Study objectives and endpoints
Objective
Endpoint
Analysis 
method
Primary objective
LIK066 10mg qd
LIK066 2.5mg qd
LIK066 50mg qd
Empagliflozin 25mg qd
Placebo qd
Epoch 2
Epoch 3 Randomization (n = 496)
Epoch 4
2 w ks
12 w eeks
24 w eeks
2 w ks
Screening (n = ~1000)
V1
V101
V199/201 V202
V203
V204
V299/301
V302
V399
LIK066 10mg qd
Empagliflozin 25mg qd
Placebo qd
LIK066 50mg qd
LIK066 2.5mg qd
Placebo qd  run-in
10
mg
Epoch 1
A
(n=62)
B
(n=62)
C
(n=124)
D
(n=124)
E
(n=124)
Pre-Screening (optional)


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Objective
Endpoint
Analysis 
method
To determine the dose-response signal 
and assess the dose-response 
relationship of LIK066  2.5mg, 10mg, 
and 50mg qd as measured by the 
change from baseline (BL) in NT-
proBNP relative to placebo after 12 
weeks of treatment in T2DM patients 
with HF

Change from BL in log-
transformed NT-proBNP at 
Week 12 (i.e., log-transformed 
ratio of NT-proBNP (pg/mL) 
collected at Week 12 to BL)
Section 2.5
Secondary objectives
To evaluate the effect of all LIK066 
doses vs placebo at 12 weeks and 36 
weeks on:
Change from BL in glycated 
haemoglobin (HbA1c)
Change from BL in fasting 
plasma glucose (FPG)
Change from BL in weight
Change from BL in body 
composition (bio-impedance in 
all patients where appropriate 
and dual-energy x-ray 
absorptiometry (DXA) in a 
subset of patients
Change from BL in sitting 
systolic blood pressure (SBP) 
and diastolic blood pressure 
(DBP)
Change from BL in the fasting 
lipid profile and hs-CRP
Change from BL in 24h urinary 
glucose and sodium excretion, in 
a subset of patients
Change from BL in left atrial 
size and volume assessed by 
echocardiography 
Change from BL in NYHA class

Change from BL in HbA1c 

Change from BL in FPG 

Change from BL in weight

Change from BL in body 
composition (total body fat 
mass, visceral fat mass and lean 
body mass, assessed by bio-
impedance) 

Change from BL in
body 
composition (total body fat 
mass, visceral fat level, lean 
body mass, assessed by DXA, 
and body water (calculated),  in 
a subset of patients) 

Change from BL in SBP and 
DBP 

Percentage change from BL in  
fasting lipid profile (TG, total 
cholesterol, HDL cholesterol, 
LDL cholesterol, calculated 
VLDL cholesterol and non-
HDL cholesterol, lipoproteins 
(apolipoprotein 
A-I, 
apolipoprotein B)) 

Change from BL in log-
transformed hs-CRP

Change from BL in 24h urinary 
glucose and sodium excretion 
(in a subset of patients)

Change from BL in left atrial 
size and volume assessed by 
echocardiography 
Section 
2.6.1


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Objective
Endpoint
Analysis 
method

Change from BL in NYHA 
class
To evaluate the effect of all LIK066 
doses vs empagliflozin at 12 weeks and 
36 weeks on:
Change from BL in HbA1c
Change from BL in FPG
Change from BL in weight
Change from BL in body 
composition (bio-impedance in 
all patients where appropriate 
and DXA in a subset of patients
Change from BL in sitting 
systolic blood pressure (SBP)
and diastolic blood pressure 
(DBP)
Change from BL in the fasting 
lipid profile and hs-CRP
Change from BL in 24h urinary 
glucose and sodium excretion, in 
a subset of patients 

Change from BL in HbA1c 

Change from BL in FPG 

Change from BL in weight

Change from BL in body 
composition (total body fat 
mass, visceral fat mass and lean 
body mass, assessed by bio-
impedance) 

Change from BL in
body 
composition (total body fat 
mass, visceral fat level, lean 
body mass, assessed by DXA, 
and body water (calculated),  in 
a subset of patients) 

Change from BL in SBP and 
DBP 

Percentage change from BL in  
fasting lipid profile (TG, total 
cholesterol, HDL cholesterol, 
LDL cholesterol, calculated 
VLDL cholesterol and non-
HDL cholesterol, lipoproteins 
(apolipoprotein 
A-I, 
apolipoprotein B)) 

Change from BL in log-
transformed hs-CRP

Change from BL in 24h urinary 
glucose and sodium excretion 
(in a subset of patients)
Section 
2.6.1
To evaluate the change from BL to 36 
weeks in all LIK066 doses vs placebo 
on NT-proBNP

Change from BL in log-
transformed 
NT-proBNP 
at 
Week 36 (i.e., log-transformed 
ratio of NT-proBNP (pg/mL) 
collected at Week 36 to BL)
Section 
2.6.1


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Objective
Endpoint
Analysis 
method
To evaluate safety (adverse events 
(AEs) and lab parameters) and 
tolerability of LIK066 over 12 weeks 
and over 36 weeks for all patients

Adverse events (AEs)

Deaths

Laboratory data

Vital signs

ECG

Liver events

Renal events
Section 
2.6.2
To evaluate 24h urinary calcium and 
phosphate excretion after 12 weeks 
and after 36 weeks in a subset of 
patients

Change from BL in 24h urinary 
calcium 
and 
phosphate
excretion
(in a subset of 
patients)
Section 
2.6.2.8
To evaluate bone mineral density 
(BMD) in a subset of patients

