Clinical trial NCT01528254
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 Diabetes Mellitus Vildagliptin Elderly Patients
Sponsor: Novartis Pharmaceuticals
Start date: 2012-03-30; Completion date: 2019-04-04
Enrollment: 2004 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to determine whether the initiation of a vildagliptin plus metformin combination regimen would result in more durable glycemic control than metformin monotherapy in treatment-naïve patients with type-2 diabetes mellitus (T2DM).

Detailed description:
This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period. Following a screening visit (Visit 1) and a screening period of up to 2 weeks, treatment-naïve patients, meeting all eligibility criteria entered the run-in period at Visit 2.

* Run-in period: At Visit 2, in all eligible patients, metformin treatment was initiated and/or up-titrated. At the end of the 3-week run-in period, patients who were able to tolerate a total dose of at least 1000 mg and up to 2000 mg daily proceeded to randomization and started in Period 1.
* Period 1 (vildagliptin/metformin combination versus metformin): At Visit 3, patients were randomized 1:1 to one of the following study regimens:

  * Metformin up to 1000 mg bid plus vildagliptin 50mg bid or
  * Metformin up to 1000 mg bid plus matching placebo bid

The duration of Period 1 could differ between patients depending on the time when the second of two HbA1c measurements taken at two consecutive visits after randomisation confirmed HbA1c ≥ 7.0%.

• Period 2 (vildagliptin/metformin combination versus vildagliptin add-on to metformin): In the case of two consecutive HbA1c measurements ≥7.0% from two consecutive study visits during Period 1, patients who were randomised to the placebo arm in Period 1 received vildagliptin 50 mg bid. Patients who were randomised to the active vildagliptin 50 mg bid arm in Period 1 continued to receive vildagliptin 50 mg bid. All patients continued to take their metformin dose unchanged. Period 2 remained masked to the patient and both patients and investigators remained masked to the treatment allocation in Period 1.

If, during Period 2, therapy intensification was required in accordance with the local guidelines, the patient entered Period 3. The duration of Period 2 could differ between patients. End of Period 2 was considered when insulin treatment was initiated, or alternatively when the patient was discontinued because insulin treatment was not initiated in Period 3.

• Period 3 (insulin initiation): In Period 3, patients were to be initiated on open-label insulin. The study drug regimen continued unchanged and remained masked to the patient in Period 3 and both patients and investigators remained masked to the treatment allocation in Period 1.

Arms: arm 1: Metformin + vildagliptin arm 2: Metformin + Placebo of vildagliptin
Interventions: intervention 1: Placebo of vildagliptin intervention 2: vildagliptin intervention 3: Metformin
Intervention descriptions: intervention 1: None intervention 2: One tablet (50 mg oral) of vildagliptin in the morning and one tablet in the evening with or without food. intervention 3: Twice daily (bid) regimen during or after meals at the same time as vildagliptin.

Protocol documents:
Prot_001.pdf: 
Clinical Development
LAF237/Galvus
Clinical Study Protocol CLAF237A23156 / NCT01528254
A 5-year study to compare the durability of glycemic 
control of a combination regimen with vildagliptin & 
metformin versus standard-of-care monotherapy with 
metformin, initiated in treatment-naïve patients with type 2 
diabetes mellitus
Authors:
Document type:
Amended Protocol Version
EUDRACT number:
2011-003712-23
Version number:
V04 (clean)
Development phase:
IV
Release date:
22-Oct-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 24 May 2011


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 4 ...........................................................................................................................11
Amendment 3 ...........................................................................................................................12
Amendment 2 ...........................................................................................................................14
Amendment 1 ...........................................................................................................................15
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.2
Purpose ..................................................................................................................23
2
Study objectives.................................................................................................................24
2.1
Primary objectives .................................................................................................24
2.2
Secondary objectives .............................................................................................24
24
3
Investigational plan ...........................................................................................................25
3.1
Study design...........................................................................................................25
3.1.1
Run-in period ........................................................................................25
3.1.2
Period 1: vildagliptin/metformin combination versus metformin.........25
3.1.3
Period 2: vildagliptin/metformin combination versus vildagliptin 
add-on to metformin..............................................................................26
3.1.4
Period 3: insulin initiation.....................................................................26
3.1.5
Meal-test................................................................................................27
3.2
Rationale of study design.......................................................................................27
3.3
Rationale of dose/regimen, duration of treatment .................................................28
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................28
3.6
Risks ......................................................................................................................28
4
Population..........................................................................................................................29
4.1
Inclusion criteria ....................................................................................................29
4.2
Exclusion criteria...................................................................................................30
5
Treatment...........................................................................................................................32
5.1
Investigational and control treatment ....................................................................32
5.2
Treatment arms......................................................................................................32


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5.3
Treatment assignment............................................................................................32
5.4
Treatment masking ................................................................................................33
5.5
Treating the patient................................................................................................33
5.5.1
Patient numbering .................................................................................33
5.5.2
Dispensing the study drug.....................................................................33
5.5.3
Supply, storage and tracking of study drug...........................................34
5.5.4
Instructions for prescribing and taking study drug ...............................34
5.5.5
Permitted dose adjustments and interruptions of study drug ................35
5.5.6
Rescue medication ................................................................................35
5.5.7
Concomitant treatment..........................................................................36
5.5.8
Prohibited treatment..............................................................................36
5.5.9
Discontinuation of study drug and premature subject withdrawal........36
5.5.10
Emergency unmasking of treatment assignment...................................37
5.5.11
Study completion and post-study treatment..........................................38
5.5.12
Early study termination.........................................................................38
6
Visit schedule and assessments .........................................................................................38
6.1
Information to be collected on screening failures..................................................43
6.2
Patient demographics/other BL characteristics .....................................................43
6.3
Treatment exposure and compliance .....................................................................43
6.4
Efficacy..................................................................................................................44
6.4.1
HbA1c ...................................................................................................45
6.4.2
FPG and indices of β-cell function and insulin resistance....................45
6.4.3
Meal-test................................................................................................45
6.4.4
Appropriateness of efficacy assessments..............................................46
6.5
Safety.....................................................................................................................46
6.5.1
Physical examination ............................................................................46
6.5.2
Vital signs..............................................................................................47
47
6.5.4
Laboratory evaluations..........................................................................47
6.5.5
Abnormal LFTs.....................................................................................48
6.5.6
Hypoglycemic events............................................................................50
6.5.7
ECG.......................................................................................................51
6.5.8
Pregnancy and assessments of fertility .................................................51
6.5.9
Appropriateness of safety measurements..............................................51
6.6
Other assessments..................................................................................................52
52


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6.6.2
Resource utilisation...............................................................................52
52
6.6.4
Pharmacokinetics (PK)..........................................................................52
6.6.5
Pharmacogenetics/pharmacogenomics .................................................52
52
7
Safety monitoring..............................................................................................................53
7.1
AEs ........................................................................................................................53
7.2
SAE reporting........................................................................................................54
7.3
Pregnancies............................................................................................................55
7.4
Data monitoring committee...................................................................................55
7.5
Adjudication committees.......................................................................................56
8
Data review and database management.............................................................................56
8.1
Site monitoring ......................................................................................................56
8.2
Data collection.......................................................................................................56
8.3
Database management and quality control............................................................57
9
Data analysis......................................................................................................................57
9.1
Analysis sets ..........................................................................................................57
9.2
Patient demographics and other BL characteristics...............................................58
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................58
9.4
Analysis of the primary variable(s) .......................................................................59
9.4.1
Variable.................................................................................................59
9.4.2
Statistical model, hypothesis, and method of analysis..........................59
9.4.3
Handling of missing values/censoring/discontinuations.......................60
9.4.4
Supportive analyses...............................................................................60
9.5
Analysis of secondary variables ............................................................................61
9.5.1
Key secondary variables .......................................................................61
9.5.2
Other efficacy secondary 
 variables ...............................61
9.5.3
Safety variables .....................................................................................66
9.5.4
Resource utilisation...............................................................................67
67
9.5.6
PK..........................................................................................................67
9.5.7
Pharmacogenetics/pharmacogenomics .................................................67
67
9.5.9
PK/pharmacodynamics .........................................................................67
9.6
Sample size calculation..........................................................................................67


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9.7
Power for analysis of key secondary variables......................................................68
9.8
Interim analyses.....................................................................................................68
10 Ethical considerations........................................................................................................68
10.1
Regulatory and ethical compliance........................................................................68
10.2
Informed consent procedures.................................................................................68
10.3
Responsibilities of the investigator and IRB/IEC..................................................69
10.4
Publication of study protocol and results...............................................................69
11 Protocol adherence ............................................................................................................69
11.1
Protocol amendments.............................................................................................70
12 References .........................................................................................................................70
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................72
14 Appendix 2: testing for patients with elevated LFTs ........................................................73
List of tables
Table 6-1
Assessment schedule (year 1-2)............................................................39
Table 6-2
Assessment schedule (year 3-5)............................................................41
Table 6-3
Laboratory evaluations..........................................................................48
Table 6-4
Guidance for abnormal liver enzymes and related tests........................48
Table 6-5
Recording and classification of glycemia study diary data...................51
Table 13-1
Vital signs notable range deviations .....................................................73
List of figures
Figure 3-1
Study design..........................................................................................27


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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical classification system
AUC
area under the curve
bid
bis in die (twice a day)
BL
baseline
BMI
body mass index (=body mass (kg)/(body height (m))2)
CFR
United States code of federal regulation
CHF
congestive heart failure
CK-MB
creatinine kinase muscle-brain-type isoenzyme
CPK
phosphocreatine kinase
CRF 
case record form
CRO
contract research organisation
CV
cardiovascular
DMC
Data Monitoring Committee
DPP-4
dipeptidyl peptidase-4
DS&E
drug safety & epidemiology
ECG
electrocardiogram
EDC
electronic data capture
EOS
end of study
FAS
full analysis set
FPG
fasting plasma glucose
γ-GT
γ-glutamyl transferase
GCP
good clinical practice
GFR
glomerular filtration rate
GIP
glucose-dependent insulinotropic peptide
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated hemoglobin
HBsAg
hepatitis B surface antigen


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hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high density lipoprotein
IB
investigator brochure
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
IN
investigator notification
IgM
immunoglobulin M
IRB
institutional review board
IRT
interactive response technology
ISR
insulin secretion rate
LDL
low density lipoprotein
LFT
liver function tests
M
molar (mol/L)
MDRD
modification of diet in renal disease
MI
myocardial infarction
NYHA
New York health association
OAD
oral anti-diabetic drug
OGIS
oral glucose insulin sensitivity
PK
pharmacokinetics
PPS
per protocol set
PSD
premature subject discontinuation
qd
quaque die (once daily)
RAN
randomised
RBC
red blood cells
REB
research ethics board
SAE
serious adverse event
SAF
safety
SCR
screening-only
SDD
study drug discontinuation


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SOC
system organ class
SU
sulfonylurea
SUSAR
suspected unexpected serious adverse reaction
T2DM
type-2 diabetes mellitus
TG
triglyceride
TIA
transient ischemic attack
TSH
thyroid stimulating hormone
TZD
thiazolidinedione
UKPDS
United Kingdom Prospective Diabetes Study
ULN
upper limit of normal
VLDL
very low density lipoprotein
WBC
white blood cells


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Glossary of terms
Assessment
A procedure used to generate data required by this study protocol.
Background therapy
Oral anti-diabetic drug (OAD), if any, that is being used by the patients at 
screening (see also “Treatment-naïve patient” below).
Baseline (BL)
Day when patient takes first dose of study medication.
Completion of the study
Point/time when all randomised patients have completed the 5-years 
treatment period or discontinued the study prematurely.
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol).
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with United States Code of Federal Regulation 
(CFR) 21 Section 312.3 and is synonymous with “investigational new 
drug”.
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an interactive response technology (IRT)
system.
Patient number
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
patient in the study (see Section 5.5.1).
Period
A subdivision of the study. In this study the 3 periods are likely to be 
different between patients (see Section 3.1).
Premature subject discontinuation
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time 
all study drug administration is discontinued and no further assessments 
are planned.
Randomisation number
A unique identifier assigned to each randomised patient, corresponding to 
a specific treatment arm assignment.
Rescue medication
Rescue medication is medication to treat the patient for type 2 diabetes 
mellitus (T2DM) when the patient temporarily cannot use the study drug 
regimen due to adverse events (AEs) or untoward events that require 
temporary dose adjustments. In this study, insulin should preferably be 
used as rescue medication (see Section 5.5.6).
Run-in period
The time between Visit 2 and Visit 3 where metformin will be initiated or 
up-titrated as described in Section 3.1.1.
Study drug discontinuation
Point/time at which the last dose of study drug was taken (in this protocol, 
this can be earlier but no later than at Visit 23).
Study drug
Any drug administered to the patient as part of the required study 
procedures; includes the investigational drugs metformin, vildagliptin (or 
matching placebo in Period 1 only), insulin (in Period 3 only).
Study drug regimen
The combination of study drugs taken by a patient in this study. The 
combination will be different depending on the period in the study in which 
the patient is at a given time.
Time to insulin initiation
The time to insulin initiation is defined as the time from randomization (Visit 
3) to the date of initiation of insulin therapy prescribed in Period 3 (i.e. for 
treatment intensification according to local guidelines) or to the date of 
discontinuation from the study in Period 2 due to not being able or 
unwillingness to initiate insulin therapy for treatment intensification in 
Period 3 (see Section 9.5.2.2).
Treatment-naïve patient
Patients not having ever received any anti-diabetic medication, or patients 
who, after the diagnosis of T2DM ≤24 months ago, have received anti-


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diabetic medication cumulatively for not more than 3 months, and have not 
received any anti-diabetic treatment within 3 months prior to Visit 1 (only 
metformin up to 2000mg daily is allowed within 1 month prior to Visit 1).
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points.


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Amendment 4
Amendment rationale
The protocol is being amended based on a health authority request to incorporate the 
redefined order of analysis in the protocol to align with the final, published statistical analysis 
plan. The loss of glycaemic control was analysed as a secondary endpoint instead of a primary 
endpoint, and an additional detail was provided for the confirmatory visit for the primary 
analysis of time to initial treatment failure.  Following this, only one primary endpoint 
approach was included in the statistical analysis plan analysis and the multiple testing method 
was removed.
Changes to the protocol
The second primary endpoint was removed from Section 2.1 and moved to Section 2.2 as a 
secondary endpoint.  References to appropriate sections in the statements were updated.
In Section 6.4, the second primary endpoint was removed and entered as a secondary endpoint.
In Section 9.4.1 and Section 9.4.2 only the remaining primary endpoint was described, and 
reference to the (previously existing) second primary endpoint was removed. The text was 
further adjusted to clarify the initial treatment failure (confirmed by the second of the two 
HbA1c measurements ≥7.0%). Text referring to the (previously existing) second primary 
endpoint was removed from Section 9.4.3. In Section 9.4.4 the time to first treatment failure 
was clarified, as well as the descriptive subgroup analysis.
The (previously existing) second primary endpoint was described as secondary endpoint in 
Section 9.5.2.2, as well as various other related corrections.
The text on the power calculation for the removed primary endpoint was deleted from Section 
9.6, as well as the text for the overall power of the study. The significance levels were 
adjusted.
The appropriate changes were also made in the protocol synopsis.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation.


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Amendment 3
Amendment rationale
The protocol is being amended to accommodate the inclusion of an adjudication committee
and a data monitoring committee (DMC), and specify timelines for safety reporting.
Furthermore, due to a metformin 500mg tablet variant introduced in the study with 
organoleptic properties which were not well perceived by subjects, the protocol now allows 
the temporary use of commercial metformin 500mg tablets.
There are some minor corrections as well.
Changes to the protocol
 
 
Section 3.1.1 has been amended to clarify that the minimum dose of metformin required at 
randomisation is 1000mg per day; this is now in line with the rest of the study protocol.
Section 3.1.2 has been amended to clarify that the metformin dose must not exceed 2000mg 
daily during the dose adjustments permitted in the first 4 weeks of Period 1.
In Section 4.2, a typographical error has been corrected to clarify the permitted use of anti-
diabetic medication prior to Visit 1.
In Section 5.1, a sentence has been added to clarify that in untoward situations where patients 
cannot use the study open label metformin 500mg tablets, temporarily commercial open label
metformin 500mg tablets can be used.
In Section 5.5.5, a clarification has been added regarding the permitted dose adjustments and 
interruptions. In Section 6.1 and Section 7.1, timelines applicable to safety reporting have 
been clarified. According to the amended protocol, adverse event and serious adverse event 
reporting must now commence at the time of informed consent.
Table 6-3 has been expanded to clarify that C-peptide is measured as part of the standard 
chemistry laboratory panel.
Section 7.4 and Section 9.8 now include an outline on involvement of a DMC requested by 
the Steering Committee. There is limited evidence with DPP-4 inhibitors in the early T2DM 
population with mild hyperglycaemia or systematically collected safety data up to 5 years
which demands looking into early cardiovascular outcomes but also safety of oral antidiabetic 
medications. The LAF237A23156 study provides a new territory for retrieval of a 
considerable pool of independently validated safety data (up to 10’000 patient years).
Section 7.5 now includes an outline on involvement of an adjudication committee. Results of 
recent studies with oral antidiabetic medications (reported after the start of the 
LAF237A23156 study) led the Steering Committee to request the addition of a cardiovascular 
adjudication committee. The importance of LAF237A23156 from the perspective of early 


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cardiovascular outcomes requires adjudicated events that will satisfy a need for independently 
validated cardiovascular event data.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation.


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Amendment 2
Amendment rationale
The protocol is being amended to include additional clarification related to the occurrence of a 
contraindication against the treatment with metformin or vildagliptin during the study and to 
ensure only patients who received appropriate diet and exercise training with respect to 
lifestyle modifications prior to enrolment may be included.
Changes to the protocol
In Section 4.1, a new inclusion criterion has been added to emphasise the need for patients to 
having received appropriate diet and exercise regime instructions related to lifestyle 
modifications prior to enrolment.
In Section 5.5.9, the occurrence of a contraindication against treatment with metformin or 
vildagliptin during the study has been added as a reason to discontinue a patient prematurely
from the study.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation.


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Amendment 1 
Amendment rationale
The protocol is being amended to include an additional meal-test for patients who are 
participating in the meal-test sub-study at Visit 4. This change, together with the additional 
meal-tests, will enable the evaluation of the rate of loss in β-cell function and the rate of 
change in insulin sensitivity based on the meal-test. Furthermore, clarification related to the 
timing of administration of the study drug at the visits when the meal-test is performed is 
inserted.
Changes to the protocol
In Table 6-1, the meal-test has been added for Visit 4. Additionally, in Section 6.4 the rate of 
loss in β-cell function has been corrected to be calculated from Visit 4 (week 13) onwards 
instead of baseline.
In Section 6.4.3, it is clarified that at baseline (Visit 3), the study drug regimen will be 
administered to the patient after the meal-test. For the subsequent tests the study drug regimen
will be administered 15 minutes before the start of the meal.
Corrections have been made to Section 9.5.2.1 and Section 9.5.2.2 to describe that the rate of 
loss in β-cell function is being calculated from Visit 4 (week 13) onwards instead of baseline.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the institutional review board 
(IRBs)/independent ethics committee (IECs) and health authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the informed consent, sites are 
required to update and submit for approval a revised informed consent that takes into account 
the changes described in this amended protocol.


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Protocol synopsis
Title of study: a 5-year study to compare the durability of glycemic control of a combination regimen 
with vildagliptin & metformin versus standard-of-care monotherapy with metformin, initiated in 
treatment-naïve patients with type 2 diabetes mellitus.
Purpose and rationale: the purpose of this study is to determine whether the initiation of a vildagliptin 
plus metformin combination regimen would result in more durable glycemic control than metformin 
monotherapy in treatment-naïve patients (see Glossary of terms) with T2DM. The results of this study 
may be used to support decision-making of national and international diabetes guidelines working 
groups.
Objectives:
Primary objectives:
To demonstrate the superiority of combination of vildagliptin 50mg bid and metformin over metformin 
monotherapy in treatment-naïve patients with T2DM by testing the hypothesis that the risk of 
confirmed initial treatment failure (defined as HbA1c ≥ 7.0%, see Section 9.4.1) is lower with the 
combination of vildagliptin and metformin compared to that with metformin monotherapy.
Secondary objectives:
To evaluate the effect of initiation of combination regimen with vildagliptin plus metformin compared 
with metformin monotherapy in treatment-naïve patient with T2DM within up to 5 years of treatment, 
with regards to:

The long-term efficacy of combination of vildagliptin 50mg bid and metformin over metformin 
monotherapy in treatment-naïve patients with T2DM by comparing the rate of loss in glycemic 
control over time (estimated annualised slope of HbA1c over time using a random coefficient 
model, see Section 9.5.2) between the combination vildagliptin plus metformin and metformin 
monotherapy.

Progression of HbA1c from 26 weeks after the start of Period 2 to the end of Period 2 (see 
Section 3.1.3) assessed by rate of loss in glycemic control over time.

Progression of FPG evaluated by the rate of loss in glycemic control over time assessed by 
estimated annualised slope of FPG over time for periods defined in Section 6.4.

Change in HbA1c as defined in Section 6.4.

Safety and tolerability.
In a subgroup of patients, to evaluate the effect of initiation of combination regimen with vildagliptin 
plus metformin compared with metformin monotherapy, with regards to:

β-cell function assessed by insulin secretion rate (ISR)/glucose area under the curve 
(AUCglucose) during a standard meal-test (see Section 3.1.5, Section 6.4.3 & Section 9.5.2.1) 
at timepoints indicated in Table 6-1 & Table 6-2 for periods defined in Section 6.4.

Insulin resistance assessed by oral glucose insulin sensitivity (OGIS) during a standard meal-
test at timepoints indicated in Table 6-1 & Table 6-2 for periods defined in Section 6.4.


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Population: The population will consist of males and females (non-fertile or of childbearing potential 
using a medically approved birth control method) with T2DM. It is expected to screen approximately 
4000 patients in order to randomise 2000 patients in this outpatient, international, multi-center clinical 
study.
A standard meal-test to evaluate β-cell function and insulin sensitivity (see Section 3.1.5) will be 
performed in a subgroup of patients.
Inclusion/Exclusion criteria: 
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1.
Written informed consent must be obtained before any assessment is performed.
2.
Confirmed diagnosis of T2DM by standard criteria.
3.
T2DM diagnosed ≤ 24 months ago.
4.
HbA1c ≥6.5% and ≤7.5% at Visit 1.
5.
Patients who are treatment-naïve, defined in this protocol as:

Patients not having ever received any anti-diabetic medication.

Patients who, after the diagnosis of T2DM ≤24 months ago, have received anti-diabetic 
medication cumulatively for not more than 3 months, and have not received any anti-
diabetic treatment within 3 months prior to Visit 1 (only metformin ≤2000mg daily is 
allowed within 1 month prior to Visit 1), see also Section 4.2.

Patients who initiated metformin within 1 month prior to Visit 1 and take a total daily dose 
of maximum 2000mg metformin at Visit 1.
6.
Age ≥18 and ≤70 years old at Visit 1.
7.
Body mass index (BMI) ≥22 and ≤40 kg/m2 at Visit 1.
8.
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use effective methods of contraception during dosing of study treatment. 
Effective contraception is defined as a method accepted as per local regulations and include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.

Female sterilisation (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment.

Male sterilisation (at least 6 months prior to screening). For female subjects on the study, 
the vasectomised male partner should be the sole partner for that subject.

Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository.


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
Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device or intrauterine system.

In case of use of oral contraception women should have been stabile on the same pill for 
a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation 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.
9.
Agreement to take the study medication as required by the study procedures.
10. Lifestyle interventions:

Agreement to continue current diet and exercise regime throughout the duration of the 
study, unless otherwise instructed by the investigator.

Only patients who receive appropriate diet and exercise training with respect to lifestyle 
modifications prior to enrolment may be included in the clinical study.
11. .Ability to comply with all study requirements and willingness to participate in a 5-year study.
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human chorionic 
gonadotropin (hCG) laboratory test.
2.
Use of any of the following medications as assessed at Visit 1:

Any anti-diabetic treatment within 3 months prior to visit 1 (except for metformin which is 
allowed within 1 month prior to Visit 1, see Section 3.1 and Section 4.1) or any anti-
diabetic treatment for more than 3 consecutive months or adding up to a total of more 
than 3 months in the last 2 years.

Use of weight control products including weight-loss medications in the previous 3 
months.

Chronic oral (>7 consecutive days), parenteral or intra-articular corticosteroid treatment 
within 8 weeks prior to Visit 1.

Treatment with growth hormone within the previous 6 months.

Treatment with any drug or use of herbal medicine of known and frequent toxicity to a 
major organ, or that may interfere with the interpretation of the efficacy and safety data 
during the study.
3.
A history or evidence of any of the following:

Acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar state 
(including coma) within the past 6 months.

Current diagnosis of congestive heart failure (NYHA III or IV).

Myocardial infarction (MI) within the past 6 months.

Coronary artery bypass surgery or percutaneous coronary intervention within the past 6 
months.

Stroke or transient ischemic attack (TIA) within the past 6 months.

Unstable angina within the past 3 months.