Change from BL in BMD (in a 
subset of patients)
Section 
2.6.2.9


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Objective
Endpoint
Analysis 
method
2
Statistical methods
The following section contains important information on detailed statistical methodology used 
for analysis and reporting purposes.
2.1
Data analysis general information
Data will be analyzed by Novartis Biostatistics and Statistical Reporting (SR) according to the 
statistical analysis Section 9 of the study protocol using SAS Version 9.4 or higher. Data 
collected during the study will be analyzed after the completion of the study. Due to the early 
termination of the study, the planned analyses for a full/complete CSR (as outlined in the study 
protocol) may not provide clinically and/or statistically meaningful results. As a result, only 
limited planned efficacy analyses (as per study protocol) will be performed (see details in 
Section 2.5, 2.6.1.2, 2.7.1.2). Treatment group in the following sections refers to LIK066 2.5mg 
qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg qd and Placebo qd unless 
specified otherwise.  
In general, continuous variables will be summarized descriptively by n, mean, SD, median, 
minimum (min), Q1 (25th percentile), Q3 (75th percentile) and maximum (max), while 
categorical variables will be summarized descriptively by count and percentage of patients in 
each category. Graphical presentation of summary data will also be provided as applicable.
2.1.1
General definitions 
Study treatment, study medication or study drug
In this document, “study treatment”, “study medication” or “study drug” refers to the 
investigational, control drug or placebo of this study. Run-in study treatment, study medication 
or study drug refers to placebo matching LIK066/placebo matching Empagliflozin assigned to 
the patients during placebo run-in; double-blind study treatment, study medication or study drug 
refers to LIK066 2.5mg qd, LIK066 10mg qd, LIK066 50mg qd, Empagliflozin (up-titrated 
from 10mg qd to 25mg qd after 2 weeks) or placebo matching LIK066/placebo matching 
Empagliflozin assigned to a patient at randomization.
Run-in period
Run-in period refers to Epoch 2 (placebo run-in).
Double-blind period
Double-blind period refers to Epoch 3 (treatment period 1) + Epoch 4 (treatment period 2).


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Baseline and study day
Baseline is defined as the last measurement obtained before or at the randomization visit. 
The first day of administration of randomized study treatment (first dose) is defined as Day 1
for the study. If the date of first administration is missing, then randomization date will be used 
as Day 1.
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, study 
day for a particular event date is calculated as [Date of event] – [Date of first dose] + 1. For the 
dates before Day 1, study day for an event date is calculated as [Date of event] – [Date of first 
dose]. Duration of an event will be calculated as [Event end date] – [Event start date] + 1. The 
descriptor “Day 0” will not be used.  
2.2
Analysis sets
The following analysis populations will be defined for statistical analysis. Subjects without 
valid written informed consent will be excluded from all analysis sets. Rules of exclusion 
criteria of analysis sets are detailed in Appendix 5-4. The analysis sets are defined as follows:
Screened set (SCR) – All patients who signed the informed consent. The SCR includes only 
unique screened patients, i.e., in the case of re-screened subjects only the chronologically last 
screening data is counted.
Enrolled set (ENR) – All patients who entered the run-in epoch. 
Randomized set (RAN) – All patients who received a randomization number, regardless of 
receiving trial medication.
Safety set (SAF) (double-blind phase) – All patients who received at least one dose of double-
blind study drug. Patients will be analyzed according to treatment received. Treatment received 
will be considered identical to the randomized treatment if the patient has received at least one 
dose of the randomized treatment.
Full analysis set (FAS) – All patients in RAN who were not mis-randomized*. Following the 
intent-to-treat (ITT) principle, patients are analyzed according to the treatment they have been 
assigned to at the randomization. 
* Mis-randomized patients are those who have not been qualified for randomization and who 
have been inadvertently randomized into the study, but have not received double-blind study 
drug. Mis-randomized patients are defined as cases where IRT contacts were made by the site 
either prematurely or inappropriately prior to confirmation of the patient’s final randomization 
eligibility and double-blind medication was not administered to the patient. These patients were 
subsequently discontinued from the study. 


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2.2.1
Subgroup of interest
Subgroups will be defined to explore the consistency of treatment effects and safety profiling 
on selected parameters between the subgroups and the overall population. 
In Table 2-1, we have listed all subgroups defined for this study and the ways to derive them. 
Also note that only important parameters or variables in these analyses will have subgroup 
analyses. The details about the parameters having subgroup analyses will be presented in the 
corresponding sections as appropriate. Also, additional subgroups may be formed later for 
regional or country-wise analyses as applicable.
Table 2-1
Specification of subgroups
Subgroup
Method of 
derivation
Disposition/ 
Background & 
Demographics / 
Exposure
Efficacy
Safety
Baseline LVEF 
(< 45% vs. ≥ 45%)
Derived, using data 
at baseline
x
x
x
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number and percentage of patients successfully screened will be presented. In addition, the 
reasons for screen failures will be provided. For patients who are screened more than once, the 
information from the last screening will be used in the summary. 
The number and percentage of patients completed and failed in the run-in period will be 
summarized. The reasons for run-in failures will be summarized. The analysis set is the ENR. 
The number of patients randomized (RAN), included in the full analysis set (FAS) and safety 
set (SAF) will be presented by treatment group. The number and percentage of patients who 
have completed Epoch 3 (treatment period 1) and Epoch 4 (treatment period 2), respectively,
will be summarized by treatment group using the RAN. The number and percentage of patients
who discontinued and the reasons for discontinuation will be presented for each treatment group
using the RAN. The number and percentage of patients with protocol deviations as well as non-
protocol deviation criteria leading to exclusion from analysis sets will be presented by treatment 
group for the RAN. 
2.3.2
Demographics and baseline characteristics
The following demographic and baseline characteristics will be summarized by randomized 
treatment group for patients in the FAS population: 

Continuous variables
Age (years)
Height (cm)


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Weight at screening (kg)
BMI at screening (kg/m2)
SBP at baseline (mmHg) 
DBP at baseline (mmHg)
Pulse at baseline (bpm)
Respiratory rate at baseline (bpm)
eGFR at baseline (mL/min/1.73m2)
LVEF at baseline (%)
NT-proBNP at baseline (pg/mL)
Tobacco consumption (pack year(s))
Alcohol consumption (drink(s) per day)

Categorical variables
Age (<65 years vs. ≥65 years, <75 years vs. ≥75 years)
Sex (Male vs. Female)
Race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other)
Ethnicity (Hispanic or Latino, East Asian, Southeast Asian, South Asian, West Asian, 
Russian, Mixed ethnicity, Not reported, Unknown, Other)
Region* (North America, Latin America, Europe, Asia Pacific and Others)
LVEF at baseline (< 45% vs. ≥ 45%)
NYHA class at screening (Class I, II, III, IV)
NYHA class at baseline (Class I, II, III, IV)
NT-proBNP at baseline (< median vs. ≥ median)
Smoker (Never, Current, Former)
Alcohol consumption (0, > 0 - 1, >1 - 2, >2 - 3, >3 drink(s) per day) 
* Region is defined as follows: 
       North America (Canada, United States),
       Latin America (Argentina, Guatemala, Mexico), 
       Europe (Austria, Belgium, Bulgaria, Croatia, Czech Republic, Denmark, Germany, 
Hungary, Ireland, Italy, Netherlands, Norway, Poland, Spain, United Kingdom), 
       Asia Pacific and Others (South Korea, Singapore, South Africa, Taiwan)
The above analyses will also be performed by subgroup: baseline LVEF (< 45% vs. ≥45%).
2.3.3
Medical history 
Any condition entered on the medical history CRF will be coded using the MedDRA dictionary. 
The number and percentage of patients with each medical history condition will be provided by
primary system organ class (SOC), preferred term (PT) and treatment group.


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The number and percentage of patients with hypertension and dyslipidemia on the protocol 
solicited medical history CRF page will be summarized by treatment group. Heart failure and 
diabetes history will be summarized descriptively by treatment group for the following: prior 
history of heart failure (yes/no), primary HF etiology (ischemic/no-ischemic), prior heart failure 
hospitalization (yes/no), number of heart failure hospitalization in the last 12 months and type 
2 diabetes history (yes/no). The FAS will be used for the above analyses.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The duration of double-blind treatment exposure during double-blind period will be 
summarized by treatment group both descriptively in days (mean, standard deviation, minimum, 
Q1, median, Q3, and maximum) and by duration category in weeks (≤2, >2-4, >4-8, >8-12, >12-
24, > 24) for the SAF. 

Duration of exposure (days) = date of last dose of double-blind study drug – date of first 
dose of double-blind study drug + 1

Duration of exposure (weeks) = (date of last dose of double-blind study drug – date of 
first dose of double-blind study drug  + 1)/7
SAF will be used for the above analyses.
2.4.2
Prior, concomitant and post therapies
Prior medications are defined as any recorded medication taken and stopped prior to the date of 
the first dose of the double-blind study drug. 
Concomitant medications for the double-blind period are any medications given at least once 
between the day of first dose of double-blind study medication and the end of the double-blind 
period, including those which started pre-BL and continued into the treatment period. 
Similarly, prior non-drug therapies are defined as any recorded non-drug therapy taken and 
stopped prior to the date of the first dose of the double-blind study drug. Concomitant non-drug 
therapies for the double-blind period are defined as any recorded non-drug therapy given
between the day of first dose of double-blind study medication and the end of the double-blind 
period.
Prior and concomitant medications will be summarized separately by ATC, PT and treatment 
group. Prior and concomitant non-drug therapies will be summarized separately by primary 
SOC, PT and treatment group.
The number and percentage of patients meeting rescue criteria and taking rescue medication, 
and duration of exposure to rescue medication during double-blind period will be summarized 
by treatment group. 
The number and percentage of patients on anti-diabetic medications at baseline (randomization 
visit) will be summarized by treatment group and medication types as follows:


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
Any anti-diabetic medication (insulin or OADs)
o
Insulin
o
OADs (used as single pills)

Metformin

SU - Sulfonylureas (including Sulfonamides)

AGIs

TZDs

DPP-4 inhibitors

GLP-1 analogues
o
Combination of OADs

Phenformin + SU

Metformin + SU

Metformin + TZD

SU + TZD

Metformin + DPP-4 inhibitor

Metformin + AGI

DPP-4 inhibitor + TZD
o
Other
The search criteria for the anti-diabetic medications by type are included in Appendix 5.5.
The use of prohibited medications, defined in Table 2-2, will also be summarized. 
Table 2-2
Prohibited mediation for reporting
Prohibited Medication 
Drug record No. or ATC
SGLT2 inhibitors
A10BK
Clarithromycin
00984601
Telithromycin
01548701
Itraconazole
00780701
Ketoconazole
00532501
Voriconazole
01510101
Posaconazole
01762801
Probenecid
00045101
Valproic Acid
00228501
Mefenamic Acid
00044201
The SAF will be used for the above analyses. 


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2.5
Analysis of primary objective
In general, NT-proBNP data follows a log-normal distribution. Therefore a log-transformation 
on the NT-proBNP data will be performed before all statistical analyses are carried out. The 
analysis results will then be back-transformed for ease of data interpretation. The primary 
endpoint will be analyzed using the FAS.
2.5.1
Primary endpoint
The primary efficacy variable is log-transformed ratio of NT-proBNP (pg/mL) collected at 
Week 12 to BL (i.e., change from BL in log-transformed NT-proBNP at Week 12). 
2.5.2
Statistical hypothesis, model, and method of analysis
The Multiple Comparison Procedure-Modeling (MCP-MOD) method (Pinheiro et al, 2006 & 
Pinheiro et al, 2014) as described in the study protocol will not be performed for the primary
endpoint. The following analysis will be performed instead as an exploratory analysis for NT-
proBNP. Statistical testing of hypotheses on the endpoint will be performed at the two-sided 
0.05 significance level.
The change from baseline in log-transformed NT-proBNP at Week 12 will be analyzed using a 
mixed effect model of repeated measures (MMRM) in which LVEF at baseline (< 45% vs.  ≥
45%), treatment group, visit, and treatment group-by-visit interaction will be included as fixed-
effect factors, and baseline log-transformed NT-proBNP will be included as a covariate, with a 
common unstructured covariance matrix for all treatment groups. The analysis will be 
performed based on change from baseline in log-transformed NT-proBNP at all post-baseline 
scheduled visits up to Week 12 and based on likelihood method with an assumption of missing 
at random (MAR) for missing data. Based on the MMRM model, the estimates and the 95% 
confidence intervals will be provided for the adjusted means of the change from baseline in log-
transformed NT-proBNP at Week 4 and at Week 12 for each treatment group, and for the 
adjusted mean difference at Week 4 and at Week 12. 
The treatment effect (mean difference) of LIK066 doses vs. Placebo or LIK066 doses vs. 
empagliflozin will be analyzed using the MMRM model as described above including all 
treatment groups: LIK066 2.5mg qd, LIK066 10gm qd, LIK066 50mg qd, Empagliflozin 25mg 
qd and Placebo qd. For the comparison of LIK066 doses vs. Placebo, the treatment effects of 
LIK066 2.5mg qd vs. Placebo qd, LIK066 10mg qd vs. Placebo qd, and LIK066 50mg qd vs. 
Placebo qd will be presented; For the comparison of LIK066 doses vs. EMPA, the treatment 
effects of LIK066 2.5mg qd vs. Empagliflozin 25mg qd, LIK066 10gm qd vs. Empagliflozin 
25mg qd, and LIK066 50mg qd vs. Empagliflozin 25mg qd will be presented. The analysis 
results will be back-transformed for ease of data interpretation.
2.5.3
Handling of missing values/censoring/discontinuations
No imputation will be performed for missing NT-proBNP values. 