Sustained and clinically relevant ventricular arrhythmia.


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
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.

Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or 
secondary forms of diabetes (e.g. Cushing’s syndrome or acromegaly-associated 
diabetes).

Malignancy of an organ system (other than localised basal cell carcinoma of the skin) 
treated or untreated, within the past 5 years, regardless of whether there is evidence of 
local recurrence or metastases.

Hepatic disorder defined as:

acute or chronic liver disease, evidence of hepatitis, cirrhosis or portal hypertension.

history of imaging abnormalities that suggest liver disease (except hepatic steatosis), 
such as portal hypertension, capsule scalloping, cirrhosis.
4.
Any of the following significant laboratory abnormalities as assessed at Visit 1:

Clinically significant thyroid stimulating hormone (TSH) outside of the normal range.

Renal dysfunction defined as calculated creatinine clearance <60ml/min/1.73m2 via 
modified diet in renal disease (MDRD) formula.

Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x upper 
limit of normal (ULN) at Visit 1, confirmed by repeat measure within 3 working days.

Total bilirubin > 2 x ULN and/or direct bilirubin > 1 x ULN confirmed by repeat measure 
within 3 working days.

Positive Hepatitis B surface antigen (HbsAg).

Positive Hepatitis C antibody test (anti-hepatitis C virus (HCV)).

Elevated fasting triglycerides (TGs) >500mg/dL.

Clinically significant laboratory abnormalities which, in the opinion of the investigator, 
cause the patient to be considered inappropriate for inclusion in the study.
5.
Any of the following electrocardiogram (ECG) abnormalities at Visit 1:

Second or third degree atrio-ventricular block without a pacemaker.

Long QT syndrome or corrected QT >500ms.
6.
Previous or current participation in any vildagliptin clinical study.
7.
History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
8.
Concurrent medical condition that may interfere with the interpretation of efficacy and safety data 
during the study.
9.
Donation of ≥500mL or more of blood, significant blood loss equaling to at least one unit of blood 
within the past 2 weeks or a blood transfusion within the past 8 weeks.
10. Potentially unreliable and/or those judged by the investigator to be unsuitable for the study.
11. Use of an investigative drug within 30 days or 5 half-lives of the drug, whichever is longer.
12. Inability to comply with the study procedures or medications.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
Investigational and control therapy: The sponsor will provide the following double-blind study 
medication (Period 1):

Vildagliptin 50mg tablets.

Vildagliptin 50mg matching placebo tablets.
The sponsor will provide the following single-blind study medication (Period 2 and Period 3):


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
Vildagliptin 50mg tablets.
The sponsor will provide the following open label study medication (Period 1, 2 and 3):

Metformin 500mg tablets.
No other drugs will be supplied. Medication will be supplied in bottles. Sufficient medication will be 
provided for treatment according to the study protocol.
Study design: this is a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with 
a run-in period and up to 5 years treatment period (see Figure 3-1).
Efficacy assessments:
Primary

HbA1c measurements at visits indicated in Table 6-1 & Table 6-2 to determine the time to 
confirmed initial treatment failure (see Section 9.4.1).
Secondary

HbA1c measurements at visits indicated in Table 6-1 & Table 6-2 to determine the rate of loss 
in glycemic control over time (estimated annualised slope of HbA1c over time using a random 
coefficient model), from Visit 5 to the end of Period 1 (see Section 9.5.2).

HbA1c measurements at visits indicated in Table 6-1 & Table 6-2 to determine the rate of loss 
in glycemic control from 26 weeks after the start of Period 2 to end of Period 2 (see Section 
3.1.3).

FPG measurements at visits indicated in Table 6-1 & Table 6-2 to determine the rate of loss 
in glycemic control,  i) from Visit 5 to the end of Period 1; ii) from 26 weeks after start of 
Period 2 to end of Period 2 (see Section 3.1.3).

HbA1c measurements at visits indicated in Table 6-1 & Table 6-2 to determine the change in 
HbA1c from BL to end of study (EOS).

C-peptide measurements collected during a meal-test performed at visits indicated in Table 6-
1 & Table 6-2 to determine:

The change in AUC of ISR/G as an assessment of β-cell function (see Section 6.4.3 & 
Section 3.1.5) from BL to: i) initial treatment failure; ii) end of Period 2 (see Section 3.1.3); iii) 
EOS.

The rate of loss of β-cell function from Visit 4 (week 13) to: i) initial treatment failure; ii) end of 
Period 2 (see Section 3.1.3); iii) EOS.

Insulin measurements collected during a meal-test performed at visits indicated in Table 6-1
& Table 6-2 to determine:

OGIS as an assessment of change in insulin sensitivity (see Section 3.1.5 & Section 6.4.3) 
from BL to: i) initial treatment failure; ii) end of Period 2 (see Section 3.1.3); iii) EOS.

Rate of change in insulin sensitivity from Visit 4 (week 13) to: i) initial treatment failure; ii) end
of Period 2 (see Section 3.1.3); iii) EOS.


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Other assessments: physical examination, vital signs, 
 monitoring of hematology, blood 
chemistry and urine tests, ECG, incidence of hypoglycemia events, AEs/SAEs (see Section 7), new or 
progression of existing micro-vascular and macro-vascular complications, new onset micro-
albuminuria, progression to renal insufficiency, 
.
Data analysis: the primary statistical hypothesis of time to confirmed initial treatment failure will be 
assessed by a 1-sided test of superiority of the combination treatment with vildagliptin + metformin 
versus metformin monotherapy with α-level of 0.025 of the hazard-ratio between the combination 
treatment vildagliptin + metformin and metformin monotherapy being equal or greater than 1 as the 
null hypothesis, versus the 1-sided alternative hypothesis that the hazard-ratio is less than 1: H01: 
λvildagliptin+metformin/λmetformin ≥ 1 versus  Ha1: λvildagliptin+metformin/λmetformin < 1, where λvildagliptin+metformin and 
λmetformin are the hazard-rates of the confirmed initial treatment failure for vildagliptin 50mg bid + 
metformin up to 1000mg bid and metformin up to 1000mg bid monotherapy respectively. The time to 
failure will be derived as the time from randomization to the second of two consecutive visits at which 
HbA1c ≥7.0% is measured, starting from Visit 4 (13 weeks after randomization). The primary efficacy 
analysis will use a Cox proportional hazard regression model to assess the probability of confirmed 
initial treatment failure, with treatment as classification variable and BL HbA1c as a covariate. The 
hazard-ratio and associated 95% confidence interval as well as the p-value estimated from the above 
model will be presented by treatment.
The secondary 
 efficacy endpoints will be analysed in the full FAS as appropriate.
Demographic and background data as well as safety data will be summarised by treatment 
appropriately.


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1
Introduction
1.1
Background
T2DM is a chronic progressive disease characterised by insulin resistance, pancreatic β-cell 
dysfunction and hyperglucagonemia resulting in chronic hyperglycemia. Patients with 
uncontrolled T2DM are at significantly increased risk of long-term micro- and macrovascular 
complications that increase morbidity, mortality and healthcare costs (IDF, 2009). In the 
United Kingdom Prospective Diabetes Study (UKPDS) intensive treatment policy compared 
with conventional therapy in newly diagnosed patients with T2DM resulted in significant 
reduction of microvascular and macrovascular complications (UKPDS 33, 1998; UKPDS 34, 
1998). This protective effect seen in the intensive group was further maintained during the 
observational study period, despite the loss of difference in glycosylated hemoglobin (HbA1c), 
suggesting a legacy effect of maintaining strict glycemic control already from diagnosis
(Holman et al, 2008).
Life-style intervention targeted to reduce body weight is regarded as the first-line treatment 
for T2DM, but its success rates and long-term efficacy are limited. Therefore consensus 
guidelines recommend that metformin should be concurrently initiated with life-style 
interventions (ADA-EASD, 2009). Metformin is a biguanide which reduces hepatic glucose 
output and food consumption, and long-term follow up has suggested that it has positive 
effect on cardiovascular (CV) outcomes in overweight and obese patients (UKPDS 34, 1998). 
Other OADs, such as sulfonylureas (SU) and pioglitazone, are usually considered as second-
line therapies, as they are associated with safety concerns, including side effects such as 
hypoglycemia and weight gain or increasing the risk of congestive heart failure (CHF), and 
bone fractures in women (ADA-EASD, 2009). In the UKPDS, SU and metformin initially 
improved glycemic control, followed by progressive deterioration of HbA1c over the 12 years 
of follow-up (UKPDS 33, 1998; UKPDS 34, 1998). Furthermore, evaluation of the β-cell 
function indicated that at the time of diagnosis of T2DM 50% of the β-cell function was lost 
with further decline of around 4% per year (UKPDS 16, 1995). More recently, the ADOPT 
study found an annual reduction of β-cell function with metformin of 3.1% versus 2.0% with 
rosiglitazone in patients with T2DM with a diabetes duration of up to 3 years who had not 
received (systematically) antidiabetic treatment. The cumulative incidence of monotherapy 
failure, defined as fasting plasma glucose (FPG) exceeding 180mg/dL (10.0mM), at 5 years 
was 21% with metformin and 15% with rosiglitazone (32% risk reduction, p<0.001), at failure 
rates 4.3 and 2.9 per 100 patient-years, respectively (Kahn et al, 2006).
The most recent addition to the antidiabetic drugs are the glucagon-like peptide-1 (GLP-1)-
based therapies. Both GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors 
have shown significant improvement in glycemic control with low risk of hypoglycemia and 
weight neutrality or weight reduction (Nauck et al, 2010). In addition, GLP-1 appears to have 
a role in pancreatic islet development and regeneration. Studies in rodents show that GLP-1 
and its analogs stimulate β-cell growth and replication to increase islet mass (Drucker et al, 
2003; Stoffers et al, 2000; Xu et al, 1999). GLP-1 supports the differentiation of pancreatic 
duct cells into insulin-producing cells (Bulotta et al, 2002; Hardikar et al, 2002), and also may 
inhibit -cell apoptosis (Farilla et al, 2002; Li et al, 2003; Wang et al, 2001).


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Vildagliptin is a member of the DPP-4 inhibitor drug class. It is a highly-selective substrate 
for the DPP-4 catalytic site with a slow reaction rate, which blocks the usually rapid
degradation of GLP-1 and glucose-dependent insulinotropic peptide (GIP) (Villhauer et al, 
2003). Vildagliptin increases plasma level of GLP-1 and GIP, which improves the sensitivity 
of the β- and α-cell to glucose; there are also extra-pancreatic effects which contribute to 
improved insulin sensitivity and attenuate weight gain (Ahrén et al, 2011). In clinical studies, 
vildagliptin has been shown to reduce HbA1c, FPG & postprandial plasma glucose levels 
(Rosenstock et al, 2007; Goke et al, 2008; Kikuchi et al, 2009; D’Alessio et al, 2009; Ahrén et 
al, 2004; Bosi et al, 2009; Garber et al, 2008; Fonseca et al, 2007). The human data available 
with vildagliptin at present show good safety and tolerability at the dose levels used clinically 
(up to 100mg daily) (Ligueros-Saylan et al, 2010; Schweizer et al, 2011). Additional 
information regarding vildagliptin is available in the investigator brochure (IB).
The pharmacological actions of vildagliptin, particularly related to enhancement of glucose-
dependent insulin secretion, are complementary to those of metformin. The safety and 
efficacy of co-administration of vildagliptin and metformin for treatment of T2DM, either as 
separate tablets or as a fixed dose combination, has been demonstrated in numerous clinical 
studies (Ahrén et al, 2004; Bosi et al, 2009; Matthews et al, 2010). In a 24-week study in 
T2DM patients with HbA1c between 7.5% and 11.0%, the combination of vildagliptin 
50mg/metformin 1000mg has shown superior glycemic control to each of the components in 
the combination (Bosi et al, 2009), however it is not known how this initial difference in the 
glycemic control would evolve over time. No long term data related to the effect of 
combination anti-diabetic therapies including a DPP-4 inhibitor on the durability of glycemic
control are available in patients with more preserved β-cell function, i.e. newly diagnosed, or 
treatment-naïve patients with mild hyperglycemia.
While some guidelines advocate initiation of therapy with metformin already at diagnosis 
with consequent stepwise addition of other anti-diabetic treatments (ADA-EASD 2009), 
others recommend initiation combination therapy if patient’s HbA1c is in the range 7.6%-
9.0% (AACE/ACE, 2009). A more proactive approach with early combination treatment has 
been suggested (Del Prato et al, 2005). So far no long-term study has compared treatment 
initiation with combination therapy versus the standard-of-care metformin monotherapy in 
newly diagnosed or treatment-naïve patients. Considering the protective effect on the β-cell 
which vildagliptin may have in treatment-naïve patients with mild hyperglycemia (Scherbaum 
et al, 2008; Mathieu, 2008), it is of scientific and clinical practice interest to address the 
question if a combination regimen including vildagliptin/metformin given as initial therapy 
can provide more durable glycemic control compared with the standard-of-care metformin 
monotherapy.
1.2
Purpose 
The purpose of this study is to determine whether the initiation of a vildagliptin plus 
metformin combination regimen would result in more durable glycemic control than
metformin monotherapy in treatment-naïve patients (see Glossary of terms) with T2DM. The 
results of this study may be used to support decision-making of national and international 
diabetes guidelines working groups.


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2
Study objectives
2.1
Primary objectives

To demonstrate the superiority of combination of vildagliptin 50mg bid and metformin 
over metformin monotherapy in treatment-naïve patients with T2DM by testing the 
hypothesis that the risk of confirmed initial treatment failure (defined as HbA1c ≥ 7.0%, 
see Section 9.4.1) is lower with the combination of vildagliptin and metformin compared 
to that with metformin monotherapy.
2.2
Secondary objectives
To evaluate the effect of initiation of combination regimen with vildagliptin plus metformin 
compared with metformin monotherapy in treatment-naïve patient with T2DM within up to 5 
years of treatment, with regards to:

The long-term efficacy of combination of vildagliptin 50mg bid and metformin over 
metformin monotherapy in treatment-naïve patients with T2DM by comparing the rate of 
loss in glycemic control over time (estimated annualised slope of HbA1c over time using a 
random coefficient model, see Section 9.5.2) between the combination vildagliptin plus 
metformin and metformin monotherapy.

Progression of HbA1c from 26 weeks after the start of Period 2 to the end of Period 2 (see 
Section 3.1.3) assessed by rate of loss in glycemic control over time.

Progression of FPG evaluated by the rate of loss in glycemic control over time assessed by 
estimated annualised slope of FPG over time for periods defined in Section 6.4.

Change in HbA1c as defined in Section 6.4.

Safety and tolerability.
In a subgroup of patients, to evaluate the effect of initiation of combination regimen with 
vildagliptin plus metformin compared with metformin monotherapy, with regards to:

β-cell function assessed by insulin secretion rate (ISR)/glucose area under the curve 
(AUCglucose(0-2h)) during a standard meal-test (see Section 3.1.5, Section 6.4.3 & Section 
9.5.2.1) at timepoints indicated in Table 6-1 & Table 6-2 for periods defined in Section 6.4.

Insulin resistance assessed by oral glucose insulin sensitivity (OGIS) during a standard 
meal-test at timepoints indicated in Table 6-1 & Table 6-2 for periods defined in Section 
6.4.


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3
Investigational plan
3.1
Study design
This is a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a 
run-in period and up to 5 years treatment period (see Figure 3-1). Following a screening visit 
(Visit 1) and a screening period of up to 2 weeks, treatment-naïve patients (see Section 4.1 or 
Glossary of terms), meeting all eligibility criteria will enter the run-in period at Visit 2.
3.1.1
Run-in period
At Visit 2, all eligible patients will receive lifestyle instructions (diet and exercise) according 
to local practice. Metformin treatment will be initiated and/or up-titrated as follows:
Treatment-naïve patients
Metformin will be initiated at a dose 500mg qd. Patients will be instructed to up-titrate 
metformin to 1000mg daily after one week if gastrointestinal (GI) side effects have not 
occurred and to 1000mg or 1500mg daily two weeks after Visit 2. If GI side effects occur, 
patients may stay another week on the same dose of metformin. An unscheduled visit can be 
performed in order to adjust the metformin dose if deemed necessary.
Up to three weeks after Visit 2 patients will return to the site for Visit 3. Patients who are able 
to tolerate a total dose of at least 1000mg daily will be randomised.
Patients who have initiated metformin within 1 month prior to Visit 1
Patients taking a daily dose of ≥500mg and <1000mg will be instructed to up-titrate their dose 
weekly (for 2 weeks or 1 week, respectively) in 500mg increments to 1500mg or a maximum 
tolerated dose (see Figure 3-1). Patients on a dose ≥500mg and <1000mg will have first up-
titration to 1000mg daily. If GI side effects occur during up-titration, the patient should be 
instructed to go back to the previously tolerated dose, and then try to increase the dose again 
by 500mg. Patients who are able to tolerate a total dose of at least 1000mg daily will be 
randomised.
Patients taking metformin ≥1000mg and ≤2000mg daily at Visit 1 will directly proceed to 
randomisation and start in Period 1.
3.1.2
Period 1: vildagliptin/metformin combination versus metformin
At Visit 3, patients will be randomised 1:1 to one of the following study regimens:

Metformin up to 1000mg bid plus vildagliptin 50mg bid or 

Metformin up to 1000mg bid plus matching placebo bid.


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During the first 4 weeks of Period 1 the metformin dose can be adjusted (increased or 
decreased, but not below 1000mg daily or above 2000mg). An unscheduled visit can be 
performed in order to adjust the metformin dose if deemed necessary. The objective is to 
optimise metformin dose to 2000mg daily or to the maximum tolerated dose. Patients who are 
unable to tolerate a total daily dose of 1000mg metformin will be discontinued. The 
metformin dose at week 4 post-randomisation and the vildagliptin 50mg bid or matching 
placebo bid dose should remain unchanged throughout the duration of the study, except for 
AEs or untoward events that may require dose reduction or interruption (see Section 5.5.5).
Any anti-diabetic medication other than the study drug regimen is not allowed during Period 1, 
except if the patient had temporarily reduced/interrupted the treatment regimen due to AEs or 
untoward events that require temporary dose adjustments. In such cases dose adjustments or 
interruptions of the study drug are permitted (see Section 5.5.5). Patients who, during Period 1, 
take anti-diabetic medication other than the study drug regimen (except for AEs or untoward 
events that require temporary dose adjustments, see Section 5.5.5) will be discontinued from 
the study.
The duration of Period 1 may differ between patients depending on the time when the second 
of two HbA1c measurements taken at two consecutive visits after randomisation (Table 6-1 &
Table 6-2) confirms HbA1c ≥ 7.0%.
3.1.3
Period 2: vildagliptin/metformin combination versus vildagliptin add-
on to metformin 
In the case of two consecutive HbA1c measurements ≥7.0% from two consecutive study visits 
during Period 1, scheduled according to Table 6-1 & Table 6-2, patients in both arms will 
receive new vildagliptin study medication packs. The investigator will contact the IRT system 
within 2 weeks after the receipt of the second of the two elevated HbA1c measurements. The 
IRT system will assign the new vildagliptin study medication packs. Patients who were 
randomised to the placebo arm in Period 1 will now receive vildagliptin 50mg bid. Patients 
who were randomised to the active vildagliptin 50mg bid arm in Period 1 will continue to 
receive vildagliptin 50mg bid. All patients will continue to take their metformin dose 
unchanged. Period 2 will remain masked to the patient and both patients and investigators will 
remain masked to the treatment allocation in Period 1.
Any anti-diabetic medication other than the study regimen is not allowed during Period 2, 
except if the patient had temporarily reduced/interrupted the treatment regimen due to AEs or 
untoward events that require temporary dose adjustment/interruption (see Section 5.5.5).
If, during Period 2, therapy intensification is required in accordance with the local guidelines, 
the patient will enter Period 3.
The duration of Period 2 may differ between patients. End of Period 2 is considered when 
insulin treatment is initiated, or alternatively when the patient is discontinued because insulin 
treatment is not initiated in Period 3 (see Section 3.1.4).
3.1.4
Period 3: insulin initiation
In Period 3, patients must be initiated on insulin. Patients who will have their therapy 
intensified with anti-diabetic treatment other than insulin must be discontinued from the study. 


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Reasons for intensifying treatment with other anti-diabetic treatment may be (but are not 
limited to) the patient being unwilling to initiate insulin therapy or insulin cannot be initiated 
according to local diabetes treatment guidelines.
Open-label insulin, preferably basal insulin, should be initiated if local guidelines criteria for 
insulin initiation are met during Period 2. The type of insulin and insulin regimen are at 
investigator’s discretion. The study drug regimen will continue unchanged and will remain 
masked to the patient in Period 3 and both patients and investigators will remain masked to 
the treatment allocation in Period 1.
Figure 3-1
Study design
Screening
&
informed
consent
= 1000mg metformin = 1 
month
500mg metformin 
= 1 month 
Naive patient
m
etform
in
Run
in
Random
isation
&
firstdose
W
eek
1:
m
etform
in
0.5g
W
eek
2
m
etform
in
1g
W
eek
3
m
etform
in
=
1g
Period 1: metformin + 
vildagliptin 50mg bid
Period 2: metformin + 
vildagliptin 50mg bid
Period 1: metformin + 
placebo 50mg bid
Period 2: metformin + 
vildagliptin 50mg bid
Period 3: metformin + 
vildagliptin 50mg bid
+ insulin
Week -5
Day 1
V1
Subsequent visits
V3
V2
Week -3
Run-in period
> 500mg < 1000 metformin 
= 1 month
Screen
Year 5
V23
Period 3: metformin + 
vildagliptin 50mg bid
+ insulin
Double blind
Single blind
3.1.5
Meal-test
A standard meal-test will be performed in selected experienced sites at visits indicated in 
Table 6-1 & Table 6-2 in a subgroup of 380 patients in order to assess the progression of β-
cell function and insulin sensitivity (see Section 6.4.3).
3.2
Rationale of study design
Up to 2-week screening period will be used to ensure that the entry criteria are met and to 
allow time for test results to be received and evaluated prior to randomisation. Up to 3-week 
run-in period is foreseen for the up-titration of metformin in order to minimise its GI side 
effects for treatment-naïve patients. After randomisation, study visits are scheduled every 13 
weeks in order to monitor HbA1c progression over time and determine the time to failure. In 
case initial treatment fails to maintain HbA1c<7.0%, confirmed at two consecutive study 
visits (according to Table 6-1 & Table 6-2), vildagliptin will be added to metformin in the 
metformin-only arm in Period 2. In Period 3, insulin is considered based on local guidelines. 
This is a standard parallel-group 2-arm study comparing the two different treatment 
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3.3
Rationale of dose/regimen, duration of treatment
The selected doses and regimen (vildagliptin 50mg bid/metformin up to 1000mg bid and 
matching placebo bid/metformin up to 1000mg bid) are approved for use in patients with 
T2DM and are optimal doses achieving therapeutic effect in this population.
A 5-year study period will allow demonstrating a difference in the durability of the glycemic 
effect between a combination regimen with vildagliptin/metformin and the current standard-
of-care, metformin monotherapy (Kahn et al, 2006). Vildagliptin is chosen as add-on to 
metformin since it has similar efficacy as other OADs suitable for add-on therapy to 
metformin (SUs or TZDs), but with a better weight profile than SUs and TZDs, and lower risk 
of hypoglycemia than SUs. Insulin is chosen as therapy in Period 3 as it is proposed in 
guidelines after failure of dual combination therapy (ADA, 2009).
3.4
Rationale for choice of comparator
Metformin up to 1000mg bid is chosen as the comparator treatment as it is currently 
recommended as initial treatment by diabetes guidelines. Metformin improves glycemic 
control and, when used as monotherapy, is associated with very low risk of hypoglycemia and
weight neutrality or weight loss.
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks
At the doses currently marketed in many countries, vildagliptin alone and in combination 
treatment with metformin is an effective treatment and overall tolerability and safety are good.
A study performed with initiation of vildagliptin + metformin in drug-naïve patients with 
T2DM (CLAF237A2302) showed that this combination is effective and safe and carries no 
risk of hypoglycemia. Therefore it is expected that the early introduction of vildagliptin in this 
study will have positive effect without additional risk for the patient. Hence, the use of a 
combination of metformin and vildagliptin, as proposed in the study, can be justified and 
patients treated with vildagliptin in the study are expected to benefit from HbA1c reductions. 
For patients with T2DM whose hyperglycemia is not optimally controlled on a therapy with 
metformin, even if only moderately above the target threshold, combination therapy with a 
second OAD is typically started in line with treatment guidelines. The vildagliptin dose of 
50mg bid is in accordance with the approved product information of vildagliptin as add-on 
therapy to metformin.
The risks of the study are judged to be acceptable. Metformin and vildagliptin are both well-
profiled and their risks well known. The safety profile of vildagliptin is also well documented 
and this study does not deviate from the dosages or treatment durations already studied. 
Safety laboratory tests are performed regularly and a range of AEs of interest are reviewed on 
an ongoing basis. The study, as designed, does not expose patients to unacceptable risks and, 
within the constraints of a robust clinical study, conforms to current practice in the treatment 
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4
Population
The population will consist of males and females (non-fertile or of childbearing potential 
using a medically approved birth control method) with T2DM.
It is expected to screen approximately 4000 patients in order to randomise 2000 patients in 
this outpatient, international, multi-center clinical study.
A standard meal-test to evaluate β-cell function and insulin sensitivity (see Section 3.1.5) will 
be performed in a subgroup of patients.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Confirmed diagnosis of T2DM by standard criteria.
3. T2DM diagnosed ≤ 24 months ago.
4. HbA1c ≥6.5% and ≤7.5% at Visit 1.
5. Patients who are treatment-naïve, defined in this protocol as:

Patients not having ever received any anti-diabetic medication.