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2.5.4
Supportive analyses
Summary statistics (n, mean, standard deviation (SD), median, Q1, Q3, minimum, maximum,
geometric mean and its 95% confidence interval) will be presented by visit and treatment for 
NT-proBNP and change from BL in NT-proBNP in the double-blind period, for all patients and 
by baseline LVEF (< 45% vs. ≥45%). Figures will be produced to visually show the mean 
changes by visit over 12 weeks of Epoch 3 for each treatment group, for all patients and by 
LVEF group (< 45% vs.  ≥ 45% at baseline). 
2.6
Analysis of secondary objectives
The secondary efficacy variables will be analyzed in the FAS. Statistical testing of hypotheses 
on the secondary efficacy endpoints will be performed at the two-sided 0.05 significance level 
without adjustment for multiplicity. Safety variables will be analyzed in the SAF.  
2.6.1
Efficacy variables
2.6.1.1
Variables
For the comparison of LIK066 doses vs. placebo and LIK066 doses vs. empagliflozin (EMPA) 
at Week 12 and Week 36:

Change from BL in HbA1c 

Change from BL in FPG 

Change from BL in SBP and DBP 

Change from BL in weight

Change from BL in body composition (total body fat mass, visceral fat mass and lean 
body mass, assessed by bio-impedance) 

Change from BL in body composition (total body fat mass, visceral fat level, lean body 
mass, assessed by DXA, and body water (calculated),  in a subset of patients) 

Percentage change from BL in  fasting lipid profile (TG, total cholesterol, HDL 
cholesterol, LDL cholesterol, calculated VLDL cholesterol and non-HDL cholesterol, 
lipoproteins (apolipoprotein A-I, apolipoprotein B)) 

Change from BL in log-transformed hs-CRP

Change from BL in 24h urinary glucose and sodium excretion (in a subset of patients)
For the comparison of LIK066 doses vs. placebo at Week 12 and Week 36:

Change from BL in left atrial size and volume assessed by echocardiography 

Change from BL in NYHA class
For the comparison of LIK066 doses vs. placebo at Week 36:

Change from BL in log-transformed NT-proBNP 
2.6.1.2
Analysis method
Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum and maximum) 
will be provided by visit and treatment for the following variables in the double-blind period, 
for measurement at each visit and change from baseline values:

HbA1c


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
FPG

SBP and DBP

Weight

Body composition (total body fat mass, visceral fat level and lean body mass, assessed 
by bio-impedance) 

Body composition (total body fat mass, visceral fat mass, lean body mass, assessed by 
DXA, and body water (calculated),  in a subset of patients) 

24h urinary glucose and sodium excretion (in a subset of patients)

Left atrial size and volume assessed by echocardiography
In addition, summary statistics will be provided for left atrial size and volume by baseline LVEF 
(< 45% vs.  ≥ 45%). 
For the analysis of NT-proBNP, please see details in Section 2.5.
Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum and maximum) 
will be provided by visit and treatment for the following variable in the double-blind period, for 
measurement at each visit and percentage change from baseline values:

Fasting lipid profile (TG, total cholesterol, HDL cholesterol, LDL cholesterol, 
calculated VLDL cholesterol and non-HDL cholesterol, lipoproteins (apolipoprotein A-
I, apolipoprotein B)) 
Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum, 
geometric mean and its 95% confidence interval) will be provided by visit and treatment for hs-
CRP in the double-blind period, for measurement at each visit and change from baseline values.
The change from BL in NYHA class at a given visit is a three-category ordinal variable 
(improved/unchanged/worsened) with the following definition: 1. Improved, if NYHA class 
decreases at least one level from BL; 2. Unchanged, if NYHA class is unchanged from BL; 3. 
Worsened, if NYHA class increases at least one level from BL. NYHA class (I/II/III/IV) will 
be summarized by visit and treatment group using frequency and percentage. A visit-based shift 
table will be provided to summarize the NYHA class shifting from BL
All secondary efficacy data will be listed at the individual patient level.
2.6.2
Safety analyses
The safety analyses described in this section will be performed for the SAF. 
2.6.2.1
Adverse events (AEs)
Treatment emergent adverse events (TEAEs) during the double-blind period are defined as any 
AE with start date on or after the start date of the first dose of the study drug during the double-
blind period.
The number and percentage of patients with the following types of treatment emergent adverse 
events during the double-blind period will be provided by primary SOC, PT and treatment group


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in separate tables: AEs, SAEs, AEs leading to study drug discontinuation, AEs suspected to be 
study drug related, and AEs leading to study drug interruption. TEAEs during the double-blind 
period will also be summarized by primary SOC, PT, maximum severity and treatment group. 
The most common TEAEs (>=10% in any treatment group) during the double-blind period will 
be presented by PT in descending order of frequency in the investigational study drug arm, 
LIK066 50 mg qd.
The following rules apply to the above AE summaries:

If a patient has multiple AEs within a primary system organ class during the double-blind 
period, the patient will be counted only once in that primary system organ class

If a patient has multiple occurrences of an AE with the same PT during the double-blind 
period, this patient will be counted only once at that PT level.