Patients who, after the diagnosis of T2DM ≤24 months ago, have received anti-
diabetic medication cumulatively for not more than 3 months, and have not received 
any anti-diabetic treatment within 3 months prior to Visit 1 (only metformin ≤2000mg 
daily is allowed within 1 month prior to Visit 1), see also Section 4.2.

Patients who initiated metformin within 1 month prior to Visit 1 and take a total daily 
dose of maximum 2000mg metformin at Visit 1.
6. Age ≥18 and ≤70 years old at Visit 1.
7. Body mass index (BMI) ≥22 and ≤40 kg/m2 at Visit 1.
8. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use effective methods of contraception during dosing of study 
treatment. Effective contraception is a method accepted as per local regulations and
include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilisation (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.

Male sterilisation (at least 6 months prior to screening). For female subjects on the 
study, the vasectomised male partner should be the sole partner for that subject.


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
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device or intrauterine system.

In case of use of oral contraception women should have been stabile on the same pill 
for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation 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.
9. Agreement to take the study medication as required by the study procedures.
10. Lifestyle interventions:

Agreement to continue current diet and exercise regime throughout the duration of the 
study, unless otherwise instructed by the investigator.

Only patients who receive appropriate diet and exercise training with respect to
lifestyle modifications prior to enrolment may be included in the clinical study.
11. Ability to comply with all study requirements and willingness to participate in a 5-year 
study.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test.
2. Use of any of the following medications as assessed at Visit 1:
a. Any anti-diabetic treatment within 3 months prior to visit 1 (except for metformin 
which is allowed within 1 month prior to visit 1, see Section 3.1 and Section 4.1) or
any anti-diabetic treatment for more than 3 consecutive months or adding up to a total 
of more than 3 months in the last 2 years.
b. Use of weight control products including weight-loss medications in the previous 3 
months.
c. Chronic oral (>7 consecutive days), parenteral or intra-articular corticosteroid 
treatment within 8 weeks prior to Visit 1.
d. Treatment with growth hormone within the previous 6 months.
e. Treatment with any drug or use of herbal medicine of known and frequent toxicity to 
a major organ, or that may interfere with the interpretation of the efficacy and safety 
data during the study.


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3. A history or evidence of any of the following:
a. Acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar state 
(including coma) within the past 6 months.
b. Current diagnosis of congestive heart failure (NYHA III or IV).
c. Myocardial infarction (MI) within the past 6 months.
d. Coronary artery bypass surgery or percutaneous coronary intervention within the past 
6 months.
e. Stroke or transient ischemic attack (TIA) within the past 6 months.
f.
Unstable angina within the past 3 months.
g. Sustained and clinically relevant ventricular arrhythmia.
h. 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.
i.
Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or 
secondary forms of diabetes (e.g. Cushing’s syndrome or acromegaly-associated 
diabetes).
j.
Malignancy of an organ system (other than localised basal cell carcinoma of the skin) 
treated or untreated, within the past 5 years, regardless of whether there is evidence of 
local recurrence or metastases.
k. Hepatic disorder defined as:

acute or chronic liver disease, evidence of hepatitis, cirrhosis or portal 
hypertension.

history of imaging abnormalities that suggest liver disease (except hepatic 
steatosis), such as portal hypertension, capsule scalloping, cirrhosis.
4. Any of the following significant laboratory abnormalities as assessed at Visit 1:
a. Clinically significant thyroid stimulating hormone (TSH) outside of the normal range.
b. Renal dysfunction defined as calculated creatinine clearance <60ml/min/1.73m2 via 
modified diet in renal disease (MDRD) formula.
c. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x upper 
limit of normal (ULN) at Visit 1, confirmed by repeat measure within 3 working days.
d. Total bilirubin > 2 x ULN and/or direct bilirubin > 1 x ULN confirmed by repeat 
measure within 3 working days.
e. Positive Hepatitis B surface antigen (HbsAg).
f.
Positive Hepatitis C antibody test (anti-hepatitis C virus (HCV)).
g. Elevated fasting triglycerides (TGs) >500mg/dL.
h. Clinically significant laboratory abnormalities which, in the opinion of the 
investigator, cause the patient to be considered inappropriate for inclusion in the study.
5. Any of the following electrocardiogram (ECG) abnormalities at Visit 1:
1. Second or third degree atrio-ventricular block without a pacemaker.
2. Long QT syndrome or corrected QT >500ms.
6. Previous or current participation in any vildagliptin clinical study.
7. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.


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8. Concurrent medical condition that may interfere with the interpretation of efficacy and 
safety data during the study.
9. Donation of ≥500mL or more of blood, significant blood loss equaling to at least one unit 
of blood within the past 2 weeks or a blood transfusion within the past 8 weeks.
10. Potentially unreliable and/or those judged by the investigator to be unsuitable for the study.
11. Use of an investigative drug within 30 days or 5 half-lives of the drug, whichever is longer.
12. Inability to comply with the study procedures or medications.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Investigational and control treatment
The sponsor will provide the following double-blind study medication (Period 1):

Vildagliptin 50mg tablets.

Vildagliptin 50mg matching placebo tablets.
The sponsor will provide the following single-blind study medication (Period 2 and Period 3):

Vildagliptin 50mg tablets.
The sponsor will provide the following open label study medication (Period 1, 2 and 3):

Metformin 500mg tablets.
Temporarily, in untoward situations where a subject cannot use the study open label 
metformin 500mg tablets, open label commercial metformin 500mg can be used.
No other drugs will be supplied. Medication will be supplied in bottles. Sufficient medication 
will be provided for treatment according to the study protocol.
5.2
Treatment arms
Patients will be assigned in a ratio of 1:1 to one of two treatment arms:

Metformin up to 1000mg bid plus vildagliptin 50mg bid (Period 1). In Period 2 and 3 
these patients will receive metformin up to 1000mg bid plus vildagliptin 50mg bid.

Metformin up to 1000mg bid plus vildagliptin placebo 50mg bid (Period 1). In Period 2 
and 3 these patients will receive metformin up to 1000mg bid plus vildagliptin 50mg bid.
5.3
Treatment assignment
At Visit 3 all eligible patients will be randomised via IRT to one of the treatment arms. The 
investigator or his/her delegate will contact the IRT system after confirming that the patient 
meets all the inclusion criteria and no exclusion criterion. The IRT system will assign a
randomisation 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 randomisation number will not be communicated to the user.


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The randomisation numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomisation list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomisation numbers. These 
randomisation 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 study drug packs containing each of the 
study drugs.
The randomisation scheme for patients will be reviewed and approved by a member of the 
randomisation office within the Audit Readiness, Validation and Randomisation department.
5.4
Treatment masking
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
masked to the identity of the treatment from the time of randomisation until database lock, 
using the following methods: (1) randomisation data are kept strictly confidential until the 
time of unmasking, and will not be accessible by anyone else involved in the study & (2) the 
identity of the treatments will be concealed by the use of study drugs that are all identical in 
packaging, labeling, schedule of administration and appearance.
Unmasking will only occur in the case of patient emergencies (see Section 5.5.10) and at the 
completion of the study (see Section 5.5.11).
5.5
Treating the patient
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. Upon signing the 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 are assigned consecutive 
numbers (e.g. the second patient is assigned patient number 2, the third patient is assigned 
patient number 3 etc.). The investigator or his/her staff will contact the IRT system and 
provide the requested identifying information for the patient to register them into the IRT 
system. For studies using electronic case record forms (eCRFs), only the assigned patient 
number should be entered in the field labeled “Patient ID” on the electronic data capturing 
(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 randomised for any reason, the IRT system 
must be notified within 2 days that the patient was not randomised. The reason for not being 
randomised will be entered on the screening log, and the Demography eCRF should be 
completed.
5.5.2
Dispensing the study drug
Each study site will be supplied by Novartis with study drug. The study drug packaging has a 
2-part label. A unique number is printed on each part of this label which corresponds to one of 
the 2 treatment arms. Investigator staff will identify the study drug package(s) to dispense to 


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the patient by contacting the IRT system 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.
All drug kits assigned by the IRT system will be recorded in the IRT database.
5.5.3
Supply, storage and tracking of study drug
Study drug 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 
designated staff have access. Upon receipt, all study drugs should be stored according to the 
instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol.
Medication labels will comply with the legal requirements of each country. They will contain
no information about the patient but will carry the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Monitoring of drug accountability will be performed by 
the field monitor during site visits and at the completion of the study. Patients will be asked to 
return all unused study drug and packaging to the study center at each study visit, at the time 
of study drug discontinuation or premature subject withdrawal.
At the completion of the study, and as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
5.5.4
Instructions for prescribing and taking study drug
The investigator should ensure that the patient clearly understands the dosing instructions 
outlined below.

At Visit 2, each patient will be dispensed study drug consisting of 1 bottle of metformin 
500mg oral tablets. This is sufficient medication for the run-in period of up to 3 weeks 
until Visit 3.

From Visit 3 to Visit 22, each patient will be dispensed the study medication consisting of 
3 bottles of vildagliptin 50mg oral tablets (or matching placebo in Period 1) and 3 bottles 
of metformin 500mg oral tablets. This is sufficient medication for the period of 13 weeks
between subsequent visits.
Patients will be instructed to take one tablet of vildagliptin (or matching placebo in Period 1) 
in the morning and one tablet in the evening with or without food. Metformin should be taken 
in a bid regimen (depending on the total daily dose) during or after meals at the same time as
vildagliptin (or matching placebo). Study drug should be taken the same time throughout the 
study.
No study drug should be taken on the morning of a study visit. Patients should arrive in the 
fasting state; i.e. no food or drinks (except water) minimum 8h before the next scheduled visit. 


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The study medication will be taken after the completion of all study procedures for that visit 
prior to the first meal of the day (for patients performing a meal-test, see Section 6.4.3). If the 
patient has not fasted for an adequate period of time, the collection of fasting laboratory 
evaluations must be rescheduled. The study drug regimen (or, if applicable, rescue medication 
as defined in Section 5.5.6) should not be taken prior to obtaining the fasting laboratory test 
samples.
If a dose is missed and the patient realizes this within 3h, the study drugs should be taken
otherwise the patient should take the next scheduled dose.
Previously dispensed medication bottles, including any remaining study medication, must be 
returned to the study center at each study visit.
All prescribed dosages, all study drugs dispensed to the patient and all dose changes during 
the study must be recorded on the appropriate Study Drug Dosage Administration Record 
eCRF(s).
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 optimise 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.
5.5.5
Permitted dose adjustments and interruptions of study drug
During the first 4 weeks of Period 1, the metformin dose can be adjusted if GI side effects 
occur (see also Section 3.1.2).
For patients who suffer AEs or untoward events that require temporary dose adjustments, dose 
adjustments or interruptions are permitted in order to keep the patient on the regimen:

Study drug regimen adjustments are restricted to a period of maximum of 4 consecutive 
weeks.

No more than 3 periods of study drug regimen adjustments are allowed for each individual 
patient during the whole study after randomisation.

Patients are allowed to receive rescue medication during this period, as described in 
Section 5.5.6.
Any study regimen changes must be recorded on the appropriate Dosage Administration 
Record eCRF(s).
5.5.6
Rescue medication
Use of rescue medication (defined in the Glossary of terms) is not allowed, except for patients 
who suffer AEs or untoward events that require temporary dose adjustments (see Section 
5.5.5). During these temporary dose adjustment periods, patients may receive rescue 
medication (preferably insulin).
Any rescue medication must be recorded on the Concomitant Medications/Significant Non-
Drug Therapies eCRF.


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5.5.7
Concomitant treatment
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient 
starts treatment with study drug must be listed on the Concomitant Medications/Significant 
Non-Drug Therapies eCRF.
5.5.8
Prohibited treatment
Use of the following medications is prohibited during the course of this study:

Treatment with any OAD other than the study drug regimen (see Glossary of terms) as 
detailed in the study protocol, except rescue medication as described in Section 5.5.6 (e.g. 
following a permitted dose adjustment as described in Section 5.5.5).

Long-term (>4 consecutive weeks) oral, parenteral or intra-articular corticosteroid 
treatment.

Weight control products including weight-loss medications.

Treatment with growth hormones or growth hormone analogs.

Treatment with any drug with a known and frequent toxicity to a major organ or that may 
interfere with the interpretation of the efficacy and safety data.

Treatment with an investigational drug other than study drug.
All other prior and concomitant non-study medications (not specifically contra-indicated in 
the exclusion criteria, see Section 4.2) are allowed.
5.5.9
Discontinuation of study drug and premature subject withdrawal
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Completion eCRF.
The investigator can be guided by the following criteria but may discontinue patients from 
study participation at anytime during the study based on clinical judgment.
Study drug must be discontinued for a given patient and the patient withdrawn from 
participation in the study if the investigator determines that continuation would result in a 
significant safety risk for that patient. In addition, the following circumstances require that 
study drug treatment and patient participation in the study be discontinued:
1. Patient withdrawal of informed consent.
2. The occurrence of an AE or clinically significant laboratory change or abnormality that, in 
the judgment of the investigator, warrants discontinuation from the study.


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3. Occurrence of ketoacidosis or clinically significant ketosis. Patients with evidence of 
ketoacidosis/ketosis should be discontinued from the study and treated appropriately 
according to local guidelines.
4. Liver enzyme elevations (see Section 6.5.5 and Table 6-4 for specific actions, reporting 
and follow-up).
5. Use of prohibited treatment as per Section 5.5.8.
6. Patients in Period 2 requiring treatment intensification according to local guidelines (see 
Section 3.1.3) who do not initiate insulin treatment in Period 3 (see Section 3.1.4).
7. Any protocol deviation that results in a significant risk to the patient’s safety.
8. Patients becoming pregnant during the study (see Section 6.5.8).
9. Occurrence of a contraindication against treatment with metformin or vildagliptin during
the study.
The appropriate personnel from the site and Novartis will assess whether study drug treatment 
should be discontinued for any patient whose treatment was inadvertently unmasked for any 
reason.
The investigator must contact the IRT system to register the patient’s discontinuation from 
study drug.
Patients who are prematurely withdrawn from study participation will not be replaced by 
newly enrolled patients.
5.5.10
Emergency unmasking of treatment assignment
Emergency unmasking should only be undertaken when it is essential to treat the patient 
safely and efficaciously. Most often, study drug discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency unmasking is performed using the IRT system. When the 
investigator contacts the system to unmask the treatment for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to unmask the treatment
of the patient. The investigator will then receive details of the drug treatment for the specified 
patient and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the Clinical Trial Head that a patient’s study drug 
regimen was unmasked.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT system in case of emergency. The investigator will inform the patient how to 
contact his/her backup in cases of emergency when he/she is unavailable. The investigator 
will provide protocol number, study drug name if available, patient number, and instructions 
for contacting the local Novartis office, or any entity to which it has delegated responsibility 
for emergency unmasking, to the patient in case emergency unmasking is required at a time 
when the investigator and backup are unavailable.


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5.5.11
Study completion and post-study treatment
The study will be considered completed for an individual patient when he/she completes the 5 
years treatment period. The study as a whole will be considered completed when all 
randomised patients have completed the 5 years treatment period or discontinued the study
prematurely.
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to 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.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.5.12
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as described in Section 6 for 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 institutional review 
boards (IRBs) and/or independent ethics committees (IECs) of the early termination of the 
study.
6
Visit schedule and assessments
Visits are scheduled as indicated in Table 6-1 & Table 6-2. An “X” in Table 6-1 & Table 6-2
indicates which assessments are to be performed during each visit.
Patients who discontinue study drug before completing the study, and those who prematurely 
withdraw from 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 (Visit 23) will be performed. At a 
minimum, they will be contacted for safety evaluations during the 30 days following the last 
intake of study drug, including final contact at the 30-day point. Documentation of attempts to 
contact the patient should be recorded in the source documents.


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Table 6-1
Assessment schedule (year 1-2)
Visit
1
2
3
4
5
6
7
8
9
10
11
Week
-5
-3
BL
13
26
39
52
65
78
91
104
Assessments
Screening log (see Section 6.1)
X
Informed consent
S
Inclusion/exclusion criteria (see Section 4.1 & Section 4.2)
S
S
Demography (see Section 6.2)
X
Medical history/current conditions
X
Smoking history
X
History of diabetes & complications
X
Hepatitis screen (see Section 6.5.4)
X
TSH (see Section 6.5.4)
X
Serum pregnancy test (see Section 6.5.8)
X
X
Physical examination (see Section 6.5.1)
S
Randomisation
S
Efficacy
HbA1c (see Section 6.4.1)
X
X
X
X
X
X
X
X
X
X
X
FPG (see Section 6.4.2)
X
X
X
X
X
X
X
X
X
X
X
Fasting insulin (see Section 6.4.2)
X
X
X
Safety
Vital signs including height (see Section 6.5.2)
X
Vital signs (see Section 6.5.2)
X
X
X
X
X
X
X
X
X
X
ECG (see Section 6.5.7)
X
X
X
Hematology (see Section 6.5.4)
X
X
X
X
Chemistry (see Section 6.5.4)
X
X
X
X
Liver function test (LFT) testing only (see Section 6.5.4)
X
X
X
X


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Visit
1
2
3
4
5
6
7
8
9
10
11
Week
-5
-3
BL
13
26
39
52
65
78
91
104
Fasting lipid profile & TGs (see Section 6.5.4)
X
X
X
X
Urinalysis (incl. albumin/creatinin ratio, see Section 6.5.4)
X
X
X
X
Urine pregnancy test (see Section 6.5.8)
X
X
X
X
AEs (see Section 7.1)
X
X
X
X
X
X
X
X
X
X
Serious adverse events (SAEs, see Section 7.2)
X
X
X
X
X
X
X
X
X
X
Medication Records
History of anti-diabetic medication therapy
X
Dose administration record – vildagliptin
X
X
X
X
X
X
X
X
X
Dose administration record – metformin
X
X
X
X
X
X
X
X
X
X
Dose administration record – insulin
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Drug dispensing
S
S
S
S
S
S
S
S
S
S
Drug accountability/medication check
S
S
S
S
S
S
S
S
S
Administrative procedures
Call IRT system
S
S
S
S
S
S
S
S
S
S
S
Dispense glucometer and instructions
S
Glycaemia study diary review
S
S
S
S
S
S
S
S
S
Study completion (see Section 5.5.11)
Sub-studies
Meal-test (see Section 6.4.3)
X
X
X
X
S = Source documents only; X = Assessment to be recorded in the eCRF.


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Table 6-2
Assessment schedule (year 3-5)
Visit
12
13
14
15
16
17
18
19
20
21
22
23 
SDD 
and/or 
PSD
Week
117
130
143
156
169
182
195
208
221
234
247
260
Assessments
Screening log (see Section 6.1)
Informed consent
Inclusion/exclusion criteria (see Section 4.1 & Section 4.2)
Demography (see Section 6.2)
Medical history/current conditions
Smoking history
History of diabetes & complications
Hepatitis screen (see Section 6.5.4)
TSH (see Section 6.5.4)
Serum pregnancy test (see Section 6.5.8)
X
Physical examination (see Section 6.5.1)
S
Randomisation
Efficacy
HbA1c (see Section 6.4.1)
X
X
X
X
X
X
X
X
X
X
X
X
FPG (see Section 6.4.2)
X
X
X
X
X
X
X
X
X
X
X
X
Fasting insulin (see Section 6.4.2)
X
X
X
Safety
Vital signs including height (see Section 6.5.2)
Vital signs (see Section 6.5.2)
X
X
X
X
X
X
X
X
X
X
X
X
ECG (see Section 6.5.7)
X
X
X
Hematology (see Section 6.5.4)
X
X
X
Chemistry (see Section 6.5.4)
X
X
X


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Visit
12
13
14
15
16
17
18
19
20
21
22
23 
SDD 
and/or 
PSD
Week
117
130
143
156
169
182
195
208
221
234
247
260
LFT testing only (see Section 6.5.4)
X
X
X
Fasting lipid profile & TGs (see Section 6.5.4)
X
X
X
Urinalysis (incl. albumin/creatinin ratio, see Section 6.5.4)
X
X
X
Urine pregnancy test (see Section 6.5.8)
X
X
X
AEs (see Section 7.1)
X
X
X
X
X
X
X
X
X
X
X
X
SAEs (see Section 7.2)
X
X
X
X
X
X
X
X
X
X
X
X
Medication Records
History of anti-diabetic medication therapy
Dose administration record – vildagliptin
X
X
X
X
X
X
X
X
X
X
X
X
Dose administration record – metformin
X
X
X
X
X
X
X
X
X
X
X
X
Dose administration record – insulin
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Drug dispensing
S
S
S
S
S
S
S
S
S
S
S
Drug accountability/medication check
S
S
S
S
S
S
S
S
S
S
S
S
Administrative procedures
Call IRT system
S
S
S
S
S
S
S
S
S
S
S
S
Dispense glucometer and instructions
Glycaemia study diary review
S
S
S
S
S
S
S
S
S
S
S
S
Study completion (see Section 5.5.11)
X
Sub-studies
Meal-test (see Section 6.4.3)
X
X
X
SDD = Study Drug Discontinuation; PSD = Premature Subject Discontinuation; S = Source documents only; X = Assessment to be recorded in the eCRF.


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6.1
Information to be collected on screening failures
Patients who were screened for participation in the study, but never took study drug nor were 
randomised into the study (Visit 3) are considered screening failures.
The following information must be recorded on the respective eCRFs for all screening failures: 
demography (Demography eCRF) and primary reason for why the patient was not randomised 
(Screened Subject Entering Next Phase eCRF).
Hypoglycemic events occurring between Visit 1 and Visit 3 will only be captured for those 
patients who are randomised at Visit 3. AE reporting will start at the time of informed consent.
The site must access the IRT system to record screening failures.
6.2
Patient demographics/other BL characteristics
Demography information such as date of birth, sex, race & ethnicity will be collected at visits 
indicated in Table 6-1. BMI will be calculated from the height measured at BL and 
 
measured at visits indicated in Table 6-1 & Table 6-2. The detailed medical history 
will be collected including previous liver and/or bile duct disease (e.g. viral liver infections, 
fatty liver, steatohepatitis, chronic hepatitis, cirrhosis, gallstones, hepatobiliary surgery, 
primary biliary cirrhosis, primary sclerosing cholangitis, portal hypertension, etc.).
Smoking history and history of diabetes and complications (date of diabetes diagnosis, 
whether proliferative retinopathy, non-proliferative retinopathy, nephropathy or neuropathy, 
prior/concomitant CV conditions (e.g. angina, MI, CHF, cardiac arrhythmia, coronary 
revascularisation, TIA, stroke, subarachnoid hemorrhage) are present and their respective 
dates of diagnosis) will be collected at visits indicated in Table 6-1.
Protocol required tests will be analysed by the central laboratory for samples taken at Visit 1 
to determine patient eligibility. The ECG will be performed locally.
At Visit 1 prior discontinued and continuing medications must be recorded (e.g. anti-diabetic 
medication, metformin history, insulin history, anti-hypertension and lipid-lowering 
medications) on the appropriate eCRFs.
6.3
Treatment exposure and compliance
Compliance with study drug administration will be assessed by the investigator and/or study 
personnel at each visit using pill counts and information provided by the patient. This 
information must be captured in the source documents. The site will also be required to 
complete the appropriate Dosage Administration Record eCRF(s) to record any study drug 
regimen changes or interruptions.
Study drug regimen
Patients must remain on the study drug regimen for the duration of the study. For treatment-
naïve patients at BL, no anti-diabetic medication other than the study drug regimen can be 
used, except according to Section 5.5.6. For patients who had started use of up to 2000mg 
daily metformin up to 1 month before Visit 1 (see Section 4.1 & Section 4.2), information 


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regarding the metformin use including the start date of the metformin use & the daily dose 
prior to entry into the study will be collected on the Anti-diabetic Medication Taken Prior To 
Entry Into The Study eCRF. The total daily dose of drug administered during the study will be 
collected on the appropriate Dosage Administration Record eCRF(s).
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/Significant Non-Drug Therapies eCRF.
Rescue medication
Information regarding the administration of rescue medication will be recorded on the 
appropriate eCRF as per Section 5.5.6.
6.4
Efficacy
The following efficacy measurements and assessments will be made at time-points indicated 
in Table 6-1 & Table 6-2.
Primary

HbA1c measurements at visits indicated in Table 6-1 & Table 6-2 to determine the time to 
confirmed initial treatment failure (see Section 9.4.1).
Secondary

HbA1c measurements at visits indicated in Table 6-1 & Table 6-2 to determine the rate of 
loss in glycemic control over time (estimated annualised slope of HbA1c over time using a 
random coefficient model), from Visit 5 to the end of Period 1 (see Section 9.5.2).

HbA1c measurements at visits indicated in Table 6-1 & Table 6-2 to determine the rate of 
loss in glycemic control from 26 weeks after the start of Period 2 to end of Period 2 (see 
Section 3.1.3).

FPG measurements at visits indicated in Table 6-1 & Table 6-2 to determine the rate of 
loss in glycemic control,  i) from Visit 5 to the end of Period 1; ii) from 26 weeks after 
start of Period 2 to end of Period 2 (see Section 3.1.3).

Descriptive summary of HbA1c measurements at visits indicated in Table 6-1 & Table 6-2.

C-peptide measurements collected during a meal-test performed at visits indicated in
Table 6-1 & Table 6-2 to determine:

The change in AUC of ISR/G as an assessment of β-cell function (see Section 6.4.3 & 
Section 3.1.5) from BL to: i) initial treatment failure; ii) end of Period 2 (see Section 
3.1.3); iii) EOS.

The rate of loss of β-cell function from Visit 4 (week 13) to: i) initial treatment failure; 
ii) end of Period 2 (see Section 3.1.3); iii) EOS.

Insulin measurements collected during a meal-test performed at visits indicated in Table 
6-1 & Table 6-2 to determine:


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
OGIS as an assessment of change in insulin sensitivity (see Section 3.1.5 & Section 
6.4.3) from BL to: i) initial treatment failure; ii) end of Period 2 (see Section 3.1.3); iii) 
EOS.

Rate of change in insulin sensitivity from Visit 4 (week 13) to: i) initial treatment 
failure; ii) end of Period 2 (see Section 3.1.3); iii) EOS.
6.4.1
HbA1c
HbA1c will be measured on a blood sample obtained at visits indicated in Table 6-1 & Table 
6-2 and analysed at a central laboratory.
6.4.2
FPG and indices of β-cell function and insulin resistance
Samples for FPG and fasting insulin will be collected at visits indicated in Table 6-1 & Table 
6-2.
6.4.3
Meal-test
A standard breakfast meal-test will be performed at visits indicated in Table 6-1 & Table 6-2
in a subgroup of patients (see Section 3.1.5 & Section 4). Blood samples will be collected at -
20min, 0min (start of the meal test), 15min, 30min, 60min, 90min & 120min. Plasma glucose, 
insulin and C-peptide will be determined in these samples. Indices of β-cell function and 
insulin sensitivity will be calculated as defined in Section 2.2.
The standard breakfast (500kcal; 60% carbohydrate, 30% fat and 10% protein (Pratley et al, 
2008)) may consist of the following:

180mL orange juice (grapefruit juice is not allowed).

2 slices (60g) bread; white, wheat or rye, plain or toasted.

2 tablespoons (30g) jam or preserves.

1 tablespoon (15g) butter (regular or salted) or margarine.

120mL whole milk (3-4% fat) or equivalent amount of cheese plus 120mL water.


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
Decaffeinated coffee or tea if desired.
Samples will be analysed by a central laboratory. Laboratory manuals will be provided to 
participating sites with detailed information on sample collection, handling, and shipment.
At BL, the study drugs will be administered to the patient after the meal-test. For the 
subsequent tests (see Table 6-1 and Table 6-2) the study drugs will be administered 15min
before the start of the meal.
6.4.4
Appropriateness of efficacy assessments 
The efficacy variables selected are standard for a clinical study evaluating the long-term effect 
of different treatments on the durability of glycemic control in patients with T2DM.
6.5
Safety

Physical examination.

Vital signs.

Monitoring of hematology, blood chemistry and urine tests.

LFT.

ECG.

Pregnancy (see Section 6.5.8 & Section 7.3).

Incidence of hypoglycemia events.

All treatment emergent AEs/SAEs (see Section 7).
 
 
 
 
The endpoints for the safety objective include treatment emergent AEs (including 
hypoglycemia events), SAEs, laboratory test results and vital signs.
Incidence of confirmed hypoglycemic events, of all symptomatic episodes and of severe 
hypoglycemia (defined as an event requiring assistance from another person and associated 
with either self-monitoring blood glucose ≤3.1mM (≤ 56mg/dL), see Table 6-5).
6.5.1
Physical examination
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions eCRF (see also Section 
6.2). Significant findings made after the start of study drug which meet the definition of an 
AE must be recorded on the AE eCRF.


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6.5.2
Vital signs
Vital signs include blood pressure and pulse measurements. After the patient has been sitting 
for five minutes, with back supported and both feet placed on the floor, systolic and diastolic 
blood pressure will be measured using an automated validated device, with an appropriately 
sized cuff. In case the cuff sizes available are not large enough for the patient's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
Clinically notable vital signs are defined in Appendix 1.
 
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. Laboratory evaluations are listed in Table 
6-3.
Hematology
Hematology as listed in Table 6-3 will be analysed at visits indicated in Table 6-1 & Table 6-
2.
Clinical chemistry (standard)
Clinical chemistry (standard) as listed in Table 6-3 will be analysed at visits indicated in 
Table 6-1 & Table 6-2.
Clinical chemistry (LFTs only)
Clinical chemistry (LFTs only) as listed in Table 6-3 will be analysed at visits indicated in 
Table 6-1 & Table 6-2.
Urinalysis
Urine will be analysed as listed in Table 6-3 at visits indicated in Table 6-1 & Table 6-2. The 
urine albumin/creatinine ratio will be assessed at visits indicated in Table 6-1 & Table 6-2. 
Urine will also be used to assess pregnancy (see Section 6.5.8).
Fasting lipid profile & TGs
Fasting lipid profile and TGs will be measured at visits indicated in Table 6-1 & Table 6-2. 
TGs, total cholesterol, HDL and LDL cholesterol will be measured. VLDL and non-HDL 
cholesterol will be calculated. LDL cholesterol will be calculated if TGs ≤400mg/dL 
(4.52mM). If TGs >400mg/dL (4.52mM), then direct LDL cholesterol measurement will be 
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Other measurements
TSH will be measured at visits indicated in Table 6-1.
Hepatitis screen (including hepatitis B test, surface antigen HBsAg, hepatitis C test, HCV
antibodies) will be measured at visits indicated in Table 6-1, and will be repeated in the event 
of an elevated LFT test result according to Table 6-4.
Table 6-3
Laboratory evaluations
Category
Parameter
Hematology with 
differential
RBC (total), WBC (total), platelet count (direct), hemoglobin, hematocrit, 
basophils (absolute, %), eosinophils (absolute, %), lymphocytes 
(absolute, %), monocytes (absolute, %), neutrophils (absolute, %)
Chemistry (standard)
ALT, albumin, alkaline phosphatase, AST, bilirubin (direct), bilirubin (total), 
blood urea nitrogen, calcium (total), chloride, high-sensitivity c-reactive 
protein (hsCRP), phosphocreatine kinase (CPK), CK-MB if CPK elevated, 
creatinine, γ-glutamyl transferase (γ-GT), GFR via MDRD formula, lactate 
dehydrogenase, potassium, protein (total), sodium, uric acid, c-peptide
Chemistry (LFT only)
ALT, AST, bilirubin (direct), bilirubin (total), alkaline phosphatase
Chemistry (fasting lipid 
profile & TGs)
TG, total cholesterol, HDL, LDL, VLDL (calculated), non-HDL cholesterol 
(calculated), LDL (calculated if TGs ≤400mg/dL (4.52mM) or directly 
measured if TGs >400mg/dL (4.52 mM))
Chemistry (hepatitis 
screen)
HBsAg, hepatitis C antibody, HCV antibodies
Chemistry (TSH)
TSH
Chemistry (serum 
pregnancy)
β-hCG
Urinalysis
blood, glucose, ketones, leukocytes, pH, protein, pregnancy (β-hCG), urine 
albumin/creatinine ratio
6.5.5
Abnormal LFTs
Elevations of AST and/or ALT ≥3 x ULN, with or without elevations of bilirubin, are 
considered clinically significant. Sources of liver injury/toxicity should be sought before 
ascribing the cause of the elevation to the study drug.
Table 6-4
Guidance for abnormal liver enzymes and related tests
Category
Definition
Action
Clinical 
symptoms
Icterus.
Any SAE indicative of hepatitis, 
liver failure or its complications.
Immediately discontinue patient.
Ensure appropriate specialist assessment & care.
Report as an SAE within 24h to Novartis.
Establish diagnosis/causality.
ALT or AST
≥ 3x ULN + total bilirubin > 2x 
ULN.
Immediately discontinue study drug and retest, if 
confirmed then discontinue the patient.
Ensure appropriate specialist assessment & care.
Report as an SAE within 24h to Novartis.
Establish diagnosis/causality.
Asymptomatic, isolated 
Ensure appropriate assessment and care.


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Category
Definition
Action
elevation ≥ 3 to < 5x ULN.
Repeat LFT on weekly basis. If LFT elevation ≥3 
to <5 x ULN persists >4 weeks, discontinue the 
patient, and report as an AE on the eCRF.
Asymptomatic, isolated 
elevation ≥ 5 to < 8x ULN.
Ensure appropriate specialist assessment & care.
If LFT elevation persists (repeat at 3 days), 
discontinue the patient.
Report as an AE on the eCRF.
Establish diagnosis/causality.
Asymptomatic, isolated 
elevation ≥ 8x ULN.
Immediately discontinue study drug and retest. If 
confirmed, then discontinue the patient.
Ensure appropriate specialist assessment & care.
Report as an SAE within 24h to Novartis.
Establish diagnosis/causality.
Total 
bilirubin
Asymptomatic, isolated 
elevation ≥ 3 x ULN.
Ensure appropriate specialist assessment and 
care.
Report as an AE on the eCRF.
If elevation persists >2 weeks, discontinue the 
patient.
Establish diagnosis/causality.
Whenever possible, every attempt should be made to identify and treat the underlying cause(s). 
Additional medical history should be sought for recent events:

Alcoholic history: specific query, quantified by drink per day/week/month, recent 
celebration or binges.

Over the counter medication, herbal agents or alternative medical therapies, illicit drug use, 
e.g. cocaine, methamphetamine, etc.

New symptoms that suggest viral infection or autoimmune events.

Other active medical conditions, with special mention of heart failure, palpitation, syncope 
or episode of hypotension, sepsis or parenteral nutrition.

Symptoms at the time of onset, specifically mentioning rash, fever, abdominal pain, 
fatigue and itching. Search for alternative medical causes such as cholelithiasis and 
ascending cholangitis, history of intercurrent illness (e.g. viral syndrome), hepatitis, or 
potential exposure to viral hepatitis (e.g. transfusion).

Potential exposure to environmental or chemical hepatotoxins (e.g., carbon tetrachloride, 
benzene) should also be assessed.

Drug-related causes of hepatitis should be considered (e.g. acetaminophen, amiodarone, 
aspirin, chlorpromazine, dantrolene, erythromycin, halothane, isoniazid, methyldopa,
nitrofurantoin, oxyphenisatin, perhexiline maleate, phenytoin, propylthiouracil, rifampin,
sulfonamides, tetracyclines).
At any time during the study if any of the criteria in Table 6-4 are met, repeat the test, then 
complete the specified action. Refer to Appendix 2, Panel A, and perform laboratory tests and 


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abdominal ultrasound as recommended. Additional investigations after the assessment by 
specialist might include tests described in Appendix 2, Panel B.
In all cases, maintain progress reports of the event until resolution or stabilisation occurs. Any 
laboratory findings must be documented in the AE eCRF.
6.5.6
Hypoglycemic events
At Visit 1, patient education regarding hypoglycemic symptoms and treatment should occur. 
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., adrenergic symptoms such as 
tachycardia, palpitations, shakiness, cholinergic symptoms such as sweating, central 
symptoms such as dizziness, hunger, blurred vision, impairment of motor function, 
confusion or inappropriate behavior).

Review of appropriate treatment for events (oral glucose intake).
At Visit 2 (or Visit 3 for patients who proceed directly to Visit 3 after Visit 1 according to 
Section 3.1.1), the home glucose monitor and glycaemia study diary should be given to the 
patient and the hypoglycemic information discussed at Visit 1 should be reviewed:

The use of a home glucose monitor must be explained. A home glucose monitor will be 
provided with all appropriate supplies. Blood glucose should be measured each time the 
patient experiences symptoms which may be suggestive of hypoglycemia, as well as other 
time points which may be recommended by the investigator.

Review of the glycemia study diary. Any time the patient experiences symptoms which 
he/she suspects are related to hypoglycemia, the patient should be instructed to take a 
blood glucose measurement and treat the event as appropriate. Patients should record the 
event in the study diary, including: 

The glucose value.

Any relevant associated information.

Time of occurrence in relation to the last medication and to the last meal intake.

The treatment used.

The response to the treatment used.

Additionally, if a patient performs routine measurements of blood glucose, any 
asymptomatic plasma glucose < 56mg/dL (< 3.1mM) - corresponding to a whole 
blood glucose level < 50mg/dL or < 2.8mM - should be treated and recorded in the 
glycemia study diary.

The patient should return the study diary at the next scheduled visit.
Data entry
The glycemia study diary will be reviewed by the study staff at each visit and assessed 
according to Table 6-5.


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Table 6-5
Recording and classification of glycemia study diary data
Severity
Symptoms
Plasma glucose
Action taken
Classification
Patient able to 
initiate self-
treatment if 
necessary
Symptoms 
suggestive of 
hypoglycemia
< 3.1mM
(56mg/dL)
Enter in Glycemia 
Study Diary eCRF
Hypoglycemic event, 
grade 1
Symptoms 
suggestive of 
hypoglycemia 
≥ 3.1mM
(56mg/dL)
Enter in Glycemia 
Study Diary eCRF
AE
Symptoms 
suggestive of 
hypoglycemia
Not taken
Enter in Glycemia 
Study Diary eCRF
AE
Asymptomatic
< 3.1mM
(56mg/dL)
Enter in Glycemia 
Study Diary eCRF
Asymptomatic low 
blood glucose
Patient is unable 
to initiate self-
treatment and 
requires 
assistance of 
another person or 
hospitalisation
Symptoms 
suggestive of 
hypoglycemia 
< 3.1mM
(56mg/dL)
Enter in Glycemia 
Study Diary eCRF 
& report as SAE
Hypoglycemic event, 
grade 2 & SAE
Symptoms 
suggestive of 
hypoglycemia 
Not taken
Enter in Glycemia 
Study Diary eCRF 
& report as SAE
Suspected 
hypoglycemic event, 
grade 2 & SAE
6.5.7
ECG
Standard 12-lead ECGs will be performed at visits indicated in Table 6-1 & Table 6-2. They 
will be analysed locally and interpretation of the tracing must be made by a qualified 
physician and documented on the 12-lead ECG Evaluation eCRF. Each ECG tracing should 
be labeled with the study number, patient initials, patient number, date, and kept in the source 
documents at the study site. Only clinically significant abnormalities should be reported on 
the 12-Lead ECG Evaluation eCRF. Clinically significant abnormalities should also be 
recorded on the Relevant Medical History/Current Medical Conditions eCRF.
6.5.8
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have urine pregnancy tests (see 
Section 6.5.4). A positive urine pregnancy test requires immediate interruption of study drug 
until serum β-hCG is performed and found to be negative. If positive, the patient must be 
discontinued from the study (see Section 5.5.9).
Pregnancy will also be tested on a serum sample at visits indicated in Table 6-1 & Table 6-2.
6.5.9
Appropriateness of safety measurements
The safety measurements are standard for this type of study.


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6.6
Other assessments
6.6.2
Resource utilisation
Not applicable.
6.6.4
Pharmacokinetics (PK)
Not applicable.
6.6.5
Pharmacogenetics/pharmacogenomics
Not applicable.


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7
Safety monitoring
7.1
AEs
An AE is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after informed consent even if the event is not considered to be related to 
study drug. Study drug includes the investigational drug under evaluation and the comparator 
drug or placebo that is given during any phase of the study. Medical conditions/diseases 
present before starting study drug are only considered AEs if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute AEs only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy.
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test, or other assessments. 
All AEs must be recorded on the AE CRF with the following information:
1. The severity grade [mild, moderate, severe].
2. Relationship to the study drug(s) (suspected/not suspected).
3. Duration (start and end dates or if continuing at final visit).
4. Whether it constitutes an SAE.
An SAE is defined as an event which:


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
Is fatal or life-threatening.

Results in persistent or significant disability/incapacity.

Constitutes a congenital anomaly/birth defect.

Requires inpatient hospitalisation or prolongation of existing hospitalisation, unless 
hospitalisation is for:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition.

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug.

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission.

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition.

Is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements, see Section 7.2.
All AEs should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e. further observation only), study drug dosage adjusted/temporarily 
interrupted, study drug permanently discontinued due to this AE, concomitant medication 
given, non-drug therapy given, patient hospitalised/patient’s hospitalisation prolonged. The 
action taken to treat the AE should be recorded on the AE eCRF.
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the 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 IB or will be communicated between IB updates in the form of investigator 
notifications (INs). This information will be included in the patient informed consent and 
should be discussed with the patient during the study as needed.
7.2
SAE reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
must be reported to Novartis within 24h of learning of its occurrence.
Any SAEs experienced after this 30-day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 


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submitted within 24h of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
Information about all SAEs is collected and recorded on the SAE report form. The 
investigator must assess the relationship of any SAE to study drug, complete the SAE report 
form in English, and send the completed, signed form by fax within 24h to the local Novartis 
drug safety & epidemiology (DS&E) department. The telephone and telefax number of the 
contact persons in the local DS&E department, specific to the site, are listed in the 
investigator folder provided to each site. The original copy of the SAE report form and the fax 
confirmation sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same person to whom the original SAE report form was 
sent, using a new SAE report form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the treatment
was unmasked or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the IB or package insert (new occurrence) and is 
thought to be related to the Novartis study drug, a DS&E department associate may urgently 
require further information from the investigator for health authority reporting. Novartis may 
need to issue an IN to inform all investigators involved in any study with the same drug 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 European community directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
7.3
Pregnancies
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24h of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Pregnancy should be recorded on a “clinical study pregnancy form” and reported by the 
investigator to the local Novartis DS&E department. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the 
Novartis study drug of any pregnancy outcome. Any SAE experienced during pregnancy must 
be reported on the SAE report form.
7.4
Data monitoring committee
An independent data monitoring committee (DMC) is overseeing this study. This committee, 
comprised of external experts in diabetes, cardiology and statistics, reviews the safety 
experience for this study at regular intervals.


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7.5
Adjudication committees
Program wide selected clinical events will be reviewed by independent adjudication 
committees. This measure is designed to ensure the objectivity, reliability and validity of the 
event classification. Details of the committee and procedures for reporting and case 
definitions are detailed in a separate document (adjudication charter).
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 eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
good clinical practice (GCP), the progress of enrollment, and to ensure that study drug is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits.
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 original informed consent form 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 eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific monitoring plan. The identity of the subjects will 
remain confidential.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRFs using 
fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
data queries, allow the data to be confirmed or corrected before transfer of the data to the 
contract research organisation (CRO) working on behalf of Novartis. The investigator must 
certify that the data entered into the eCRFs are complete and accurate. After database lock, 
the investigator will receive the patient data in an appropriate form for archiving at the 
investigational site.


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8.3
Database management and quality control
Novartis or CRO staff 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. Obvious errors are corrected by Novartis personnel (or a 
CRO working on behalf of Novartis). Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper data query form 
will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back 
to Novartis staff (or CRO staff working on behalf of Novartis) who will make the correction 
to the database. The signed copy of the data query form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the World Health 
Organisation Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system (ATC). Medical history/current medical conditions and AEs will be 
coded using the medical dictionary for regulatory activities terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomisation codes and data about all study drug dispensed to the patient and all IRT 
recorded dosage changes will be tracked using an IRT system. The system will be supplied by 
a vendor, who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO).
Each occurrence of an unmasking via IRT will be reported to the clinical team and the 
monitor. The unmasking functionality will remain available until completion or upon request 
of Novartis.
9
Data analysis
9.1
Analysis sets
The following analysis data sets will be defined for this study.
Screened-only (SCR) set: consists of all patients who were screen failed after the first visit or 
who entered the run-in phase but were not randomised. Except for the tabulation and listing of 
individual patients in this SCR set with the reasons for not being randomised, no other 
analysis will be performed in this analysis set.
Randomised (RAN) set: consists of all randomised patients.
Full-analysis set (FAS): consists of all randomised patients who received at least one dose of 
study medication and had at least one post-randomization assessment of any efficacy 
parameter. Following the intent-to-treat principle, subjects will be analysed according to the 
treatment they were assigned to at randomization.
Safety (SAF) set: consists of all patients who received at least one dose of study medication.
Patients will be analysed according to the treatment received.


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The Per-protocol set (PPS) is a subset of the FAS. It consists of all randomised patients in the 
FAS patients who take at least one dose of study medication and have no major protocol 
deviations affecting the primary endpoint analyses.
The major protocol deviations leading to exclusion from the PPS will be specified prior to 
unbinding the database with respect to treatment.
9.2
Patient demographics and other BL characteristics
Demographic, background data and key efficacy variables at BL will be summarised for all 
randomised patients (RAN set) by treatment group that patients were assigned to at 
randomization using frequency and percentage for qualitative variables (gender, race, 
ethnicity, age group, smoker status, BMI group, and BL HbA1c group, groupings as for the 
subgroups described in Section 9.4.4), and mean, standard deviation, median, minimum and 
maximum for quantitative variables (age, height, weight, BMI, duration of T2DM, BL HbA1c
and FPG).
BMI will be calculated from the collected variables height (in m) and weight (in kg) at Visit 1.
BL HbA1c and FPG are the values obtained at randomization (Visit 3) or at an earlier visit 
(scheduled or unscheduled) which was closest to Day 1 (visit 3) if Day 1 values are missing.
BL comparability among the treatment groups will be examined using a χ2 test for the 
qualitative variables, and using a two-sample t-test for the quantitative variables (these p-
values are provided for descriptive purposes, and are not to be considered to define any formal 
basis for determining factors which should be included in statistical analysis model).
In addition, all relevant medical history and history of diabetes and complications will be 
summarised by primary system organ class (SOC), preferred term and treatment using 
frequency tables.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
The duration on the study medication (in weeks) during the overall randomised treatment
period will be computed for all patients using the following algorithm:
(last study drug date – Visit 3 date )/7 or
(last study visit date – Visit 3 date + 1)/7 if the last study drug date is missing or 
incomplete.
Duration will be set to 0 for patients who did not take any study drug.
The above defined duration will be summarised according to the treatment patients are 
assigned to at randomization for the RAN set both descriptively (i.e., mean, standard 
deviation, median, minimum and maximum) and by duration category (≥0 and <13 weeks, 
≥13 and <26 weeks..., in 13-week intervals cumulatively up to ≥260 weeks).
The study Period 1 duration (in weeks) will be also similarly summarised in the RAN set. The 
study Period 1 duration is defined as (initiation date of new study vildagliptin packs due to 
treatment failure – visit 3 date)/7 for patients who entered study Period 2. The study Period 1 
duration is the same as overall study duration for patients who did not enter into Period 2.


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The study period from randomization to the end of Period 2 will be computed for all patients 
who initiate insulin in Period 3 and for patients discontinuing the study in Period 2 due to
being unable or unwillingness to initiate insulin for treatment intensification in Period 3.
Prior and concomitant therapies taken during the randomised double-blind period will be 
summarised by ATC class and preferred term according to the treatment patients are assigned 
to at randomization in the RAN set.
9.4
Analysis of the primary variable(s)
9.4.1
Variable
The primary efficacy variable is time to confirmed initial treatment failure. The confirmed 
initial treatment failure is defined as a patient with HbA1c measurements ≥7.0% at two 
consecutive scheduled visits as defined in Table 6-1 & Table 6-2, starting from Visit 4 (Week 
13). The time to confirmed initial treatment failure is defined as the time from randomization
until the time when the second of the two HbA1c measurement ≥7.0% was determined after at 
least 13 weeks of treatment (Visit 4). The rationale of starting the treatment failures count 
from Visit 4 is that treatment guidelines consider as treatment failure patients who do not 
achieve HbA1c <7.0% after 3 months of treatment (ADA-EASD, 2009).
9.4.2
Statistical model, hypothesis, and method of analysis
Time to initial treatment failure
The primary statistical hypothesis of time to confirmed initial treatment failure will be 
assessed by a 1-sided test of superiority of the combination treatment with vildagliptin + 
metformin versus metformin monotherapy with α-level of 0.025 of the hazard-ratio between 
the combination treatment vildagliptin + metformin and metformin monotherapy being equal 
or greater than 1 as the null hypothesis, versus the 1-sided alternative hypothesis that the 
hazard-ratio is less than 1:
H01: λvildagliptin+metformin/λmetformin ≥ 1
versus
Ha1: λvildagliptin+metformin/λmetformin < 1
where λvildagliptin+metformin and λmetformin are the hazard-rates of the confirmed initial treatment 
failure for vildagliptin 50mg bid + metformin up to 1000mg bid and metformin up to 1000mg 
bid monotherapy respectively.
The time to confirmed failure will be derived as the time from randomization to the second of 
two consecutive visits at which HbA1c ≥7.0% is measured, starting from Visit 4 (13 weeks 
after randomization).
The primary efficacy analysis will use a Cox proportional hazard regression model to assess 
the probability of confirmed initial treatment failure, with treatment as classification variable 
and BL HbA1c as a covariate. The hazard-ratio and associated 95% confidence interval as 
well as the p-value estimated from the above model will be presented by treatment.