An AE with increased severity should be considered and recorded as a new AE.
All TEAEs during the double-blind period will be summarized descriptively by primary SOC, 
PT and treatment in the following subgroups: baseline LVEF < 45% vs. ≥45%.
All AEs will be listed at the individual patient level. The listings will include those AEs reported 
during the screening and run-in period, and AEs reported after study discontinuation for those 
who discontinue the study prior to the end of the study.  
Deaths occurred during the double-blind period will be summarized descriptively (using 
number and percentage of patients) by primary SOC and principal cause of death. All deaths 
will be listed.
2.6.2.2
Adverse events of special interest / grouping of AEs
AEs of special interest that are defined in the Development Safety Profiling Plan (DSPP) can 
be found in the electronic case retrieval sheet (eCRS) stored in GPS.
The pre-defined issues of special interest for LIK066 including identified risks, potential risks 
and special assessments are listed below:

Bone fractures

Cardiotoxicity

Diarrhea 

Electrolyte disturbances

Genital infections

Hepatotoxicity

Hypersensitivity

Hypoglycemia

Impaired renal function

Increased LDL

Intravascular volume depletion


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
Ketoacidosis

Lower limb amputation

Pre-amputation events

Malignancy

Pancreatitis

Urinary tract infections

Venothrombotic and embolic events
Treatment-emergent AEs of special interest will be summarized for double-blind period, by risk 
category, preferred term and treatment group. Treatment emergent AEs of special interest 
during the double-blind period will also be summarized descriptively by risk category, preferred 
term and treatment group in the following subgroups: baseline LVEF < 45% vs. ≥45%.
Additional analyses for the pre-defined risks of diarrhea, ketoacidosis and hypoglycemia will 
be performed as described below:
Diarrhea events
Number of days with diarrhea events will be calculated for all patients with at least one diarrhea 
incidence and will be summarized descriptively by treatment.

Number of days for one diarrhea incidence = AE end date – AE start date +1. 

Number of days with diarrhea events for a patient = sum of days on diarrhea over all 
incidences that occurred in the double-bind period.
The number and percentage of patients with diarrhea events during the double-blind 
treatment period will also be summarized by treatment over time in the following time 
window: 0 - < 2, 2 - < 4, 4 - < 8, 8 - < 12, 12 - < 16, 16 - < 24, >=24 weeks.
Ketoacidosis events of special interest
All cases of ketoacidosis will be adjudicated by an independent committee. The frequencies and 
percentages of the adjudication confirmed ketoacidosis events will be provided by treatment. 
The site-reported ketoacidosis events will also by summarized by treatment. In addition, the 
ketoacidosis events will be listed at individual patient level, with the site-reported event profile 
and symptoms and the adjudication outcome displayed as well.
Hypoglycemic events of special interest
Hypoglycemic events entered into the study Hypoglycemic event eCRF are included in all of 
the AE summaries in Section 2.6.2.1.
In addition, there are two categories of clinically significant hypoglycemic events defined:

Severe hypoglycaemia: An event, requiring assistance of another person (third party 
assistance) to actively administer carbohydrate, glucagon, or other corrective actions, 
confirmed or not by a blood glucose measurement 


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


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2.6.2.3
Laboratory data
2.6.2.3.1 Hematology, Biochemistry and Urinalysis
Each laboratory parameter in Table 2-3 will be summarized descriptively by visit and treatment 
group for actual and change from baseline values. The summary will be provided separately for 
biochemistry, hematology and urinalysis laboratory parameters. 
Shift tables based on the standard ranges for each laboratory parameters will be provided by 
treatment group at each visit to present incidence of transitions from a baseline high, normal or 
low laboratory value to a post-baseline high, normal or low value. 
The number and percentage of patients with clinically notable laboratory results post baseline 
will be presented in accordance with Table 2-4. 
Table 2-3 Laboratory parameters
Category
Parameter(s)
Hematology
RBC (total), WBC (total), platelet count (direct), hemoglobin, hematocrit, 
basophils (absolute, %), eosinophils (absolute, %), lymphocytes 
(absolute, %), monocytes (absolute, %), neutrophils (absolute, %)
Biochemistry
ALT, albumin, alkaline phosphatase (ALP), AST, bicarbonates, bilirubin 
(direct, total), blood urea nitrogen (BUN), calcium (total), chloride (Cl-), 
creatinine, cystatin C, eGFR (MDRD), magnesium (Mg2+), phosphates, 
potassium (K+), protein (total), sodium (Na+), uric acid, γ-GT, amylase, 
lipase, serum ketones and beta hydroxybutyrate
Urinalysis
pH, specific gravity, protein, glucose, ketones, nitrites, blood, leucocytes
Urinalysis
UACR Urine albumin to creatinine ratio (spot urine), cystatin 
C/creatinine ratio (spot urine)
Table 2-4  Clinically notable laboratory values 
Parameter
Criteria (based on a percent change from baseline)
Hematology
RBC (total)
>50% increase, >20% decrease
WBC (total)
>50% increase, >50% decrease
Platelet count 
>75% increase, >50% decrease
Hemoglobin 
>50% increase, >20% decrease
Hematocrit
>50% increase, >20% decrease
Clinical chemistry
ALT
>150% increase 
AST
>150% increase
BUN
>50% increase
Creatinine
>50% increase
Total bilirubin
>100% increase
ALP
>100% increase 
Sodium
>5% increase or  >150, or decrease <130 mmol/L 