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The confirmed initial treatment failure rate over time by treatment will be summarised and 
plotted with associated 95% confidence intervals, using estimates from a Kaplan-Meier 
analysis.
The primary analysis for this primary efficacy variable will be performed using the FAS. It 
will be performed in the PP set as supportive analysis as well.
9.4.3
Handling of missing values/censoring/discontinuations
In the analysis for the primary efficacy variable of time to confirmed initial treatment failure, 
patients who discontinue the study for any reason during Period 1 (lack of efficacy, lost to 
follow-up, AE or abnormal laboratory values etc.) will be treated as censored values at the 
time of discontinuation. Patients who remain under the threshold (or whose measurement 
above the threshold is not confirmed at next scheduled visit) will be censored at the time of 
last study visit.
9.4.4
Supportive analyses
Time to first treatment failure
The time to first treatment failure will be derived as the time from randomization to the first 
of two consecutive scheduled visits (after remapping in section 1.3.3 has been applied), at 
which HbA1c ≥7.0% is measured, starting from Visit 4 (13 weeks after randomization). 
Time to first treatment failure will be analyzed in the similar way as primary analysis.
Descriptive analysis in HbA1c over time
Summaries of absolute values and change from BL to end of Period 1 in HbA1c by treatment 
group and visit will be presented in the FAS. Figures will be produced showing the mean 
HbA1c by visit during the study Period 1 for each treatment group.
In addition, the above descriptive analysis (including summary table and figure) will be 
performed on HbA1c data collected up to the end of Period 2, as well as data collected during 
the entire duration of the study.
Descriptive subgroup analysis
Summaries of absolute values and changes from BL to end of Period 1 in HbA1c will be 
presented for the following subgroups in the FAS:
1. BL HbA1c category (<7% vs. ≥7%).
2. BMI (<30kg/m2, ≥30kg/m2 at Visit 1).
3. Age at Visit 1 by tertiles.
4. Gender.
5. Race.
6. Smoking status.
7. Geographical regions.


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9. Other baseline demographic subgroups may be added as appropriate.
9.5
Analysis of secondary variables
9.5.1
Key secondary variables
Not applicable.
9.5.2
Other efficacy secondary 
variables
9.5.2.1
Secondary 
 efficacy variables
The following secondary 
 efficacy variables will be analysed. They were 
grouped by type of analyses for the convenience of describing the related analysis methods.
Variables related to the rate of change of β-cell function and insulin sensitivity

Rate of loss of β-cell function (assessed using the AUC of ISR/G) from Visit 4 (week 13)
to: i) initial treatment failure; ii) end of Period 2 (see Section 3.1.3); iii) EOS.

Rate of change in insulin sensitivity (assessed using the OGIS) from Visit 4 (week 13) to: 
i) initial treatment failure; ii) end of Period 2 (see Section 3.1.3); iii) EOS.
Variables related to the rate of loss in glycemic control over time

Rate of loss in glycemic control in HbA1c from 26 weeks after the start of Period 2 to end 
of Period 2 (see Section 3.1.3).

Rate of loss in glycemic control in FPG, i) from Visit 5 to the end of Period 1; ii) from 26 
weeks after start of Period 2 to end of Period 2 (see Section 3.1.3).
Variables related to change from BL to endpoint

Change in AUC of ISR/G (as an assessment of β-cell function) from BL to: i) initial 
treatment failure; ii) end of Period 2 (see Section 3.1.3); iii) EOS.

Change in OGIS (as an assessment of insulin sensitivity) from BL to: i) initial treatment 
failure; ii) end of Period 2 (see Section 3.1.3); iii) EOS.


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9.5.2.2
Statistical analysis methods
Rate of loss in glycemic control over time
The rate of loss in glycemic control over time will be estimated by the slope of HbA1c over 
time (in years) as a random coefficient in a linear mixed effect model: the model will be fitted 
to HbA1c data collected from Week 26 and onwards, up to and including the end of the 
Period 1 visit, i.e. up to and including the initial treatment failure date. It includes treatment 
approach, geographic region, baseline HbA1c, time (of HbA1c measurements, in years) and 
the interaction of treatment approach by time as the fixed effects, and time and intercept as a 
random effects. Treatment approach and geographic region will be considered as 
classification variables while baseline HbA1c and time are the covariates. The unstructured 
covariance will be used as the covariance structure within patients. The actual hypothesis will 
be tested using the treatment approach by time interaction term. Note that it is not an issue 
that patients who ‘fail’ at Week 26 will only contribute one data point to the analysis, as this 
is expected in only a few patients.
The mean slopes within each treatment approach and the difference in mean slopes between 
two treatment approaches as well as the p-value obtained from the test using the above model 
will be presented. Graphical representation will also be produced as required.
The analysis will be performed using the FAS. It will be performed in the PPS as supportive 
analysis as well.
The assumptions for inference using the model as described above (i.e., errors are 
independently normally distributed with constant variance) will be checked using CSR 
Section 16 table(s) by subjective examination of the presented residual plots: normal 
probability plot and residuals versus fitted values plots.


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Variables related to the rate of loss in glycemic control over time
The rate of loss in glycemic control in FPG from 26 weeks to the end of Period 1 will be 
assessed using the same random coefficient linear mixed effect model as used in the analysis 
of ‘rate of loss in glycemic control in HbA1c from Visit 5 (Week 26) to the end of Period 1’. 
This analysis is performed in the FAS only.
The rate of loss in glycemic control in HbA1c or FPG from 26 weeks after the start of Period 
2 to the end of Period 2 (see Section 3.1.3) will be assessed for patients who start insulin 
therapy in Period 3 (i.e. for treatment intensification) or discontinue the study during Period 2 
due to not being able or unwillingness to initiate insulin therapy in Period 3. The random 
coefficient linear mixed effect model used in the analysis of ‘rate of loss in glycemic control 
in HbA1c from Visit 5 (Week 26) to the end of Period 1’ will be used in this secondary 
variable. Only data collected between initiation of Period 2 to insulin initiation on patients 
who take insulin therapy in Period 3 (i.e. for treatment intensification) or who discontinued 
the study in Period 2 due to not being able or unwillingness to initiate insulin therapy in 
Period 3 will be included in this model. The analysis will be performed in the FAS only.
Variables related to the rate of change of β-cell function and insulin sensitivity
over time
The rate of change of β-cell function and insulin sensitivity (assessed using the AUC of ISR/G 
and OGIS respectively) from Visit 4 (week 13) to the end of Period 1, or from Visit 4 (week 
13) to the end of Period 2, or from Visit 4 (week 13) to the end of study will be assessed using 
a similar random coefficient linear mixed effect model used in the analysis of ‘rate of loss in 
glycemic control in HbA1c from Visit 5 (Week 26) to the end of Period 1’. This analysis is 
performed in the FAS only. Data collected up to the end of Period 1, or the end of Period 2, or 
to the end of the study will be used in the analysis for assessing the rate of change from 
baseline to end of Period 1, or from baseline to end of Period 2, or from baseline to the end of 
the study respectively.
Note that the above analyses will be performed only when sufficient patient’s data warrant 
such analyses.
Variables related to change from BL to endpoint
An analysis of covariance (ANCOVA) model with treatment, geographic region as 
classification variables and BL value as a covariate will be used to assess all secondary 
efficacy variables related to change from BL to endpoint. The least squares mean (“adjusted 
mean”) change from BL for each treatment group, the difference in the least squares mean 
changes between the two treatment groups, and the two-sided adjusted 95% confidence 
interval along with the p-value for the difference will be obtained from this analysis model 
and presented.
The endpoint is defined differently for these secondary endpoints as follows.

For change in AUC of ISR/G, OGIS, 
 
 from BL to EOS, the endpoint is defined as the final available post-
randomization assessment obtained at any visit (scheduled or unscheduled) up to final 


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scheduled study visit (Visit 23, Week 260).
 
 

For change in AUC of ISR/G, OGIS, 
 from BL to 
end of Period 2 (see Section 3.1.3), the endpoint is defined as the final available post-
randomization assessment obtained at any visit (scheduled or unscheduled), prior to or at 
the initiation of insulin therapy, up to final scheduled study visit (Visit 23, Week 260).

For change in AUC of ISR/G, OGIS, 
 from BL to 
initial treatment failure, the endpoint is defined as the final available post-randomization
assessment obtained at any visit (scheduled or unscheduled), prior to or at the start of 
additional new vildagliptin medication package use due to initial treatment failure, up to 
final scheduled study visit (Visit 23, Week 260).
Note that for meal-test related parameters (AUC of ISR/G and OGIS), the above analyses will 
be performed only when sufficient patient’s data warrant such analyses.
Supportive descriptive analysis for secondary 
 variables over 
time
Summaries of absolute values and change from BL to end of Period 1 in secondary or 
exploratory variables (including FPG, 
, AUC of ISR/G, OGIS, 
 
) by treatment group and visit will be presented in 
the FAS.
9.5.2.3
Derivation of secondary 
 variables

OGIS = p4 [(p1D0 –V(G(120)-G(90))/30)/G(90) + p3/G(0)] / [I(90)-I(0)+p2], where D0
(g/m2) is the glucose dose included in the standard meal administered to patients who 
participate in the standard meal-test (D0 =73.2 g/m2 for the standard meal as planned in 
Section 6.4.3), V =10 (ml/m2) is the assumed glucose distribution volume, G(0), G(90) 
and G(120) are glucose concentration values at oGTT timepoints 0, 90 and 120 min, I(0) 
and I(90) are insulin concentration values at timepoints 0 and 90 min, p1 = 6.5, p2 = 1951, 
p3 =4514 and p4 =792 are constants (Mari, et al 2001).
AUC of ISR/G is defined as ISR relative to glucose 0-2h (pmol/min/m2/mM) = AUC0-2hr of 
ISR/AUC0-2hr of glucose.
Calculation of ISR
Separately for each patient and each meal challenge, deconvolution is applied to estimating 
insulin secretion to assess β-cell function. C-peptide, which is co-secreted with insulin in an 
equimolar ratio, is preferred to insulin as a basis for estimating insulin secretion. 
Mathematically, we need to solve for the insulin secretion rate r given the impulse response h, 
and plasma C-peptide c, where


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.
)
(
)
(
)
(




t
ds
s
r
s
t
h
t
c
The impulse response is the PK model for an intravenously administered unit bolus dose of C-
peptide when the endogenous C-peptide production has been suppressed, i.e.
]
)
1(
)[
/
1(
)
(
)
(
)
(
s
t
s
t
e
f
fe
V
s
t
h










,
where V, f, α, and β are a subject’s parameters, which are generally unknown. However, from 
clinical studies these parameters have been estimated, and are related to a subject’s disease 
status, body surface area, age, and gender. Thus, h becomes known.
Insulin secretion rates are modeled by a piecewise continuous linear function with knots at the 
actual sampling time. Changes in slopes are penalised through a single regularisation
parameter that is determined by a root finding method to produce similar residual standard 
deviation for fitted C-peptide concentrations as would be expected from assay error standard 
deviations given in the kit instructions.
The IMMULITE 2000 C-peptide kit instructions were used to model intra-assay SD as a 
function of the true C-peptide concentration C1 expressed in conventional units of ng/mL by 
simple linear regression as:
SD = 0.04056C1 + 0.06311ng/mL.
With concentration of C-peptide expressed alternatively in SI units, i.e., C2 expressed in nM
(1ng/mL C-peptide = 0.331nM C-peptide) the equations for SD becomes:
SD = 0.04056 C2 + 0.331 × 0.06311nM.
The following ln-transformation with a shift parameter of observed and fitted C-peptide 
values is used to stabilize the variance in performing the deconvolution:
ln(C1 + 0.06311/0.04056) or ln(C2 + 0.331 × 0.06311/0.04056).
Nonlinear least squares with ISR constrained non-negative using PROC IML function 
NLPLM  in SAS® is used to solve for ISR at the sampling time points using actual sampling 
times. The bisection method is used to iteratively determine the regularisation parameter such 
that the sum of squares of the observed C-peptide minus the fitted C-peptide expressed in 
either units equals 0.040562n where n is the number of non-missing C-peptide concentrations 
in the meal challenge.
Calculation of AUC
For the patients participating in the meal-test, glucose, insulin and C-peptide are also to be 
measured at the following 7 time-points (minutes in relation to the meal time): -20min, 0min
(immediately prior to meal ingestion), 15min, 30min, 60min, 90min, 120min. Let L1, L2, …., 
L7 denote the lab measurements at these 7 time-points (i.e., L1 is the value measured at 20min 
pre-meal, L2 is the value measured at 0min pre-meal, …, L7 is the value which should be 
measured about 2h after the meal) and T1, T2, .., T7 be the corresponding times (actual times in 
units of h), the AUC0-2hr is calculated (using the trapezoidal rule) as:
AUC0-2h =


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[(L2 + L3) × (T3 – T2) + (L3 + L4) × (T4 – T3) + (L4 + L5) × (T5 – T4) + (L5 + L6) × (T6 – T5) + 
(L6 + L7) × (T7 – T6)] / 2.
9.5.3
Safety variables
The safety and tolerability of vildagliptin 50mg bid as add-on to metformin over 5-years of 
treatment will be compared to placebo as add-on to metformin based on data collected during 
the randomised treatment period in SAF set.
The assessment of safety will be based mainly on the frequency of treatment emergent AEs
(including overall AEs), SAEs, death, AEs leading to study discontinuation or study drug 
interruption & pre-specified AE risks on the number of post BL laboratory values that fall 
outside of pre-determined ranges and on the frequency and severity of hypoglycemic events 
during the randomised treatment period. Summaries for safety assessment will be presented 
for the SAF set. Unless specified otherwise, comparison will be made to BL, which will be 
the measurement taken at Visit 3, or the sample obtained at an earlier visit (scheduled or 
unscheduled) which was closest to Day 1 if Day 1 measurement is missing.
AEs will be summarised by presenting, for each treatment group (vildagliptin 50mg bid + 
metformin, placebo + metformin), the number and percentage of patients having any AE, 
having an AE in each primary SOC and having each individual AE. Any other information 
collected (e.g. severity or relatedness to study medication) will be presented as appropriate.
Laboratory data will be summarised by presenting summary statistics of raw data and change 
from BL values (means, medians, standard deviations, ranges) and by presenting the number 
and percentage of patients having notable lab values or having endpoint change from BL
meeting pre-specified percent change criteria. The identification of notable values will be 
based on the pre-specified criteria provided in the investigator binder (will also be included in 
the analysis plan). The predefined categories of liver enzyme (ALT/AST) and CPK elevations 
and persistent elevations will be summarised by treatment.
Hypoglycemia events will be included in all AE summaries. In addition, events will be 
characterised by event profile, such as ability to self-treat, self monitoring of plasma glucose 
level, precipitating event, time from last meal, time from last dose, and time of the day.
Data from other tests (e.g. vital signs including 
, ECGs) will be summarised as 
appropriate, incidences of notable values will be presented in the tables and notable values 
will be flagged in the listings.
All above safety analyses will be performed in the SAF on all available data collected during 
the entire study. In addition, key safety analyses will be performed on data obtained during
Period 1 only.


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9.5.4
Resource utilisation
Not applicable.
9.5.6
PK
Not applicable.
9.5.7
Pharmacogenetics/pharmacogenomics
Not applicable.
9.5.9
PK/pharmacodynamics
Not applicable.
9.6
Sample size calculation
A total sample size of 1000 randomised patients per treatment arm (in 1:1 allocation ratio to 
vildagliptin + metformin and metformin monotherapy) is planned.
Power calculation for the time-to-treatment failure variable
The sample size calculation assumes that all randomised patients are to be followed up for 5 
years unless patients dropped out from the study for various reasons (lack of efficacy, AEs, 


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abnormal labs, lost to follow-up etc.), and that the yearly dropout rate is 11% (estimate based 
on ADOPT data (Kahn S et al, 2006).
The existing vildagliptin study data suggest that approximately 10% of vildagliptin patients 
will have an HbA1c >7.0% after the first 3 months of the study (initial response phase), since 
those patients who are randomised with an HbA1c measurement above the failure threshold 
(7.0%) may never have an HbA1c measurement below the required threshold during the study 
and will therefore be counted as failures during the first 13 weeks. A similar proportion is 
assumed for the comparator arm. Hence it is expected that the difference in failure rate is 
likely to be small early in the study, but will diverge as the study progresses. The power 
calculations have been adjusted to take this assumption into account using statistical 
simulations.
The simulations showed that assuming an annual initial treatment failure rate of 7.1% in the 
metformin monotherapy arm (estimated based on ADOPT data), incorporating a 10% initial 
failure rate after 13 weeks in each treatment arm (due to some patients with BL HbA1c 
≥7.0%), 1000 patients per treatment arm would be sufficient to detect a hazard-ratio of 0.75 
between vildagliptin + metformin and metformin alone (corresponding to a risk reduction rate 
of 25% in vildagliptin + metformin group versus metformin alone) with approximate 66% 
power and a 1-sided significance level of 0.025 (corresponding to a 2-sided test at 0.05).
9.7
Power for analysis of key secondary variables
Not applicable.
9.8
Interim analyses
An external and independent DMC to monitor patient safety data on a regular basis during the 
course of the study will be established. The DMC may request additional safety data review. 
Such safety analyses do not inflate the type I error for the primary efficacy hypothesis testing 
and thus require no multiplicity adjustments. 
There is no efficacy interim analysis planed for the study.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guidelines for GCP, with 
applicable local regulations (including European directive 2001/20/EC, US CFR Title 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 study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 


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so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form 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.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB/IEC/REB before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC must be given to Novartis 
before study initiation. 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 clinical quality 
assurance representatives, designated agents of Novartis, IRBs/IECs/REBs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform Novartis immediately of this request.
10.4
Publication of study protocol and results
Novartis assures that 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 
finalisation of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorised deviations are permitted. If 
the 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 it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the clinical study report.


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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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. 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, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days.
12
References
AACE/ACE Consensus Statement (2009) An algorithm for glycemic control. Endocrine 
Practice; 15:540-559.
ADA-EASD Consensus Statement (2009) Medical management of hyperglycaemia in type 2 
diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. 
Diabetologia; 52:17-30.
ADVANCE Management Committee (2001) Study rationale and design of ADVANCE. 
Diabetologia; 44: 1118-1120.
Ahren B, Gomis R, Standl E, et al (2004) Twelve- and 52-week efficacy of the dipeptidyl 
peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes 
Care; 27:2874-80.
Ahren B, Foley J, Bosi E (2011) Clinical evidence and mechanistic basis for vildagliptin’s 
action when added to metformin. Diabetes Obes Metab; 13:193–203.
Bosi E, Dotta F, Jia Y, et al. (2009) Vildagliptin plus metformin combination therapy provides 
superior glycaemic control to individual monotherapy in treatment-naïve patients with type 2 
diabetes mellitus. Diabetes Obes Metab; 11:506–15.
Bulotta A, Hui H, Anastasi E, et al (2002) Cultured pancreatic ductal cells undergo cell cycle 
re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. J. Mol. 
Endocrinol. 29:347–360.
D’Alessio DA, Denny A, Hermiller L, et al (2009) Treatment with the DPP-4 inhibitor 
vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes. J Clin Endo 
Metab; 94:81-88.
Del Prato et al. (2005) Improving glucose management: ten steps to get more patients with 
type 2 diabetes to glycaemic goal. Intl J Clin Pract; 59: 1345-1355.
Drucker DJ (2003) Therapeutic potential of dipeptidyl peptidase IV inhibitors for the 
treatment of type 2 diabetes. Expert Opin. Investig. Drugs; 12:87-100.
Farilla L, Hui H, Bertolotto C, et al (2002) Glucagon-like peptide-1 promotes islet cell growth 
and inhibits apoptosis in Zucker diabetic rats. Endocrinology; 143:4397–4408.


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Fonseca V, Schweizer A, Albrecht D, et al. (2007) Addition of vildagliptin to insulin 
improves glycaemic control in type 2 diabetes. Diabetologia; 50:1148–55.
Garber A, Foley J, Banerji M, et al. (2008) Effects of vildagliptin on glucose control in 
patients with type 2 diabetes inadequately controlled with sulfonylurea. Diabetes Obes Metab; 
10:1047-1055.
Goke B, Hershon K, Kerr D, et al. (2008) Efficacy and safety of vildagliptin monotherapy 
during 2-year treatment of drug-naïve patients with type 2 diabetes: Comparison with 
metformin. Horm Metab Res; 40:892-95.
Hardikar AA, Wang XY, Williams LJ, et al (2002) Functional maturation of fetal porcine 
beta-cells by glucagon-like peptide 1 and cholecystokinin. Endocrinology; 143:3505–3514.
Holman R et al. UKPDS 80: 10-Year Follow-up of Intensive Glucose Control in Type 2 
Diabetes. NEJM; 359:1577-1589.
Holst JJ (2002) Therapy of type 2 diabetes mellitus based on the actions of glucagon-like 
peptide 1. Diabetes Metab Res Rev; 18:430-441.
IDF (2009). Diabetes Atlas; The Global Burden. http://www.diabetesatlas.org/content/global-
burden.
Kikuchi M, Nobuyuki A, Mitsutoshi K, et al. (2009) Vildagliptin dose-dependently improves 
glycemic control in Japanese patients with type 2 diabetes mellitus. Diabetes Res Clin Prac; 
83: 233-40.
Kahn S et al. for the ADOPT Study Group (2006) Glycemic Durability of Rosiglitazone, 
Metformin, or Glyburide Monotherapy. NEJM; 355:2427-2443.
Li Y, Hansotia T, Yusta B, et al (2003) Glucagon-like peptide-1 receptor signaling modulates 
beta cell apoptosis. J. Biol. Chem.; 278:471–478.
Ligueros-Saylan M, et al. (2010) An assessment of adverse effects of vildagliptin versus  
comparators on the liver, the pancreas, the immune system, the skin and in patients with 
impaired renal function from a large pooled database of Phase II and III clinical trials. 
Diabetes Obes Metab; 12:495-509.
Mari A, Ludvik B, Pacini G, et al (2001) A model-based method for assessing insulin 
sensitivity from the oral glucose tolerance test. Diabetes Care; 24: 539-548.
Mathieu C (2008) The scientific evidence: vildagliptin and the benefits of islet enhancement. 
Diabetes Obes Metab; 11 (Suppl. 2): 9–17.
Matthews DR et al. (2010) Vildagliptin add-on to metformin produces similar efficacy and 
reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 
2-year study. Diabetes Obes Metab; 12:780-789.
Pratley RE et al. (2008) Robust improvements in fasting and prandial measures of β-cell 
function with vildagliptin in drug-naïve patients: analysis of pooled vildagliptin monotherapy 
database. Diabetes Obes Metab; 10:931–938.


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Rosenstock J, Baron MA, Camisasca RP, et al (2007) Efficacy and tolerability of initial 
combination therapy with vildagliptin and pioglitazone compared with component 
monotherapy in patients with type 2 diabetes. Diabetes Obes Metab; 9:175–185.
Scherbaum W, et al. (2008) Evidence that vildagliptin attenuates deterioration of glycaemic 
control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. 
Diabetes Obes Metab; 10:1114–1124.
Schweizer et al (2011) Assessing the general safety and tolerability of vildagliptin: value of 
pooled analyses from a large safety database versus evaluation of individual studies. Journal 
of Vascular Health and Risk Management; 7 49–57.
Stoffers DA, Kieffer TJ, Hussain MA, et al (2000) Insulinotropic glucagon-like peptide 1 
agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse 
pancreas. Diabetes; 49:741–748.
UKPDS Group (1995) Overview of 6 years’ therapy of type II diabetes. A progressive disease. 
Diabetes; 44:1249-1258.
UKPDS Group (1998a) UK Prospective Diabetes Study 33: Intensive blood-glucose control 
with sulphonylureas or insulin compared with conventional treatment and risk of 
complications in patients with type 2 diabetes. Lancet; 352:837-53.
UKPDS Group (1998b) UK Prospective Diabetes Study 34: Effect of intensive blood-glucose 
control with metformin on complications in overweight patients with type 2 diabetes. Lancet; 
352:854-65.
Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, Mangold BL, 
Russell ME, Hughes TE (2003) 1-[[3-Hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-
pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with 
antihyperglycemic properties. J. Med. Chem.; 46:2774-89.
Wallace T, Matthews DR (2002) Coefficient of failure: a methodology for examining 
longitudinal β-cell function in Type 2 diabetes. Diabetic Medicine; 19: 465–469.
Wang X, Zhou J, Doyle ME, Egan JM (2001) Glucagon-like peptide-1 causes pancreatic 
duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic 
beta-cells by a cyclic adenosinemonophosphate/protein kinase A-dependent mechanism. 
Endocrinology; 142: 820–1827.
Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both beta-cell 
replication and neogenesis, resulting in increased beta-cell mass and improved glucose 
tolerance in diabetic rats. Diabetes; 48:2270–2276.
References will be made available on request.
13
Appendix 1: Clinically notable laboratory values and vital 
signs
Laboratory notable range deviations will be provided in the investigator binder.


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Table 13-1
Vital signs notable range deviations
Vital signs
Notable abnormalities
Pulse (beats/min)
either 120 + increase 25* or >130
either 50 + decrease 30* or < 40 
Blood pressure (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
Weight
a weight change of > 10% during the study
* Refers to post-BL value as compared to BL value.
14
Appendix 2: testing for patients with elevated LFTs
At the first recognition of a liver related AE an immediate blood draw for items listed on 
Panel A (see below) must be performed. After timely consultation with a gastroenterologist or 
hepatologist, Panel B below may need to be drawn.
If jaundice is present right upper quadrant ultrasound with Doppler within 24-72h should be 
performed.
Liver panel A must be performed within 24h of the abnormal LFTs
A urine sample must be collected for toxicology screen. Human immunodeficiency virus
status must be established.
A blood sample must be draw for:

HBsAg, hepatitis B core antibody (HbcAb), Hepatitis C RNA.

HAV total and immunoglobulin M (IgM).

Hepatitis E serology: IgM and immunoglobulin G.

Herpes simplex virus, cytomegalovirus & Epstein-Barr virus serology.
Liver panel B – may be required following consultation with a specialist
After a refreshed history, physical examination, and upon consultation with a 
gastroenterologist or hepatologist, tests might include:

Autoimmune disease: antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), 
anti–liver-kidney microsomal antibody (anti–LKM-1), antibodies against soluble liver 
antigen (anti-SLA), antibodies to liver-specific asialo-glycoprotein receptor, anti-
mitochondrial antibody (AMA).

Other infectious disease: malaria, tuberculosis, parasites, West Nile virus.

Wilson’s disease: serum ceruloplasmin.

Hemochromatosis genotype (C282Y, H63D mutations).

α-1 anti-trypsin level, and if low then phenotype.


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
Tests for hemolysis (LDH, peripheral smear, haptoglobin, reticulocyte count).

Liver biopsy.

SAP_000.pdf: 
Clinical Development 
LAF237/Galvus 
Clinical Study Protocol CLAF237A23156 / NCT01528254
A 5-year study to compare the durability of glycemic control of a 
combination regimen with vildagliptin & metformin versus standard-of-
care monotherapy with metformin, initiated in treatment-naïve patients 
with type 2 diabetes mellitus 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
, Novartis Trial Statistician 
, 
 Trial Statistician 
Document type: 
RAP Documentation 
Document status: 
Final V3.0 
Release date: 
7 May 2019 
Number of pages: 
41 
Property of Novartis 
Confidential 


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May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
2.2 
28NOV2018 
Section 2.1.5 - Background and demographic characteristics – 
baseline HbA1c categories were updated to be <7% and >=7%. 
  
  
2.2.1 - Definition of geographic region for efficacy analyses – 
geographic region categories were added as per Novartis decision. 
2.2.2.3 – Rate of loss in glycemic control over time – time (of HbA1c 
measurements, in years) added as random effect to the analysis 
model. 
  
  
2.3.1 - Overall experience of adverse events (AEs) – statement 
added that AEs will be analyzed by study period as well in addition 
to overall (including study events from study period 1, 2 and 3) in line 
with DMC analyses. 
Section 2.3.1.1 – statement added that AEs will be analyzed by 
study period for all subsection of AEs leading to discontinuation. 
  
  
Section 2.3.5 - Hypoglycemic events – statement added that events 
will be analyzed by study period as well in addition to overall in line 
with DMC analyses.  Added new category to plasma glucose level 
list. 
Section 2.8 – Added statement that time will be used as both a fixed 
and random effect in analyses of rate of loss of glycemic control. 
  
  
Section 2.8 - Changes in the conduct of the study or planned 
analyses – it was added that the definition of initial treatment failure 
is changed to regard the date of the second of the two consecutive 
measurements of HbA1c values >=7%. 
 
 
 
3 
06May2019 
Section 1.4 Changed duration derivation from weeks to Months. 
Section 1.6 Added the list of AEs of special interest 
Section 2.1.2 Added information of efficacy parameters to be 
considered for deviation code N02 and N03. 
Section 2.1.5 Removed definition of baseline HbA1c and FPG as it 
was redundant. Baseline is already defined in section 1.1 
Section 2.1.5 redefined age classification based on tertiles 
Section 2.1.6 redefined exposure categories in months instead of 
weeks.  
Section 2.2.1 Added table mentioning grouping for geographical 
regions 
Section 2.2.2 Removed loss of glycemic control as primary endpoint; 
provided additional detail to used confirmation visit for time to initial 
treatment failure; Since we have only one primary endpoint, 
removed multiple testing methods section 
Section 2.2.2.4 Added time to first treatment failure as supportive 
analysis; modified age categories for subgroup analysis; added 
smoking status, region and beta cell functional and insulin resistance 
as subgroups of interest; removed ethnicity 
Section 2.2.3 Added rate of glycemic control over time as secondary 
endpoint; 
 


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Version 
Date 
 
analyzed and it is outside the scope of the SAP 
Section 2.2.3.3 Added the analysis of rate of glycemic control over 
time in this section 
Section 2.3 Removed analysis on AEs of run-in failure patients. 
Section 2.3.5 Added clarification on using chi square test to compare 
events only if we have sufficient observed events. 
 
 
Section 2.7 Updated power calculations based on single primary 
endpoint and updated yearly dropout rate. 
 
 
 
 


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Table of contents 
Clinical Development ................................................................................................................. 1 
List of abbreviations ................................................................................................................... 6 
1 
Definitions and general strategy .......................................................................................... 7 
1.1 
Baseline definitions ................................................................................................. 7 
1.2 
Last On-Treatment Observation (Endpoint Observation) ....................................... 7 
1.3 
General data handling strategy ................................................................................ 8 
1.3.1 
Output data precision .............................................................................. 8 
1.3.2 
Efficacy Assessment Window / Week X Measurement ......................... 8 
1.3.3 
Laboratory visit windows ........................................................................ 9 
1.3.4 
Multiple laboratory measurements within same day ............................ 10 
1.4 
Duration of exposure to study medication ............................................................. 10 
1.5 
Treatment-Emergent Adverse Events .................................................................... 10 
1.6 
Other clinically significant events (predefined AE risks) ...................................... 10 
1.7 
Hypoglycemic Event Classifications ..................................................................... 11 
1.8 
Laboratory abnormalities ....................................................................................... 12 
1.8.1 
Clinically Significant Laboratory Abnormalities .................................. 12 
1.8.2 
Hepatic enzyme and CPK elevations .................................................... 12 
1.9 
Notable Vital Sign Abnormalities ......................................................................... 13 
1.10 
GFR formula and definition ................................................................................... 14 
2 
Statistical and analytical plans ........................................................................................... 15 
2.1 
Subjects and treatments ......................................................................................... 15 
2.1.1 
Analysis sets .......................................................................................... 15 
2.1.2 
Protocol Deviations and other criteria leading to exclusion of 
patients in analysis sets ......................................................................... 15 
2.1.3 
Patient Disposition ................................................................................ 16 
2.1.4 
Groupings for analysis .......................................................................... 17 
2.1.5 
Background and demographic characteristics ....................................... 17 
2.1.6 
Study medication ................................................................................... 18 
2.1.7 
Concomitant medication ....................................................................... 19 
2.2 
Efficacy evaluation ................................................................................................ 19 
2.2.1 
Definition of geographic region for efficacy analyses .......................... 19 
2.2.2 
Primary efficacy variables ..................................................................... 20 
2.2.3 
Secondary efficacy variables ................................................................. 22 
2.3 
Safety evaluation ................................................................................................... 29 
2.3.1 
Overall experience of adverse events (AEs) ......................................... 29 


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2.3.2 
Laboratory values .................................................................................. 31 
2.3.3 
Vital signs.............................................................................................. 32 
2.3.4 
Electrocardiograms (ECGs) .................................................................. 32 
2.3.5 
Hypoglycemic events ............................................................................ 33 
 
 34 
 
 34 
 
 34 
 
 35 
 
 35 
2.5 
Interim analyses ..................................................................................................... 36 
2.6 
Other topics ............................................................................................................ 37 
2.7 
Determination of sample size ................................................................................ 38 
2.8 
Changes in the conduct of the study or planned analyses ..................................... 39 
References ................................................................................................................................ 41 


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List of abbreviations   
AE  
adverse event  
ALT  
alanine aminotransferase  
ANCOVA  
analysis of covariance  
AST  
aspartate aminotransferase  
ATC  
anatomical therapeutic chemical classification system  
AUC 
area under the curve 
bid  
bis in die (twice a day)  
BMI  
body mass index  
BUN 
Blood urea nitrogen 
CPK  
phosphocreatine kinase  
CSR 
clinical study report 
ECG  
electrocardiogram  
eCRF 
electronic case report/record form 
EOS 
end of study 
FAS  
full analysis set  
FPG  
fasting plasma glucose  
GFR  
glomerular filtration rate  
HbA1c  
glycosylated hemoglobin  
 
 
 
 
 
 
ISR 
insulin secretion rate 
ISR/G 
insulin secretion rate/glucose 
LOCF  
last observation carried forward  
MDRD  
modification of diet in renal disease  
MedDRA  
medical dictionary for regulatory activities  
OGIS 
oral glucose insulin sensitivity 
PD 
protocol deviation  
PK 
pharmacokinetics 
PPS  
per protocol set 
RAN  
randomized set  
SAE  
serious adverse event  
SAF  
safety set  
SCR  
screened-only set  
SI 
standard international 
SMQ 
standardized MedDRA queries 
SYE 
subject year exposure 
T2DM  
type-2 diabetes mellitus  
ULN  
upper limit of normal  
VAS 
visual analogue scale 
WBC 
white blood cell 
WHO  
world health organization   
 


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1 
Definitions and general strategy 
1.1 
Baseline definitions 
Unless specified otherwise, the baseline will be the measurement obtained on Day 1, or the 
closest sample obtained at an earlier visit (scheduled or unscheduled) to Day 1, if the Day 1 
measurement is missing.   
For derived variables 
 the baseline will be derived using measurements 
obtained on Day 1, or the closest samples obtained at an earlier visit (scheduled or 
unscheduled) to Day 1, if the Day 1 measurements are missing.  Details of imputation 
methods to use if one or more of the individual measurements used in the derivation is 
missing, are detailed in section 2.2.3.1. 
Day 1 will be defined as the first day of study treatment (the earliest vildagliptin/placebo date 
as recorded on the vildagliptin/placebo dosage administration page of the eCRF). 
Vital Signs 
For blood pressure and pulse, baseline will be defined as the average of all pre-treatment 
visits, regardless of being scheduled or unscheduled.
 
 
 
Routine ECG Measurements 
ECGs are analyzed and interpreted locally for this study, hence only qualitative ECG 
measurements are recorded. ECGs are scheduled to be measured at screening (and not Day 1). 
Baseline is therefore defined as the measurement obtained at screening, unless there is a later, 
unscheduled measurement on or before Day 1 (in which case the latest of these will be used).   
 
 
 
1.2 
Last On-Treatment Observation (Endpoint Observation) 
For specified efficacy variables, clinical laboratory variables, vital signs and ECG findings, 
the measurement obtained at the last post-baseline study visit will be considered the last on-
treatment (endpoint) observation, regardless of whether it is obtained at a scheduled or 
unscheduled visit, up to the last scheduled visit.   
For specified efficacy variables, clinical laboratory variables and ECG findings, end of Period 
1 and end of Period 2 endpoints will also be of interest. The end of Period 1 endpoint is 
defined as the final available post-randomization assessment obtained at any visit (scheduled 
or unscheduled), prior to or at initial treatment failure, up to the last scheduled study visit. The 
end of Period 2 endpoint is defined as the final available post-randomization assessment 


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obtained at any visit (scheduled or unscheduled), prior to or at the initiation of insulin therapy, 
up to the last scheduled study visit. 
1.3 
General data handling strategy  
1.3.1 Output data precision 
Decimal places to be used in displays of demographic, background and duration of exposure 
variables will be as follows: 
o 3 decimal places (p-values; if p-value is less than 0.001, display <0.001), 
o 2 decimal places (standard errors and standard deviations), 
o 1 decimal place (means, medians), 
o 1 decimal place (minimums, maximums), 
o 1 decimal place (percentages), 
o if percentage = 100, no decimal is required. 
Decimal places for efficacy and other safety summary tables and listings will be as follows: 
o 3 decimal places (p-values; if p-value is less than 0.001, display <0.001), 
o data precision + 2 decimal places (standard errors and standard deviations), 
o data precision + 1 decimal place (means, medians), 
o same as data precision (minimums, maximums), 
o 1 decimal place (percentages), 
o if percentage = 100, no decimal is required. 
Decimal places for the Hematology, Biochemistry and Urinalysis tables will be as follows: 
o 2 decimal places for standard errors and standard deviations (Hematology and 
Biochemistry), 3 decimal places for standard errors and standard deviations (Urinalysis), 
o 2 decimal places for means, medians (Hematology and Biochemistry), 3 decimal places 
for means, medians (Urinalysis), 
o 2 decimal places for minimums, maximums (Hematology and Biochemistry), 3 decimal 
places for minimums, maximums (Urinalysis).  
For vital signs tables of change from baseline, 2 decimal places for mean, median, standard 
deviation, minimum and maximum will be used. 
In outputs containing estimates and p-values for inferential purposes (e.g. ANCOVA), means, 
standard errors, standard deviations and confidence intervals will be output to 2 decimal 
places for all parameters. P-values will be output to 3 decimal places; if a p-value is less than 
0.001, it will be displayed as <0.001. 
1.3.2 Efficacy Assessment Window / Week X Measurement 
For all efficacy variables, the measurements obtained at the scheduled visit corresponding to 
X weeks (e.g. 13, 26, ..., 260 weeks) of treatment as defined in the assessment schedule table 
[Tables 6-1 and 6-2 in the protocol] will be considered as Week X measurement (e.g. Week 
13, 26, ... , 260 measurements) if -28 days < (visit date - Week X date) < 28 days. The Week 
X date is the theoretical date when the visit should have occurred (e.g. if the scheduled visit is 


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visit 5, corresponding to week 26, then the Week 26 date is the treatment start date + 26 
weeks).  
Discontinuation visits will be assigned to the closest unallocated visit. For example, if a 
patient discontinues at visit 4, this discontinuation visit will be re-assigned from visit 777 to 
visit 4 (and not visit 23). This re-assigned visit value will be stored in a separate variable, i.e. 
the original value will not be overwritten. 
Efficacy data obtained at visits outside the above defined window or at unscheduled visits will 
be excluded from the analyses and tabulation of summary statistics by visit.  However, they 
will be displayed in the patient data listings. If the last on-treatment observations of the 
efficacy variables are obtained at a visit outside the above defined windows or at an 
unscheduled visit, they will still be used for the FAS analysis based on the last observation 
carried forward (LOCF) imputed endpoint (see section 1.2).  
Note that prior to implementation of these windows, the remapping of the efficacy laboratory 
parameters will be implemented. 
1.3.3 Laboratory visit windows 
Safety lab data 
The following will be implemented for non-efficacy laboratory data: 
o Safety lab data will be summarized and listed as reported on LRS panel, no additional visit 
windows will be used.  
o Laboratory “Visit dates” from the VIS panel on eCRF will not be listed, instead laboratory 
listings will present the date and day of the sample collection (obtained directly from 
LRS).  
Efficacy laboratory data 
The idea of the visit window is to ensure that as many scheduled visits as possible are 
included in summaries of efficacy parameters over time. 
For all efficacy laboratory summaries over time (tables and figures), a "re-defined scheduled 
visit" will be created as follows: 
o If scheduled visit laboratory sample already exists on database then that sample remains as 
the "re-defined scheduled visit".     
o If scheduled visit laboratory sample is missing, then search for unscheduled sample 
closest to actual scheduled visit date (theoretical date visit should have occurred based on 
treatment start date).  If unscheduled sample closest to actual scheduled visit date is within 
7 days of actual scheduled date then map this unscheduled visit to the scheduled visit 
number in the "re-defined scheduled visit".  If there is a tie between unscheduled samples 
before and after the actual visit, take the later measurement.  Note that the randomization 
visit laboratory measurement will not consider measurements from unscheduled visits 
taken after Day 1. 
All efficacy outputs will include the following footnote:  "In the case of a missing scheduled 
visit sample, the closest unscheduled visit within 7 days of scheduled visit is used."  


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1.3.4 Multiple laboratory measurements within same day 
It is possible that 2 sets of laboratory measurements may be taken with the sample date.  All 
such measurements will be included in the summaries and listings of notably abnormal or 
percent change from baseline summaries.  For the analysis of “persistent” events (where 
consecutive measurements are checked) or for the analysis of parameter over time in the 
following key safety parameters, only the highest within-day value will be included: 
o ALT 
o AST 
o Bilirubin (direct and/or total) 
o CPK 
Specifically, in the case of duplicate measurements with same sample date, only the 
maximum value will be selected.  All samples will be listed along with sample date. 
1.4 
Duration of exposure to study medication 
Treatment start date is defined as the earliest vildagliptin/placebo date as recorded on the 
vildagliptin/placebo dosage administration page of the eCRF).  
Overall duration (in months) on study medication will be computed as follows: 
If a complete last study drug date is available: 
(last study drug date – treatment start date + 1) / 30.4375,  
or if the last study drug date is missing or incomplete: 
(last visit date – treatment start date) / 30.4375, 
or if a patient received no dose of randomized double-blind medication: 
          
overall duration is set to 0. 
The study drug end date is defined as the last treatment date. The last treatment date in the 
study completion panel will be used for this study drug end date. 
1.5 
Treatment-Emergent Adverse Events 
A treatment-emerging adverse event is defined as  
o an undesirable sign, symptom, or medical condition with onset after the first dose of study 
medication or, 
o an increase in severity of an event that is present during the pre-treatment period,   
o all events included on the database will be included in AE summary tables/listings. 
1.6 
Other clinically significant events (predefined AE risks) 
For this project, there are some predefined adverse event risks that are considered of special 
interest defined as below: 
Important identified risks 
• 
Transaminase elevations and Drug-induced liver injury (DILI) 
• 
Angioedema 


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• 
Acute pancreatitis 
• 
Skin lesions (pemphigoids) 
• 
Hypoglycemia  
• 
Lactic acidosis (metformin) 
Important potential risks 
• 
Serious infections 
• 
Cardiac events in CHF (NYHA Functional Class III) patients (adjudication) 
• 
Muscle events/ myopathy/rhabdomyolysis 
• 
Neuropsychiatric events 
• 
Breast cancer 
•      Pancreatic cancer 
1.7 
Hypoglycemic Event Classifications 
Patients were educated to record hypoglycemic symptoms and treatment in a study diary. 
Study diary data were then entered in the Glycemia Study Diary or Adverse Event eCRF, 
respectively according to the following criteria. The Glycemia study diaries were reviewed by 
the study staff at each visit and assessed according to Table 1-1. Note that if glucose is 
recorded as whole blood on the eCRF, rather than plasma, then it will be converted to a 
plasma value in the derived dataset, using a conversion factor of 1.12 (i.e. plasma glucose = 
blood glucose x 1.12). 
Table 1-1 
Recording and classification of glycemia study diary data 
Severity  
Symptoms  
Plasma glucose 
Action taken  
Classification  
Patient able to 
initiate self-
treatment if 
necessary 
Symptoms 
suggestive of 
hypoglycemia 
< 3.1mmol/L 
(56mg/dL) 
Enter in 
Glycemia Study 
Diary eCRF 
Hypoglycemic 
event, grade 1 
Symptoms 
suggestive of 
hypoglycemia 
≥ 
3.1mmol/L(56mg
/dL) 
Enter in 
Glycemia Study 
Diary eCRF 
Adverse Event  
Symptoms 
suggestive of 
hypoglycemia 
Not taken  
Enter in 
Glycemia Study 
Diary eCRF 
Adverse Event  
Asymptomatic  
< 
3.1mmol/L(56mg
/dL) 
Enter in 
Glycemia Study 
Diary eCRF 
Asymptomatic low 
blood glucose 
Patient is unable 
to initiate self-
treatment and 
requires 
assistance of 
another person 
or hospitalization 
Symptoms 
suggestive of 
hypoglycemia  
< 
3.1mmol/L(56mg
/dL) 
Enter in 
Glycemia Study 
Diary eCRF & 
report as SAE 
Hypoglycemic 
event, grade 2 & 
SAE 
Symptoms 
suggestive of 
hypoglycemia  
Not taken  
Enter in 
Glycemia Study 
Diary eCRF & 
report as SAE 
Suspected 
hypoglycemic 
event, grade 2 & 
SAE 


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1.8 
Laboratory abnormalities 
Laboratory data will be presented in SI units only. 
1.8.1 
Clinically Significant Laboratory Abnormalities  
Notable ranges for selected laboratory parameters of interest as listed in Table 1-2 are the 
basis for the central laboratory to generate notable reports to alert the investigators.  The 
notable ranges will form the basis to evaluate the incidence of clinically significant laboratory 
abnormalities.   
Table 1-2 
Notable ranges (absolute) criteria of laboratory variables of specific 
interest 
 
 
Notable ranges 
 
Lab test description 
 
SI Unit 
Low 
High 
Hematology 
Total leucocytes (WBC) 
10E9/L 
≤ 2.8  
 
Total leucocytes (WBC) 
10E9/L 
 
≥ 16.0 
Platelet count (direct) 
10E9/L 
≤ 75 
 
Platelet count (direct) 
10E9/L 
 
≥ 700 
Hemoglobin 
g/L  
≤115 (m) 
≤ 95 (f) 
− 
Hematocrit 
1  
<0.37 (m) 
≤ 0.32 (f) 
− 
Eosinophils  
% 
− 
≥ 14 
Biochemistry 
Sodium 
mmol/L 
≤ 125  
 
Sodium 
mmol/L 
 
≥ 160 
Potassium 
mmol/L 
≤ 3  
 
Potassium 
mmol/L 
 
≥ 6 
Blood urea nitrogen (BUN) 
mmol/L 
− 
≥ 14.28 
Creatinine 
µmol/L 
− 
≥ 176.8 
1.8.2 
Hepatic enzyme and CPK elevations 
In addition to the notable ranges, the incidence of treatment emergent hepatic enzyme 
elevations is of interest. These are described in Table 1-3.  
Treatment emergent is defined as not meeting the criterion at any pre-baseline visit, but then 
meeting the criterion at a post-baseline visit. Consequently a patient may be classified 
treatment emergent ≥5ULN even though they were not classified as treatment emergent 
≥3ULN  (if had a result ≥3ULN at a pre-baseline visit). 
Table 1-3 
Treatment emergent hepatic enzyme and CPK elevations of interest 
ALT or AST ≥ 3*ULN  


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ALT or AST ≥ 5*ULN 
ALT or AST ≥ 8*ULN 
ALT or AST ≥ 10*ULN 
ALT or AST ≥ 20*ULN 
ALT or AST ≥ 3*ULN and Bilirubin^ ≥ 1.5*ULN 
ALT or AST ≥ 3*ULN and Bilirubin^ ≥ 2*ULN 
Bilirubin^  ≥ 2*ULN                 
Bilirubin^  ≥ 3*ULN                 
CPK ≥ 5*ULN 
CPK ≥ 10*ULN 
ALT ≥ 3*ULN 
ALT ≥ 5*ULN 
ALT ≥ 8 x ULN 
ALT ≥ 10*ULN 
ALT ≥ 20*ULN 
ALT ≥ 3*ULN and Bilirubin^ ≥ 1.5*ULN 
ALT ≥ 3*ULN and Bilirubin^ ≥ 2*ULN 
AST ≥ 3*ULN 
AST ≥ 5*ULN 
AST ≥ 8 x ULN 
AST ≥ 10*ULN 
AST ≥ 20*ULN 
Alkaline Phosphatase ≥ 1.5*ULN 
^ If only direct bilirubin is measured then direct bilirubin will be used for all criteria involving bilirubin. If 
both total and direct bilirubin are measured (i.e. are in the laboratory specifications) throughout a 
study, total bilirubin will be preferred.  The clinical study team has agreed that total bilirubin should be 
used for this study. Note that if at any visit total bilirubin has not been measured then the elevation will 
not be assessed for that visit (even if direct bilirubin has been measured). 
In addition to the overall summary of elevations defined above, the same criteria will also be 
presented, restricted to “persistent elevations” only.  Persistent elevations are those which 
meet the criterion at consecutive on-treatment measurements or at last on-treatment visit (this 
includes assessments within one day of the last dose of study treatment).  The purpose of the 
persistent definition is to remove transient elevations from the summary (i.e. those elevations 
which appeared at one visit but normalized at the next visit). 
1.9 
Notable Vital Sign Abnormalities 
Notable vital sign abnormalities 
 are defined in Table 1-4.  