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Potassium
absolute values < 3.0 mmol/L, > 5.9 mmol/L
Chloride
>10% increase, >10% decrease
Calcium
>10% increase, >10% decrease and hyper - > 2.6, 
Uric acid
>50% increase
Plasma glucose
>50% increase 
Plasma glucose
< 3.0 mmol/L (54 mg/dL)
2.6.2.3.2 Bone and renal biomarkers
Serum samples for bone and renal biomarkers will be collected from the patients participating 
in sub-study 2 at visits indicated in Table 6-1 of the study protocol.  
Urine samples for bone and renal biomarkers from the patients participating in the sub-study 
will be assessed from 24h urine collection.
Table 2-5
Biomarkers
Category
Parameter(s)
Bone biomarkers
β-c-terminal telopeptide (β-CTX1), serum procollagen type 1 N-
propeptide (sP1NP), intact parathyroid hormone (iPTH), 25-hydroxy 
vitamin D, 1,25 dihydroxy vitamin D, osteocalcin, oestradiol, Ca2+, 
Mg2+, phosphates (see also Table 6-4 of the study protocol)
Renal biomarkers
Serum cystatin C, urinary cystatin C (24h urine sample), urinary 
creatinine (24h urine sample), urinary albumin (24h urine sample), 
For each biomarker in Table 2-5, the test values and the change from baseline values will be 
summarized by visit and treatment group using n, mean, geometric mean and its 95% 
confidence interval, minimum, Q1, median, Q3, and maximum. The analyses will be performed 
in the SAF population.
2.6.2.4
Vital signs
Sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP) and sitting pulse 
will be descriptively summarized (by n, mean, standard deviation, median, Q1, Q3, minimum 
and maximum) for actual value and change from baseline values for each scheduled assessment 
visit and treatment group. A listing of all patients with notable vital sign values and changes (as 
defined in Table 2-6) will be provided.
Table 2-6
Vital signs notable range deviations
Vital sign
Notable abnormalities
Pulse (beats/min)
either 120 + increase25* or > 130
either 50 + decrease30* or < 40 
BP (mmHg)
systolic
either 180 + increase30* or > 200
either 90 + decrease30* or < 75
diastolic
either 105 + increase20* or > 115
either 50 + decrease20* or < 40
* Refers to post-BL value as compared to BL value.


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2.6.2.5
ECG 
The following variables will be descriptively summarized by visit and treatment: QTcF  duration 
(msec), heart rate (beats/min), PR duration (msec), RR duration (msec), and QRS duration 
(msec). 
The number and percentage of patients meeting the following criteria will be summarized by 
visit and treatment group for the double-blind period: 

QTcF > 500 msec

QTcF > 480 msec

QTcF > 450 msec

QTcF increases from baseline ≥ 30 msec

QTcF increases from baseline ≥ 60 msec

PR > 200 and ≤ 220 msec

PR > 220 msec

PR increases from baseline > 25% (PR > 200 msec)

QRS > 110 and ≤ 120 msec

QRS > 120 msec

QRS changes from baseline > 25 % (QRS > 110 msec)

Heart rate > 100 beats/min

Heart rate < 50 beats/min
In addition, a visit-based shift table will be provided to summarize the shifting from BL for 
each ECG parameter. 
Cutoff points below are used to define normal or abnormal criteria in the above ECG shift table:

QTcF: >450 or =<450 msec for male, or, >460 or =<460 msec for female

QRS: >120 or =<120 msec

PR: >200 or =<200 msec

HR: >100 or =<100 beats/min
A listing of ECG parameters together with newly occurring or worsening abnormalities will be 
provided. 
2.6.2.6
Liver events
The liver event and laboratory trigger definitions are specified in the Appendix 2 of the study 
protocol. Liver event data will be listed. 


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The number and percentage of patients who meet the liver toxicity criteria in Table 2-7 post 
baseline will be summarized by treatment group for the double-blind period. Listings of patients 
with clinically notable LFT values will be provided. 
Table 2-7
Criteria for evaluating liver toxicity
Parameter
Criterion
ALT or AST
ALT or AST > 3xULN
ALT or AST > 5xULN
ALT or AST > 8xULN
ALT or AST > 10xULN
Hy’s category
ALT or AST >3x ULN and TBL >1.5x ULN
ALT or AST > 3xULN & TBL > 2xULN
ALT or AST > 5xULN & TBL > 2xULN 
ALT or AST > 8xULN & TBL > 2xULN 
ALT or AST > 10xULN & TBL > 2xULN
ALT or AST > 3xULN & TBL > 2xULN & ALP ≤ 2xULN
TBL&ALP
TBL >1.5x ULN and ALP >2x ULN
TBL >2x ULN and ALP >2x ULN
Isolated TBL
TBL >1.5x ULN & ALT and AST <3x ULN and ALP <2x ULN
TBL >2x ULN & ALT and AST <3x ULN and ALP <2x ULN
TBL >3x ULN & ALT and AST <3x ULN and ALP <2x ULN
Isolated ALP
ALP >1.5x ULN &  ALT and AST <3x ULN and TBL <1.5x ULN
ALP >2x ULN &  ALT and AST <3x ULN and TBL <1.5x ULN
ALP >3x ULN & ALT and AST <3x ULN and TBL <1.5x ULN
ALP >5x ULN & ALT and AST <3x ULN and TBL <1.5x ULN
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; 
ULN: upper limit of normal.
2.6.2.7
Renal events
The specific renal alert criteria and actions are defined in the Appendix 3 of the study protocol.
Renal event data will be listed.
2.6.2.8
Other safety analyses (24h urinary calcium and phosphate excretion, 
bone mineral density (BMD))
Summary statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be provided by visit and treatment for the 24h urinary calcium, 24h urinary phosphate
excretion and BMD from sub-studies, for measurement at each visit and change from baseline
values.