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Table 1-4 
Notable vital sign abnormalities  
 
 
Notable abnormalities 
Vital signs 
 
Low 
High 
Pulse (beats/min) 
 
either ≤50 + decrease ≥30*  
or < 40  
either ≥120 + increase ≥25*  
or >130 
Blood pressure (mmHg) 
Systolic 
either ≤90 + decrease ≥30*  
or < 75  
either ≥180 + increase ≥30*  
or > 200 
 
Diastolic 
either ≤50 + decrease ≥20*  
or < 40  
either ≥105 + increase ≥20*  
or > 115 
 
 
 
 
 
* Refers to post-baseline value as compared to baseline value 
The notable abnormality of ‘> 120 + increase > 25 or > 130’ will be interpreted as that the 
value in the treatment period is > 120 and the increase from baseline is >25, or the value in the 
treatment period is > 130.  
1.10 
GFR formula and definition  
The following formula is used to estimate Glomerular Filtration Rate (GFR) modification of 
diet in renal disease (MDRD) (Rigalleau 2005): 
GFRMDRD (mL/min) × (1.73/m2) = 
 
 
175 × (serum creatinine {mg/dL}) -1.154 
 
 
× (age {years}) -0.203 
 
 
× 0.742 (if female) 
 
 
× 1.210 (if race is Black) 
GFR will be available in the raw laboratory data (and used to assess inclusion/exclusion 
criteria) but will be re-derived within the derived datasets using this RAP-specified formula. 
This will ensure consistency with other studies within the program. 
Baseline GFR (MDRD) is a derived variable calculated using the baseline serum creatinine, 
 & age value, i.e. the value obtained Day 1, or the sample obtained at an earlier 
visit (scheduled or unscheduled) which is closest to Day 1, if the Day 1 measurement is 
missing.  Hepatic function is categorized as follows: 
   Normal: 
GFR (MDRD) >80 
   Mild: 
GFR (MDRD) ≥50 - GFR (MDRD) ≤80 
   Moderate: 
GFR (MDRD) ≥30 - GFR (MDRD) <50 
   Severe: 
GFR (MDRD) <30 


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2 
Statistical and analytical plans 
Data will be analyzed 
 according to the data analysis section 9 of the study protocol 
which is available in Appendix 16.1.1 of the CSR.  Important information is given in the 
following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR. 
2.1 
Subjects and treatments 
2.1.1 Analysis sets 
Screened-only set (SCR): The SCR consists of all patients who were screen failed after the 
first visit or who entered the run-in phase but were not randomized. Except for the listing of 
individual patients in this SCR with the reasons for not being randomized, and the tabulation 
of patients in this SCR by discontinuation reason, no other analysis will be performed on this 
analysis set. 
Randomized set (RAN): The RAN consists of all randomized patients.  
Full analysis set (FAS): The FAS consists of all randomized patients who receive at least one 
dose of randomized study medication (vildagliptin or placebo) and have at least one post-
randomization assessment of any efficacy parameter. Following the intent-to-treat principle, 
patients will be analyzed according to the treatment approach they are assigned to at 
randomization. 
Safety set (SAF). The SAF consists of all patients who receive at least one dose of 
randomized study medication (vildagliptin or placebo). Patients will be analyzed according to 
the treatment approach received. If a patient receives both vildagliptin and placebo in Period 
1, then the patient will be included in the vildagliptin group. Note that the SAF allows the 
inclusion of non-randomized patients who received the study drug in error. 
Per Protocol set (PPS): The PPS is a subset of FAS and consists of all randomized patients 
who receive at least one dose of randomized study medication (vildagliptin or placebo), have 
at least one post-randomization assessment of any efficacy parameter in Period 1, do not 
discontinue the study prior to Week 26, and have no major protocol deviations occurring 
during Period 1.  
2.1.2 Protocol Deviations and other criteria leading to exclusion of patients in 
analysis sets 
Patients will be excluded from analysis based on the protocol deviations (PDs) in VAP 
Module 3 and other criteria described in Table 2-1. The PDs described in VAP Module 3 will 
be identified manually by field monitors/CTH and/or via PD programming, and will be 
provided in the VIOPTO source dataset, whilst those in (Table 2-1) will be programmed by 
Biostatistics using source data, and stored in the derived dataset NOVIOPTO. The severity 
codes assigned to each deviation as described in VAP Module 3 and Table 2-1 will be used to 
classify patients as described in Table 2-2. Note that other protocol deviations will also be 
identified. However, patients will not be excluded from analysis based on these other 
deviations (with severity code 49) including violations of entry criteria on prior use of anti-


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diabetic agents and BMI range. The subject classification as specified in Table 2-2, will be 
defined based on severity codes prior to un-blinding the database with respect to treatment.    
Table 2-1 
Other criteria leading to exclusion of patients in analysis sets 
Description of Deviation 
Deviation 
code 
Severity 
code 
Inclusion/ 
Exclusion in 
Analyses 
No dose of randomized, double-blind medication 
(vildagliptin or placebo) taken during Period 1 
N01 
8 
Excluded from 
all efficacy and 
safety 
analyses 
No post-randomization efficacy assessment during 
the treatment period (Periods 1, 2 or 3) 
N02 
0 
Excluded from 
efficacy 
analyses 
No post-randomization efficacy assessment during 
Period 1 
N03 
1 
Excluded from 
PPS analyses 
Patient discontinued from the study prior to Week 
26 
N04 
1 
Excluded from 
PPS analyses 
Subjects with no post-randomization efficacy assessment of Hba1c during the treatment 
period (Periods 1, 2 or 3) will be excluded from efficacy analyses (Deviation code N02). 
Subjects with no post-randomization efficacy assessment of Hba1c, fasting insulin, fasting 
glucose, fasting C-peptide and meal-test parameters during Period 1 will be excluded from 
PPS analyses (Deviation code N03). 
Table 2-2 
Subject classification 
Deviation Severity Codes 
Analysis set 
 0 
 1 
 8                   49 
Randomized Set (RAN) 
 Yes 
 Yes  
 Yes  
Yes 
Full Analysis Set (FAS) 
 No 
 Yes 
 No 
Yes 
Safety Set (SAF) 
 Yes 
 Yes 
 No 
Yes 
Per Protocol Set (PPS) 
 No 
 No 
 No 
Yes 
Note: yes/no means whether patients with PDs or non-PD criteria of a specific code are included (yes) 
or excluded (no) from an analysis set. 
The number and percentage of patients in the RAN with protocol deviations and other criteria 
leading to exclusion of patients from analysis sets will be tabulated by treatment approach. 
Protocol deviations that do not lead to exclusion from analysis populations will be further 
summarized for the RAN by treatment approach. Summaries will be repeated by Period. 
2.1.3 Patient Disposition 
The number and percentage of randomized patients (RAN) who completed the study and who 
discontinued will be tabulated by treatment approach. Discontinuation will be further broken 
down by reason in the tabulation. Summaries will be repeated by Period, including 
information about the number of patients continuing into the next Period.  
Completion information will be listed for the RAN. 


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Patients who were screened for the trial and entered the run-in phase but were not randomized 
(SCR) will be tabulated and listed with reasons for not being randomized. These summaries 
will include both screen failures and run-in failures (i.e. patients who discontinue within the 
screening period and patients who discontinue within the run-in period). Note that the patients 
will be presented together and not separated out into separate groups for screen failures and 
run-in failures. 
2.1.4 Groupings for analysis 
The number and percentage of patients in each analysis set will be summarized by treatment 
approach. The number and percentage of patients included in the meal test, 
 subsets will also be summarized by treatment approach. Meal 
test 
 count data will be presented as part of the efficacy 
evaluations.
 
 
2.1.5 Background and demographic characteristics 
Demographic, background data and key efficacy variables at baseline will be summarized for 
all randomized patients (RAN) by the treatment approach that patients are assigned to at 
randomization. Categorical variables gender, race, ethnicity, baseline age group, current 
smoking status, baseline GFR (MDRD) category, baseline body mass index (BMI) group, and 
baseline HbA1c group will be summarized by frequency and percentage. The continuous 
variables baseline age, height, 
, baseline BMI, duration of T2DM, baseline 
HbA1c and baseline FPG will be summarized by mean, standard deviation, median, minimum 
and maximum.  
All baseline and background characteristics (except HbA1c, FPG and GFR) will be 
summarized at study entry (screening visit) or at the randomization visit if screening (Week -
5) measurements are not collected.   
Baseline body mass index (BMI) will be calculated (i.e. not taken from the eCRF) from the 
height and weight measured at screening (Week -5), BMI = weight / height2, where weight is 
in kilograms (kg) and height is in meters (m).    
The classification of the baseline HbA1c, BMI, age category and GFR (MDRD) category are 
based on the following definitions:  
o HbA1c category (< 7% and ≥7%) 
o BMI (< 30 kg/m2 and ≥ 30 kg/m2 at Visit 1) 
o Age at Visit 1 by tertiles i.e. <48 years, 48 - < 62 years and ≥ 62 years) 
o GFR (MDRD) category (Normal: >80 mL/min, Mild: ≥50 mL/min - ≤80 mL/min, 
Moderate: ≥30 mL/min - <50 mL/min, Severe: 0 mL/min - <30 mL/min) 
Baseline comparability across treatment approaches for all randomized patients (RAN) will be 
examined in a Section 16.1 listing using a chi-square test for the categorical variables, and a 
two-sample t-test for the continuous variables. The p-values are provided for descriptive 
purposes, and will not to be considered as the formal basis for determining factors to be 
included in the statistical analysis model.  


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In addition, all relevant medical history and history of diabetes and complications will be 
summarized by primary system organ class, preferred term and treatment approach using 
frequency tables in Post-text tables for all RAN patients. 
2.1.6 Study medication 
The study consists of three treatment periods.  
In Period 1 patients will be randomized to metformin + vildagliptin 50mg bid, or metformin + 
placebo. If initial treatment fails to maintain HbA1c < 7.0%, confirmed at two consecutive 
scheduled study visits (after remapping in section 1.3.3 has been applied), starting from Visit 
4 (Week 13), then vildagliptin will be added to metformin in the metformin-only arm in 
Period 2. The Period 1 end date is defined as the date of the second of the two consecutive 
scheduled study visits, i.e. the initial treatment failure date. The Period 2 start date is defined 
as the next day. 
In Period 3, insulin is considered based on local guidelines. Both patients and investigators 
will remain masked to the treatment allocation in Period 1, and the study will compare the two 
different treatment approaches. The Period 3 start date is defined as the date of insulin 
initiation. The Period 2 end date is defined as the previous day. 
Treatments are referred to as ‘Treatment approach’ throughout this analysis plan to 
acknowledge that patients are not on the same treatment for the duration of the study. When 
summaries are detailed for the ‘Treatment Period’, they will include data from Periods 1, 2 
and 3, unless specified otherwise. 
The duration of exposure to study medication (in months) during the treatment period will be 
computed for all patients using the algorithm outlined in Section 1.4 and summarized by 
treatment approach for the RAN both descriptively (i.e., mean, standard deviation, median, 
minimum and maximum) and by 3 - monthly intervals (0 - < 3 months, 3 - < 6 months, ..., ≥ 
60 months). 
The study Period 1 duration (in months) will be also similarly summarized for the RAN. The 
study Period 1 duration is defined as (initial treatment failure date – treatment start date + 
1)/30.4375 for patients who entered study Period 2. The study Period 1 duration is the same as 
overall study duration for patients who did not enter into Period 2. 
The study period from treatment start to the end of Period 2 will be computed for all patients 
who initiate insulin in Period 3 and for patients discontinuing the study in Period 2 due to 
being unable or unwilling to initiate insulin for treatment intensification in Period 3. The 
duration will be defined as (initiation date of insulin – treatment start date)/30.4375 for 
patients who initiate insulin, and (last study drug date – treatment start date +1)/30.4375 for 
patients who do not enter Period 3. 
Total subject year exposure (SYE) will also be summarized by treatment approach for the 
RAN. SYE (years) for each treatment will be calculated as (duration of exposure in days, 
disregarding any treatment interruptions, for all subjects in that treatment approach) / 365.25. 
For patients who did not take any study medication, the exposure is set to zero. This summary 
will be repeated on Period 1 data only, and also on Vildagliptin exposure only. 


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Study medication information will be listed for the RAN, including information about 
vildagliptin, placebo, metformin and insulin use. 
2.1.7 Concomitant medication 
Concomitant therapies taken during the treatment period will be summarized by anatomical 
therapeutic chemical classification system (ATC) class and preferred term according to the 
treatment approach patients are assigned to at randomization in the RAN. The number and 
percentage of randomized patients (RAN) in each class and preferred term will be tabulated 
by treatment approach. This summary will be repeated on period 1 data only, i.e. concomitant 
therapies taken during Period 1. 
Use of anti-diabetic medications prior to study entry (as recorded on the eCRF) will be 
summarized by ATC class, preferred term and treatment approach.   
The duration and average daily dose of metformin taken during the screening and run-in 
period will be summarized descriptively (mean, standard deviation, median, minimum and 
maximum), using data from 35 days prior to screening through to 35 days after 
randomization. This will be based on information collected on the i) Metformin dosage 
administration page of the eCRF (considering only dosages which are at most 35 days after 
randomization); and ii) information collected on the prior anti-diabetic medication eCRF page 
with a preferred term containing ‘METFORMIN’ and a dose of ‘mg’ (considering only 
dosages which are at most 35 days prior to the screening visit). The average daily dose of 
metformin during this window will also be summarized categorically (<2000 mg, ≥2000 mg).  
Listings of concomitant medications and prior anti-diabetic medications will be presented by 
treatment approach and patient number. 
2.2 
Efficacy evaluation 
2.2.1 Definition of geographic region for efficacy analyses 
Centers/countries with a small number of patients will be pooled to create geographic regions. 
Larger centers/countries will be considered as their own geographic region. There are six 
geographic regions planned: Europe, Latin America, South-East Asia, East Asia, Australia 
and Africa. The pooling of centers and/or countries to create geographic regions will be 
confirmed once all patients have been randomized. The allocation of countries to the specific 
geographic regions will be as follows. 
Centers/Countries 
Geographic region 
AUT, BGR, CZE, DEU, ESP, EST, FIN, 
HUN, ISR, ITA, LTU, LVA, NOR, POL, 
ROU, RUS, SVK, TUR 
Europe 
ARG, BRA, COL, DOM, GTM, MEX, PAN, 
PER 
Latin America 
IND, MYS, PHL 
South-East Asia 
HKG, KOR, TWN 
East Asia 


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AUS 
Australia 
ZAF 
Africa 
2.2.2 Primary efficacy variables 
2.2.2.1 Variable definition 
The primary efficacy variable is time to confirmed initial treatment failure. The confirmed 
initial treatment failure is defined as a patient with HbA1c measurements ≥7.0% at two 
consecutive scheduled visits (after remapping in section 1.3.3 has been applied), starting from 
Visit 4 (Week 13). The time to confirmed initial treatment failure is defined as the time from 
randomization until the time when the second of the two HbA1c measurement ≥7.0% was 
determined after at least 13 weeks of treatment (Visit 4), i.e. the end of Period 1. The rationale 
of starting the treatment failures count from Visit 4 is that treatment guidelines consider as 
treatment failure patients who do not achieve HbA1c <7.0% after 3 months of treatment 
(ADA-EASD, 2009). 
The main study conclusion will be based on the analysis of the primary efficacy variable 
using the FAS. Analyses based on the PPS will also be performed to assess the robustness of 
the conclusion. 
2.2.2.2 Handling of missing values/censoring/discontinuations 
In the analysis for the primary efficacy variable of time to treatment failure, patients who 
discontinue the study for any reason during Period 1 (lack of efficacy, lost to follow-up, AE or 
abnormal laboratory values etc.) will be treated as censored values at the time of 
discontinuation. Patients who remain under the threshold (or whose measurement above the 
threshold is not confirmed at next scheduled visit) will be censored at the time of last study 
visit.  
No imputation will be used for missing HbA1c measurements. As detailed in section 1.3.3, re-
defined scheduled visits will be created and so it should be the case that there is always a 
measurement for a scheduled visit, as an unscheduled visit should be carried out to ensure 
there was an HbA1c value available. However, if there is a case where the HbA1c value is 
missing then when looking for consecutive scheduled visits, only visits with non-missing 
HbA1c measurements will be considered (e.g. if Visit 4 HbA1c ≥7.0%, Visit 5 HbA1c is 
missing, and  Visit 6 HbA1c ≥7.0%, then this will be considered treatment failure).  
2.2.2.3 Statistical model, hypothesis, and method of analysis 
Time to initial treatment failure 
The primary statistical hypothesis of time to initial treatment failure will be assessed by a 1-
sided test of superiority of the combination treatment with vildagliptin + metformin versus 
metformin monotherapy with α-level of 0.025 with a null hypothesis that the hazard-ratio 
between the combination treatment vildagliptin + metformin and metformin monotherapy is 
equal or greater than 1, versus the 1-sided alternative hypothesis that the hazard-ratio is less 
than 1: 


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H0: λvildagliptin+metformin/λmetformin ≥ 1 
versus 
Ha: λvildagliptin+metformin/λmetformin < 1 
where λvildagliptin+metformin and λmetformin are the hazard-rates of the initial treatment failure for 
vildagliptin 50mg bid + metformin up to 1000mg bid and metformin up to 1000mg bid 
monotherapy respectively. 
The time to confirmed failure will be derived as the time from randomization to the second of 
two consecutive scheduled visits (after remapping in section 1.3.3 has been applied), at which 
HbA1c ≥7.0% is measured, starting from Visit 4 (13 weeks after randomization).  
The primary efficacy analysis will use a Cox proportional hazard regression model to assess 
the probability of initial treatment failure, with treatment approach and geographic region as 
classification variables and baseline HbA1c as a covariate. The hazard-ratio and associated 
95% confidence interval as well as the p-value estimated from the above model will be 
presented by treatment approach. 
The initial treatment failure rate over time by treatment approach will be summarized using 
estimates and 95% confidence intervals from a Kaplan-Meier analysis. The Kaplan-Meier 
estimates will be plotted, with symbols to indicate censored values.  
The primary analysis for this primary efficacy variable will be performed using the FAS. It 
will be performed in the PPS as supportive analysis as well.  
The model assumptions will be checked by plotting the Schoenfeld residuals for the treatment 
effect obtained from the model against time. A random spread of residuals with no clear 
pattern will indicate that the proportional hazards assumption is valid. The results will be 
presented in CSR Section 16 table(s). 
2.2.2.4 Supportive analyses 
Time to first treatment failure 
The time to first treatment failure will be derived as the time from randomization to the first 
of two consecutive scheduled visits (after remapping in section 1.3.3 has been applied), at 
which HbA1c ≥7.0% is measured, starting from Visit 4 (13 weeks after randomization).  
Time to first treatment failure will be analyzed in the similar way as primary analysis. 
Descriptive analysis in HbA1c over time 
Summaries of absolute values and change from baseline to end of Period 1 in HbA1c by 
treatment approach and visit will be presented in the FAS. Figures will be produced showing 
the mean HbA1c and standard error by visit during the study Period 1 for each treatment 
approach. The summary table and figure will be repeated for PPS. 
In addition, the above descriptive analysis (including summary table and figure) will be 
performed for FAS on HbA1c data collected up to the end of Period 2, as well as data 
collected during the entire duration of the study. 


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Descriptive subgroup analysis 
Summaries of absolute values and changes from baseline to end of Period 1 in HbA1c will be 
presented by treatment approach. The analysis will be performed on FAS. The list of 
subgroups of interest is listed below: 
1. Baseline HbA1c category (<7%, ≥7%) 
2. BMI (<30kg/m2, ≥30kg/m2 at Visit 1) 
3. Age at Visit 1 by tertiles i.e. < 48 years, 48-< 62 years, ≥ 62 years 
4. Gender 
5. Race 
6. Smoking status 
7. Geographical regions 
 
  
2.2.3 Secondary efficacy variables  
2.2.3.1 Derivation of secondary 
 variables 
Rate of glycemic control over time 
The rate of loss of glycemic control over time will be estimated by an annualized slope of 
HbA1c over time from Visit 5 (Week 26) to the end of Period 1. A mixed effect model 
including a random coefficient will be used for analysis. The rationale of choosing Visit 5 as 
starting point for estimating the rate (slope) of loss of glycemic control over time is based on 
data from study CLAF237A2307 (Scherbaum W et al, 2008) where the maximal reduction in 
mean HbA1c from baseline was between 24 and 32 weeks, therefore a trend for loss in 
glycemic control is sensible to be estimated from a similar time point. 
In the analysis of the rate of loss in glycemic control over time, data used in analysis will be 
censored at the start of Period 2, i.e. the only data included in the model will be from Visit 5 
(Week 26) to the end of Period 1. 
FPG 
If the FPG value (standard non meal-test parameter) is missing, the -20 min meal-test value 
(obtained on the same day) can be used to impute.  If the -20 min value is also missing, the 0 
min value will be used.   


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Calculation of OGIS 
OGIS will be calculated as a function of glucose and insulin (meal-test laboratory 
parameters): 
OGIS = 0.5 * { 
                         [ ( (P5*(G(90)-Gc)) + 1 ) * CI_OGTT ] 
                         + sqrt {  
                                     [ ( (P5*(G(90)-Gc)) + 1 ) * CI_OGTT ] ^2  
                                     + [4 * P5 * P6 * (G(90)-Gc) * CI_OGTT]  
                                    } 
                        } 
where, 
o CI_OGTT ={ P4 * { (P1*D0) – [V*(G(120)–G(90))]/30 } / G(90) +(P3/G(0)) } 
                           / { I(90) – I(0) + P2 } 
o D0 (g/m2) is the glucose dose included in the standard meal administered to patients who 
participate in the standard meal-test (D0 =(73.2*5.551)/BSA for the standard meal as 
planned in Protocol Section 6.4.3. It will be assumed all patients receive a standard meal),  
o BSA=0.164*(Weight in kg**0.515)*((0.01*Height in cm)**0.422), 
o V =10000 (ml/m2) is the assumed glucose distribution volume,  
o G(0), G(90) and G(120) are glucose concentration values (taken from meal-test laboratory 
data) at timepoints 0, 90 and 120 min,  
o I(0) and I(90) are insulin concentration values (taken from meal-test laboratory data) at 
timepoints 0 and 90 min,  
o P1=6.5, P2=1951, P3=4514, P4=792, P5=0.0118, P6=173, Gc=5 are constants (Mari, et al 
2001). 
If the value of glucose or insulin values at 0 minutes are missing, then the -20 min meal-test 
value (obtained on the same day) can be used to impute.  If the -20 min value is also missing, 
the fasting parameter result (i.e. standard non meal-test parameter) will be used. Both glucose 


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and insulin should be imputed using the same timepoint (regardless if one has value 
available).  
No imputation will be used for missing 90 or 120 minute values. 
Calculation of ISR 
Separately for each patient and each meal-test, deconvolution is applied to estimating insulin 
secretion to assess β-cell function. C-peptide, which is co-secreted with insulin in an 
equimolar ratio, is preferred to insulin as a basis for estimating insulin secretion. 
Mathematically, we need to solve for the insulin secretion rate r given the impulse response h, 
and plasma C-peptide c, where 
 
The impulse response is the PK model for an intravenously administered unit bolus dose of C-
peptide when the endogenous C-peptide production has been suppressed, i.e. 
 
where V, f, α, and β are a subject’s parameters, which are generally unknown. However, from 
clinical studies these parameters have been estimated, and are related to a subject’s disease 
status, body surface area, age, and gender. Thus, h becomes known. 
Insulin secretion rates are modeled by a piecewise continuous linear function with knots at the 
actual sampling time. Changes in slopes are penalized through a single regularization 
parameter that is determined by a root finding method to produce similar residual standard 
deviation for fitted C-peptide concentrations as would be expected from assay error standard 
deviations given in the kit instructions. 
The IMMULITE 2000 C-peptide kit instructions were used to model intra-assay SD as a 
function of the true C-peptide concentration C1 expressed in conventional units of ng/mL by 
simple linear regression as: 
SD = 0.04056C1 + 0.06311ng/mL. 
With concentration of C-peptide expressed alternatively in SI units, i.e., C2 expressed in nM 
(1ng/mL C-peptide = 0.331nM C-peptide) the equations for SD becomes: 
SD = 0.04056 C2 + 0.331 × 0.06311nM. 
The following ln-transformation with a shift parameter of observed and fitted C-peptide 
values is used to stabilize the variance in performing the deconvolution: 
ln(C1 + 0.06311/0.04056) or ln(C2 + 0.331 × 0.06311/0.04056). 