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2.9
Interim analysis
Not applicable
3
Sample size calculation
The study planned to randomize approximately 496 patients in total, allocated in the ratio of 
1:1:2:2:2 to the LIK066 2.5mg qd, 10mg qd, 50mg qd, empagliflozin and placebo treatment 
groups, respectively. 
The following power calculations are based on the primary efficacy variable of log-transformed 
ratio of NT-proBNP at Week 12 to baseline. Due to the lack of available data in this patient 
population there is uncertainty on the standard deviation (SD) of the log-transformed ratio of 
week 12 to BL in NT-proBNP. Therefore calculations are provided for assumptions of SD in 
the range of 0.8, 0.85 to 0.9 to reflect the impact of this uncertainty on the power estimation. 
Based on the data from the PARAMOUNT HF study (data on file), a SD of 0.85 was considered 
a reasonable estimate.
Assuming a one-sided 2.5% significance level (with adjustments for multiple comparisons 
using the MCP-MOD), a sample size of approximately 496 patients (124 each in placebo and 
LIK high dose; 62 each in LIK low doses; 124 in empagliflozin that is not included in the dose-
response modeling)  will provide a mean power (over all candidate models) of 75%(or 90%) to 
detect a dose response signal, assuming that the underlying true maximum NT-proBNP 
reduction on LIK066 vs placebo is 25% (or 30%), and the standard deviation (on the log scale) 
is 0.85.
Table 3-1
Power for detecting a significant dose response signal*
Effect size for best dose
SD
Average power
Minimum power†
20%
0.8
58%
54%
20%
0.85
53%
49%
20%
0.9
48%
45%


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Effect size for best dose
SD
Average power
Minimum power†
25%
0.8
80%
76%
25%
0.85
75%
71%
25%
0.9
70%
66%
30%
0.8
93%
91%
30%
0.85
90%
88%
30%
0.9
87%
84%
* Assumes 372 patients in LIK066 and placebo arms with effective sample size of 336 patients due to an 
effect of missing data equivalent to 10% fewer patients. Calculations were performed using the DoseFinding
package in R.
† Power for a significant dose-response contrast test across all scenarios in Figure 2-1. The candidate model 
Emax with ED50 of 3mg has the lowest power.
Power consideration for assessing the glucose-lowering potential at Week 12
To explore the glucose-lowering potential of LIK066 vs. placebo or empagliflozin (EMPA), the 
treatment difference in HbA1c change from BL to Week 12 will be considered.
Table 3-2 Comparison of LIK versus placebo (at 2-sided alpha of 0.05)
Expected 
treatment 
difference 
SD
Power
LIK high dose (n=124) versus placebo 
(n=124)*
0.5%
1
96%
Any LIK low dose (n=62) versus 
placebo (n=124)*
0.5%
1
85%
*assuming 10% information loss due to drop-out.
Table 3-3 Comparison of LIK versus empagliflozin 
Expected 
treatment 
difference
SD
Probability 
of 
the 
95% 
confidence 
interval upper bound 
< 0.4%
LIK high dose (n=124) versus EMPA 
(n=124)
0
1
84%
Any LIK low dose (n=62) versus 
EMPA (n=124)
0
1
68%
*assuming 10% information loss due to drop-out.
The calculations in Table 3-2 and 3-3 were performed using nQuery 7.0. No multiple testing 
adjustment was applied.


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4
Change to protocol specified analyses
Due to the early termination of the CLIK066B2204 study, the following major changes to the 
protocol specified analyses have been made in the SAP amendment 1:
-
“Week 12 Analysis” and “End of Study Analysis” as defined in the study 
protocol are no longer applicable. The analyses for the abbreviated CSR 
will be carried out after the completion of the study.
-
MCP-Mod will not be performed for the primary endpoint change in log-
transformed NT-proBNP at Week 12. Instead, MMRM will be 
performed as an exploratory analyses for NT-proBNP. See details in 
Section 2.5.
-
Summary statistics will be provided for selected efficacy endpoints. All 
efficacy endpoints will be listed. See details in Sections 2.5, 2.6.1.2, 
2.7.1.2.
-
Subgroup analyses will only be performed for demographics and 
baseline characteristics, primary and key secondary efficacy endpoints 
summary statistics, AEs and AEs of special interest, in the subgroups 
LVEF <45% vs. >= 45%.
5
Appendix
The missing or partially missing AE start/end date and concomitant medication start/end date
will be imputed using the Novartis ADaM Governance Board (AGB) global standard approach. 
Details will be provided in the study Programming Datasets Specifications.
5.1.1
Study drug
Any partial dates will be imputed as the earlier day of 

The last day in the month and 

The end day of the corresponding epoch
5.1.2
AE date imputation
AE end date imputation
1. If ‘month’ is missing, the end date will be set to the earliest of the (min (last visit date, 
last dose date), 31DECYYYY, and date of death). 
2. If ‘day’ is missing, the end date will be set to the earliest of the (min (last visit date, last 
dose date), 31MONYYYY, and date of death).
3. If ‘year’ is missing or AE is ongoing, the end date will not be imputed. 
AE start date imputation


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Before imputing AE start date, find the AE start reference date. 

If the (imputed) AE end date is complete and the (imputed) AE end date < treatment 
start date then AE start reference date = min (informed consent date, earliest visit date).

Else AE start reference date = treatment start date
After finding the AE start reference date:
1. If ‘year’ is missing, the date uncertainty is too high; therefore the imputed AE start date 
will be set to NULL.
2. If ‘year’ is less than the treatment start date ‘year’, the AE started before treatment; 
therefore: 
a.
If ‘month’ is missing, the AE start date will be set to 01JULYYYY.
b. If ‘day’ is missing, the AE start date will be set to 15 MONYYYY. 
3. If ‘year’ is greater than the treatment start date ‘year’, the AE started after treatment; 
therefore:
a.
If ‘month’ is missing, the AE start date will be set to 01JANYYYY. 
b. IF ‘month’ is not missing, the AE start date will be set to the later of 
(01MONYYYY, AE start reference date + 1).
4. If ‘year’ is equal to the treatment start date ‘year’
a.
If ‘month’ is missing, the AE start date will be set to the AE reference start date 
+1.
b. If ‘month’ is less than the treatment start ‘month’, the AE start date will be set 
to 15MONYYYY.
c.
If ‘month’ is equal to or greater than the treatment start ‘month’, the AE start 
date will be set to the later of (01MONYYYY, AE start reference date+1).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, imputed AE start date will be set to the (imputed) AE end date. 
5.1.3
Concomitant medication date imputation
CM end date imputation 
1. If ‘day’ is missing and ‘month/year’ are non-missing then impute date as the earlier of 
(treatment end date, and 31MONYYYY).  
2. If ‘day/month’ are missing and ‘year’ is non-missing then impute date as the earlier of 
(treatment end date, and 31DECYYYY).
3. If imputed end date is less than the start date, use the start date as the imputed end date. 
CM start date imputation 
1. If ‘year’ is missing, the start date will be set to one day prior to treatment start date. 
2. If ‘year’ is less than treatment start ‘year’, the CM started before treatment. Therefore:


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a.
If ‘month’ is missing, the start date will be set to 01JULYYYY.
b. If ‘month’ is non-missing, the start date will be set to 15MONYYYY.
3. If ‘year’ is greater than treatment start ‘year’, the CM started after treatment. Therefore
a.
If ‘month’ is missing, the start date will be set to 01JANYYYY.
b. If ‘month’ is non-missing, the start date will be set to 01MONYYYY.
4. If ‘year’ is equal to the treatment start date ‘year’
a.
If ‘month’ is missing or equal to the treatment start ‘month’, then the start date 
will be set to one day prior treatment start date.
b. If ‘month’ is less than the treatment start ‘month’, the start date will be set to 
15MONYYYY. 
c.
If ‘month’ is greater than the treatment start ‘month’, the start date will be set to 
01MONYYYY.
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date will be set to the (imputed) end date. 
5.1.3.1
Prior therapies date imputation
See Section 5.1.3.
5.1.3.2
Post therapies date imputation
See section 5.1.3.
5.2
AEs coding/grading
AEs will be coded according to MedDRA dictionary. The MedDRA version used for reporting 
will be described in the footnotes. 
Safety topics of interest, defined in the Safety Profiling Plan are defined in the Program Case 
Retrieval Sheet. Missing severity will be assumed to be severe in the summary table.
Hypoglycemia classification is presented in Table 5-1.
Table 5-1
Hypoglycemia classification
Category
Definition
Criteria as specified in 
the Hypo eCRF
Severe hypoglycemia
An event, requiring 
assistance of another 
person (third party 
assistance) to actively 
administer 
carbohydrate, 
glucagon, or other 
corrective actions, 
confirmed or not by a 
BG measurement
An event with answer 
= ‘YES’ for any one of 
the two questions:
Was third party 
assistance 
required?
Was medical 
assistance 
received?


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Category
Definition
Criteria as specified in 
the Hypo eCRF
Other clinically 
significant 
hypoglycemia
Plasma glucose < 3.0 
mmol/l (54 mg/dl)* with 
or without typical 
symptoms of 
hypoglycaemia, and 
which is handled by 
the subject 
himself/herself.
An event with answer 
= ‘YES’ to the question 
‘Glucose 
measurement taken’ 
and the plasma 
glucose < 3.0 mmol/l 
(54 mg/dl), and answer 
= NO to both 
questions:
Was third party 
assistance 
required?
Was medical 
assistance 
received?
*Blood glucose values need to be converted to plasma glucose values.
A plasma glucose of 3.0 mmol/L (54 mg/dL) corresponds to a whole blood glucose of 2.7 mmol/L (48 mg/dL)
Plasma glucose = blood glucose * 1.12.
5.3
Laboratory parameters derivations
Not applicable
5.4
Rule of exclusion criteria of analysis sets 
Criteria defining protocol deviations are referenced in the “Protocol Deviations’ tab of the Data 
Review Plan document. Protocol deviations will be classified into 5 categories as appropriate:

Selection criteria not met

Treatment deviation

Prohibited concomitant medication

Subject not withdrawn as per protocol

Other
The protocol deviations leading to the exclusion of patients from analysis sets are outlined in 
Table 5-2. In addition, the non-protocol deviation criteria leading to the exclusion of patients
from analysis sets are outlined in Table 5-3. Table 5-2 and Table 5-3 may be updated according 
to Data Review Plan document before data base lock.
Table 5-2
Protocol deviations leading to exclusion of patients from analysis sets
Deviation ID
Description of Deviation
Exclusion from Analysis 
set(s)
INCL01a
INCL01b
Informed consent not obtained 
Informed consent not signed
SCR, ENR, RAN, FAS, 
SAF
OTH07
Misrandomized in IRT
FAS


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Table 5-3
Non-protocol deviation criteria leading to exclusion of patients from 
analysis sets
Description of Deviation
Exclusion from Analysis set(s)
No study drug taken during double-blind
SAF
5.5
Search criteria for the anti-diabetic medications by type:
Combos - Codes 
match.pptx
List of 
_ingredients_anti
Category
Type
ATC code or drug code
Insulin
All insulin A10A
A10A (all insulin), and within 
this group:
A10AB, A10AC, A10AD, A10AE 
and A10AF
OADs – used as single pills
Metformin
A10BA Biguanides
SU
A10BB Sulfonylureas
A10BC Sulfonamides 
(heterocyclic)
AGIs
A10BF Alpha glucosidase 
inhibitors
TZDs
A10BG Thiazolidinediones
DPP-4i
A10BH Dipeptidyl peptidase 4 
(DPP-4) inhibitors
GLP-1 analogues
A10BJ Glucagon-like peptide-1 
(GLP-1) analogues
Combinations of OADs
See details in the above pptx 
document Combos –
Codes.pptx. Exclude 
Metformin + SGLT-2i and 
DDP-4i + SGLT-2i for this 
study  
Other
A10BX Other


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6
Reference
Pinheiro J, Bornkamp B, Bretz F (2006) Design and analysis of dose finding studies combining 
multiple comparisons and modeling procedures. Journal of Biopharmaceutical Statistics; 16(5): 
639-56.
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Statistics in Medicine; 33(10): 1646-661.