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Nonlinear least squares with ISR constrained non-negative using PROC IML function 
NLPLM in SAS® is used to solve for ISR at the sampling time points using actual sampling 
times. The bisection method is used to iteratively determine the regularization parameter such 
that the sum of squares of the observed C-peptide minus the fitted C-peptide expressed in 
either units equals 0.040562n where n is the number of non-missing C-peptide concentrations 
in the meal-test. 
Validated macros (ISR and ISR_IML2) have been provided by Novartis and will be used to 
derive the ISR in 
 production and validation programs. 
Calculation of AUC 
AUC of ISR/G is defined as ISR relative to glucose 0-2h (pmol/min/m2/mM) = AUC0-2hr of 
ISR/AUC0-2hr of glucose. (Glucose is taken from the meal-test laboratory data).  
For the patients participating in the meal-test, the laboratory parameters glucose, insulin and 
C-peptide are also to be measured at the following 7 time-points (minutes in relation to the 
meal time): -20min, 0min  (immediately prior to meal ingestion), 15min, 30min, 60min, 
90min, 120min. Let L1, L2, …., L7 denote the lab measurements at these 7 time-points (i.e., L1 
is the value measured at 20min pre-meal, L2 is the value measured at 0min pre-meal, …, L7 is 
the value measured at 2h after the meal) and T1, T2, .., T7 be the corresponding times (actual 
times in units of h), the AUC0-2hr is calculated (using the trapezoidal rule) as: 
AUC0-2h = 
[(L2 + L3) × (T3 – T2) + (L3 + L4) × (T4 – T3) + (L4 + L5) × (T5 – T4) + (L5 + L6) × (T6 – T5) + 
(L6 + L7) × (T7 – T6)] / 2. 
Note for above calculation:  
1) L1 and T1 are not used in the calculation. However, if L2 (the value at 0 min) is missing, the 
L1 (the value at –20 min) will be used in its place, but T2 should still be used in the 
calculation (i.e., no substitution of T2 with T1 is allowed). If the -20 min AND 0 min values 
are missing, the fasting value (i.e. the standard non meal-test value) will be used to impute 
the 0 min value. If the 0 minute ISR is missing due to missing 0 minute c-peptide, then the 
missing c-peptide value should be imputed using this approach, in order to obtain a non-
missing 0 minute ISR value. 
2) If Li (a lab value) is not missing, but the corresponding time Ti is missing, Ti will be 
imputed by the planned time (or scheduled time). 
3) If Li is missing at a timepoint Ti, the next available value Li+1 and timepoint Ti+1 will be 
used for calculating AUC.  
4) AUC0-2h will only be calculated for patients for whom there are at least 3 timepoints 
(including one of the first two timepoints (i.e., 0 or -20 min pre-meal), the last timepoint 
(i.e., 2 hours post-meal), and a timepoint in between) where the actual laboratory values are 
known. 


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2.2.3.2 Variable definition 
The following secondary 
 efficacy variables will be analyzed. They are grouped 
by type of analyses for the convenience of describing the related analysis methods. 
 
 
Variables related to the rate of change of β-cell function and insulin sensitivity 
• Rate of loss of β-cell function (assessed using the AUC of ISR/G) from Visit 4 (week 13) to: 
i) end of Period 1; ii) end of Period 2; iii) EOS. 
• Rate of change in insulin sensitivity (assessed using the OGIS) from Visit 4 (week 13) to:  i) 
end of Period 1; ii) end of Period 2; iii) EOS. 
Variables related to the rate of loss in glycemic control over time 
• Rate of loss in glycemic control in HbA1c from 26 weeks after the start of Period 2 to end of 
Period 2. 
• Rate of loss in glycemic control in FPG, i) from Visit 5 (week 26) to: i) end of Period 1; ii) 
from 26 weeks after start of Period 2 to end of Period 2.  
Variables related to change from baseline to endpoint 
• Change in AUC of ISR/G (as an assessment of β-cell function) from baseline to: i) end of 
Period 1; ii) end of Period 2; iii) EOS. 
• Change in OGIS (as an assessment of insulin sensitivity) from baseline to: i) end of Period 
1; ii) end of Period 2; iii) EOS. 
 
 
 
 
 
 
 
 
2.2.3.3 Statistical analysis methods 
Rate of loss in glycemic control over time 
The rate of loss in glycemic control over time will be estimated by the slope of HbA1c over 
time (in years) as a random coefficient in a linear mixed effect model: the model will be fitted 
to HbA1c data collected from Week 26 and onwards, up to and including the end of the 


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Period 1 visit, i.e. up to and including the initial treatment failure date. It includes treatment 
approach, geographic region, baseline HbA1c, time (of HbA1c measurements, in years) and 
the interaction of treatment approach by time as the fixed effects, and time and intercept as  
random effects. Treatment approach and geographic region will be considered as 
classification variables while baseline HbA1c and time are the covariates. The unstructured 
covariance will be used as the covariance structure within patients. The actual hypothesis will 
be tested using the treatment approach by time interaction term. Note that it is not an issue 
that patients who ‘fail’ at Week 26 will only contribute one data point to the analysis, as this 
is expected in only a few patients. 
The mean slopes within each treatment approach and the difference in mean slopes between 
two treatment approaches as well as the p-value obtained from the test using the above model 
will be presented. Graphical representation will also be produced as required. 
The analysis will be performed using the FAS. It will be performed in the PPS as supportive 
analysis as well. 
The assumptions for inference using the model as described above (i.e., errors are 
independently normally distributed with constant variance) will be checked using CSR 
Section 16 table(s) by subjective examination of the presented residual plots: normal 
probability plot and residuals versus fitted values plots.  
 
 
Variables related to the rate of change of β-cell function and insulin sensitivity 
over time 
The rate of change of β-cell function and insulin sensitivity (assessed using the AUC of ISR/G 
and OGIS respectively) from Visit 4 (week 13) to the end of Period 1, or from Visit 4 (week 
13) to the end of Period 2, or from Visit 4 (week 13) to the end of study will be assessed using 
a similar random coefficient linear mixed effect model used for the endpoint ‘rate of loss in 
glycemic control in HbA1c from Visit 5 (Week 26) to the end of Period 1’.  


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This analysis is performed in the FAS only. Data collected up to the end of Period 1, or the 
end of Period 2, or to the end of the study will be used in the analysis for assessing the rate of 
change from Visit 4 to end of Period 1, or from Visit 4 to end of Period 2, or from Visit 4 to 
the end of the study respectively.  
A general downward trend from Visit 4 to the end of study can be assumed for these 
parameters. 
Variables related to the rate of loss in glycemic control over time 
The rate of loss in glycemic control in HbA1c or FPG from 26 weeks after the start of Period 
2 to the end of Period 2 will be assessed for patients who start insulin therapy in Period 3 (i.e. 
for treatment intensification) or discontinue the study during Period 2 due to not being able or 
unwilling to initiate insulin therapy in Period 3. The random coefficient linear mixed effect 
model used for the endpoint ‘rate of loss in glycemic control in HbA1c from Visit 5 (Week 
26) to the end of Period 1’ will be used in this secondary variable. Only data collected 
between initiation of Period 2 to insulin initiation on patients who take insulin therapy in 
Period 3 (i.e. for treatment intensification) or who discontinued the study in Period 2 due to 
not being able or unwilling to initiate insulin therapy in Period 3 will be included in this 
model. Patients who complete the study in Period 1 or Period 2 will not be included in the 
analysis. The analysis will be performed in the FAS only. Note that it is not known how many 
patients will proceed into Period 3, so may need to later review whether the planned analysis 
for the subgroup of patients entering Period 3 (or being unable/unwilling to) is sensible. 
The rate of loss in glycemic control in FPG from 26 weeks to the end of Period 1 will be 
assessed using the same random coefficient linear mixed effect model used for the endpoint 
‘rate of loss in glycemic control in HbA1c from Visit 5 (Week 26) to the end of Period 1’. 
This analysis is performed in the FAS only. 
Variables related to change from baseline to endpoint 
An analysis of covariance (ANCOVA) model with treatment approach, geographic region as 
classification variables and baseline value as a covariate will be used to assess all secondary 
efficacy variables related to change from baseline to endpoint. The least squares mean 
(“adjusted mean”) change from baseline for each treatment approach, the difference in the 
least squares mean changes between the two treatment approaches, and the two-sided adjusted 
95% confidence interval along with the p-value for the difference will be obtained from this 
analysis model and presented. 
 
 
The assessment may be performed within two months before or after the 
actual study visit for practical reasons, so the date of the ophthalmic assessment may differ 
from the actual study visit. An endpoint is not defined for this data. 


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Supportive descriptive analysis for secondary 
 variables over 
time 
Summaries of absolute values and change from baseline to: i) end of Period 1; ii) end of 
Period 2; iii) EOS; in secondary 
 variables (including FPG, 
, AUC 
of ISR/G, OGIS, 
) by treatment approach 
and visit will be presented in the FAS. 
 
. 
2.3 
Safety evaluation 
The safety and tolerability of vildagliptin 50mg bid as add-on to metformin over 5-years of 
treatment will be compared to placebo as add-on to metformin based on data collected during 
the treatment period in SAF. All analyses will use all available data collected during the entire 
study. In addition, key safety analyses will be performed on data obtained during Period 1 
only. Patients will be analyzed according to the treatment approach they received (vildagliptin 
50mg bid + metformin, placebo + metformin).  
The incidence of treatment emergent adverse events (events started after the first dose of 
randomized study medication or events present prior to start of randomized treatment but 
increased in severity) will be summarized by primary system organ class, preferred term, 
severity and relationship to study drug. Any event captured on the database will be included in 
AE summary tables/listings. 
In order to assess safety and tolerability of vildagliptin as compared to placebo, key safety 
variables (overall AEs, SAEs, AEs leading to study drug discontinuation or study drug 
interruption, incidence of hypoglycemia, predefined AE risks, predefined categories of liver 
enzyme (ALT/AST) and CPK and persistent elevations) will also be summarized by treatment 
approach for the SAF. 
 
2.3.1 Overall experience of adverse events (AEs) 
The number and percentage of patients reporting any adverse event during the treatment 
period of the study will be summarized by primary system organ class, preferred term and 
treatment approach overall (including study periods 1, 2 and 3) and by study period.  
Percentages will be based on the number of patients in the SAF per treatment approach and 
study period. An AE will be assigned to a period if its start date is after or on the start date but 
not later than the end date of that period. All AEs will be assigned to a specific study period – 
if it is not possible to assign an AE into a specific study period of the patient based on the AE 
start date, then the event will be assigned to the last study period started by the patient. This 
will ensure that all AEs will be categorized to a specific study period   
The most common adverse events reported (≥2 % in any group) during the treatment period of 
the study will be presented in descending frequency starting from the most common event in a 
Text Table.  A complete table of all events reported in descending frequency will be prepared. 


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Adverse events that were suspected to be related to study drug will be summarized. Note that 
if the relationship to study drug is missing for any adverse event, then that adverse event will 
be assumed to be related to study drug.   
The maximum severity of all adverse events during the treatment period of the study will be 
summarized. Note that if the severity is missing for any adverse event, then that adverse event 
will be assumed to be severe.  
An overall summary of the number and percentage of patients with drug-related AEs, severe 
AEs, AEs with outcome of death, SAEs and adverse events leading to permanent 
discontinuation of treatment will be presented by study period and  treatment approach. 
The number and percentage of patients reporting any adverse event during the treatment 
period of the study will be summarized by standardized MedDRA query (SMQ) level and 
treatment approach as well. 
In addition, the number and percentage of patients reporting any adverse event during the 
treatment period will also be summarized by primary system organ class, preferred term, 
treatment approach and age group (as defined in section 2.1.5) ) overall and by treatment 
period.. 
Note that there will be no AE adjudication for this study. 
2.3.1.1 Deaths, other serious and other significant adverse events 
An overall summary of the number and percentage of deaths, serious adverse events (SAEs), 
and adverse events (including laboratory abnormalities) leading to discontinuation, study drug 
interruption or considered to be clinically significant will be presented by study period and 
treatment approach.  
Deaths 
The number and percentage of deaths will be summarized by study period and treatment 
approach and the principal cause in primary system organ class and preferred term.   
Serious adverse events (SAEs)  
The number and percentage of patients with serious adverse events (SAEs) will be 
summarized by primary system organ class, preferred term, study period and treatment 
approach.  
Other significant adverse events – adverse events leading to discontinuations 
The number and percentage of patients with adverse events that lead to discontinuation will be 
summarized by primary system organ class, preferred term, study period, and treatment 
approach.  


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Other significant adverse events – adverse events leading to dose adjustments 
or study drug interruptions  
The number and percentage of patients with adverse events that lead to dose adjustments or 
study drug interruptions will be summarized by primary system organ class, preferred term, 
study period, and treatment approach.   
Other significant adverse events – predefined adverse event risks 
The number and percentage of patients with adverse events that were predefined risks (see 
Section 1.6 for definitions) will be summarized by preferred term, predefined risk category, 
maximum severity, study period, and treatment approach.     
2.3.2 Laboratory values 
The details of laboratory parameters collected, SI units (note, only SI units will be reported), 
and normal ranges will be listed in Section 16 of CSR. Note that lipid parameters are 
summarized along with other biochemistry laboratory parameters. Meal test laboratory 
parameters (glucose, insulin and c-peptide) are for use in efficacy analyses only and so should 
not be included in safety laboratory outputs. 
Notable ranges (absolute) criteria of selected laboratory variables are defined in Section 1.8 
above. The laboratory values to be considered for notable ranges or relevant changes will 
include all post-baseline values up to the final scheduled visit, including values at 
unscheduled visits prior to the last visit. Only treatment emergent notable abnormalities will 
be considered (i.e. notably abnormal measurements which were not present at any pre-
baseline visit).  In addition to summary tables, a listing of patients with any treatment 
emergent notable laboratory results during the treatment period will be provided by treatment 
approach and patient number, along with their values at all visits, including repeated, 
unscheduled and follow-up laboratory values.  In the listing, all abnormal values outside of 
normal range and notable values will be flagged, e.g., L/H for a value being below/above 
normal range, LN/HN for a value being in notable low/high range.  
For each numerical laboratory parameter, the laboratory values will be reported in listings to 
the same precision as that for the unit in UNITCONV dataset. The precision to use in tables is 
as per Section 1.3.1. 
For continuous variables with a value <lower limit, these will be imputed as being half of the 
lower limit. For continuous variables with a value >upper limit, these will be imputed as being 
equal to the upper limit. 
2.3.2.1 Hematology 
The values of hematology laboratory test results at baseline and endpoints (End of Period 1, 
End of Period 2, End of Study) will be summarized, as well as the changes from baseline to 
each endpoint.  
The maximum/minimum value obtained during the treatment period, and the change from 
baseline to maximum/minimum value will be summarized by treatment approach for each 
hematology parameter. 


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The number and percentage of patients with abnormal hematology test results meeting notable 
criteria post-baseline, which were not present prior to randomization, will be tabulated. This 
summary will be repeated for abnormalities occurring in Period 1. 
2.3.2.2 Biochemistry 
The values of biochemistry laboratory test results at baseline and endpoints (End of Period 1, 
End of Period 2, End of Study) will be summarized, as well as the changes from baseline to 
each endpoint.   
The maximum/minimum value obtained during the treatment period, and the change from 
baseline to maximum/minimum value will be summarized by treatment approach for each 
hematology parameter. 
The number and percentage of patients with abnormal biochemistry test results meeting 
notable criteria post-baseline, which were not present prior to randomization, will be 
tabulated. This summary will be repeated for abnormalities occurring in Period 1. 
The number and percentage of patients with hepatic enzyme elevations (defined in Table 1-3), 
and persistent hepatic enzyme elevations will be presented, and the patients meeting any of 
the criteria will be listed. Note that for this study total bilirubin will be used for all criteria 
involving bilirubin. If at any visit total bilirubin has not been measured then the elevation will 
not be assessed for that visit (even if direct bilirubin has been measured). 
The liver panel A testing data for patients with hepatic enzyme elevations will be listed at 
patient level. Liver panel B testing data will not be considered as part of the RAP, but will be 
included in narratives if applicable. 
2.3.2.3 Urinalysis 
The baseline and endpoints (End of Period 1, End of Period 2, End of Study) values of 
categorical urinalysis test results will be summarized in number and percentage by treatment 
approach.  The baseline and endpoints (End of Period 1, End of Period 2, End of Study) 
values of continuous urinalysis test results will be summarized by treatment approach using 
descriptive statistics. 
2.3.3 Vital signs 
Baseline and endpoint values for blood pressure (sitting), and pulse (sitting) will be presented.  
Summary statistics for vital signs data will be presented by study visit. The summary by study 
visit will include only values obtained at the scheduled visit. 
The number of patients with notably abnormal vital signs 
 post-baseline will be 
presented. This summary will be repeated for abnormalities occurring in Period 1. The criteria 
for notable abnormalities (see Section 1.9) will be listed.   
2.3.4 Electrocardiograms (ECGs)  
Overall interpretation and details of abnormalities are collected at Screening and selected 
visits. 


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Change from the baseline ECG result to the endpoint (End of Period 1, End of Period 2, End 
of Study) ECG result will be summarized by a shift table. The number of patients with 
clinically significant abnormalities or not at baseline and at each endpoint ECG assessment 
will be tabulated. 
2.3.5 Hypoglycemic events 
Hypoglycemic events will be characterized by event profile, such as ability to self-treat, self 
monitoring of plasma glucose level, precipitating event, time from last meal, time from last 
dose, and time of the day.  
The incidence of hypoglycemic events (coded as hypoglycemia) and asymptomatic low blood 
glucose (coded as Blood Glucose Decreased), entered into the Glycemia study diary eCRF 
and meeting the event criteria defined in Table 1-1 (Section 1.7), are included in all of the AE 
summaries in Section 2.3.1.  
In addition, patients reporting at least one hypoglycemic event, the subgroup of reporting 1 
event, 2 events, and >2 events, patients discontinued due to hypoglycemic events, patients 
reporting grade 2 events, and patients reporting suspected grade 2 events will be summarized 
by numbers and percentages for each treatment approach overall (including study periods 1, 2 
and 3) and by study period. The summary will be repeated by age group (as defined in section 
2.1.5).   
The hypoglycemic events will further be summarized by event profile as follows: 
• plasma glucose level ≤2.2, >2.2–≤2.8, >2.8–<3.1 and ≥3.1 mmol/L, or Not recorded; note 
that if a patient is unable to initiate self-treatment and plasma glucose is not recorded, this 
is graded as a suspected grade 2 event) 
• grade (grade 1, grade 2 or suspected grade 2) 
• symptom (in preferred term) 
• precipitating event (None, Missed/delayed meal, Strenuous exercise, Alcohol 
consumption, Other or Not recorded) 
• severity (Mild, Moderate, Severe) 
• relationship to study drug (Not suspected, Suspected) 
• action taken (Study drug dosage adjusted / temporarily discontinued, Study drug 
permanently discontinued, Concomitant medication taken, Non-drug therapy given 
(includes oral carbohydrates), Hospitalization / prolonged hospitalization, no action taken) 
• time interval between last meal and event (0–4, >4–6, >6 hours, not recorded), 
• time interval between last dose and event (0–4, >4–6, >6 hours, not recorded), 
• 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),  
Asymptotic blood glucose events will be similarly summarized by event profile and the 
number of patients with at least one asymptomatic low blood glucose measurement will also 
be summarized.  
A listing of hypoglycemic events and asymptomatic low blood glucose events will be 
presented by treatment approach and patient number. 


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Note: As defined in Table 1-1, for patients who are able to initiate self-treatment (where 
necessary) symptoms suggestive of hypoglycemia which are not confirmed by glucose 
measurements will be recorded in the Glycemia diary eCRF.  Since these are not confirmed 
hypoglycemia events, these symptoms will not be reported in the hypoglycemia summary 
tables and listings, these symptoms will appear only in the AE tables and listings. For patients 
unable to initiate self-treatment (where necessary) symptoms suggestive of hypoglycemia that 
were not confirmed by glucose measurements will be classed as suspected hypoglycemic 
events and will therefore be reported in the hypoglycemia summary tables and listings, as well 
as the AE listings.   
Note: Self-monitoring glucose can be recorded in the database as either plasma or whole 
blood. However, only plasma glucose will be reported in the tables and listings. Thus blood 
glucose values will be converted into plasma glucose equivalent, which can be done by 
multiplying a conversion factor of 1.12, i.e., plasma glucose = blood glucose ×1.12. 
The incidence of hypoglycemia and severe hypoglycemia during Period 1 will be compared 
for the SAF using a chi-square test between the two treatment approaches for all patients 
provided that the incidence such these events is more than 5 in each treatment approach. 


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2.5 
Interim analyses 
No interim analyses are planned for this study.  


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2.6 
Other topics  
No other topics will be studied.  


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2.7 
Determination of sample size 
A total sample size of 1000 randomized patients per treatment arm (in 1:1 allocation ratio to 
vildagliptin + metformin and metformin monotherapy) is planned. 
The sample size calculation assumed that all randomized patients are to be followed up for 5 
years unless patients dropped out from the study for various reasons (lack of efficacy, AEs, 
abnormal labs, lost to follow-up etc.). Including the updated information of  the yearly 
dropout rate being approximately 4% (based on observed discontinuation rate for this study at 
the time of completion of the trial). 
The existing vildagliptin study data suggest that approximately 10% of vildagliptin patients 
will have an HbA1c >7.0% after the first 3 months of the study (initial response phase), since 
those patients who are randomized with an HbA1c measurement above the failure threshold 
(7.0%) may never have an HbA1c measurement below the required threshold during the study 
and will therefore be counted as failures during the first 13 weeks. A similar proportion is 
assumed for the comparator arm. Hence it is expected that the difference in failure rate is 
likely to be small early in the study, but will diverge as the study progresses. The power 
calculations have been adjusted to take this assumption into account using statistical 
simulations. 
The simulations showed that assuming an annual initial treatment failure rate of 7.1% in the 
metformin monotherapy arm (estimated based on ADOPT data), incorporating a 10% initial 
failure rate after 13 weeks in each treatment arm (due to some patients with baseline HbA1c 
≥7.0%), 1000 patients per treatment arm would be sufficient to detect a hazard-ratio of 0.75 
between vildagliptin + metformin and metformin alone (corresponding to a risk reduction rate 
of 25% in vildagliptin + metformin group versus metformin alone) with approximate 75% 
power and a 1-sided significance level of 0.025 (corresponding to a 2-sided test at 0.05). 
 


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2.8 
Changes in the conduct of the study or planned analyses 
The following change in the analysis is proposed in protocol amendment 3 (4th Oct 2016) 
which defers with the analysis proposed in this document. These proposed changes have come 
about through development of the RAP modules and discussions around the analyses. 
• Treatment start date to be defined as the earliest vildagliptin/placebo date, as recorded on 
the DAR page of the eCRF (i.e. do not use visit 3 date). Consistently use this definition for 
day 1 and durations related to day 1.  
• ‘+1’ should be included in duration of exposure calculation when last study drug date is 
available. 
• ‘+1’ should not be included in duration of exposure calculation when last study drug date 
is missing/incomplete. 
• Further detail added to better define the analysis sets. 
• Geographic region to be included as a classification variable in the analysis of time to 
initial treatment failure (and all similar analyses).  
• In the analysis of rate of loss in glycemic control over time, time will be included as a 
fixed effect and as a random effect. 
• In the analysis of time to insulin initiation, patients who complete the study in Period 1 or 
Period 2 will be censored at their last study visit. 
• OGIS formula revised as per 23135 study. 
• Due to the large number of patients (patients will be recruited until we have the required 
amount) and the robustness of analyses methods we can assume we will have sufficient 
patients data for the beta-cell function, insulin sensitivity, AUC of ISR/G and OGIS 
analyses. 
 
 
 
 
 
• The definition of initial treatment failure is revised to be the date of the second of the two 
consecutive measurement of HbA1c value >=7%. The rationale of this change is that this 
will be consistent with the Period 1 end date definition. The decision of this definition 
update is documented in the RAP II meeting minutes in RAP Module 1. 
• Main analysis approach includes only one primary endpoint in this SAP. As the 
probability and risk of time to initial loss of glycaemic control as primary efficacy variable 
is presented as a hazard ratio and failure rate over time, the statistical approach and power 
calculations (including the impact of the known retention) was updated accordingly while 
moving the assessment of the rate of loss of glycaemic control by an annualised slope of 
mean HbA1c over time from week 26 to the end of period 1 to be a key secondary 
analysis instead. 


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• Baseline characteristics driving the pre-planned sub-analyses to a previously unpredictable 
direction, is clearly documented in the SAP to ensure transparency and external validity of 
the study 
 
 


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References 
ADA-EASD Consensus Statement (2009) Medical management of hyperglycaemia in type 2 
diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. 
Diabetologia; 52:17-30. 
Hochberg and Tamhane (1987) Multiple Comparison Procedures. Wiley Series. 
Mari A, Ludvik B, Pacini G, et al (2001) A model-based method for assessing 
insulinsensitivity from the oral glucose tolerance test. Diabetes Care; 24: 539-548. 
Rigalleau V, Lasseur C, Perlemoine C, et al (2005) Estimation of glomerular filtration rate in 
diabetic subjects. Cockcroft formula or modification of diet in renal disease study equation?  
Diabetes Care 28:838-843.   
 
 
Scherbaum W, et al. (2008) Evidence that vildagliptin attenuates deterioration of glycaemic 
control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. 
Diabetes Obes Metab; 10:1114–1124. 
 
SAS/STAT User’s Guide, version 9.2, SAS Institute, Inc., Cary, North Carolina. 
 


Clinical Development 
LAF237/Galvus 
Clinical Study Protocol CLAF237A23156 / NCT01528254
A 5-year study to compare the durability of glycemic control of a 
combination regimen with vildagliptin & metformin versus standard-of-
care monotherapy with metformin, initiated in treatment-naïve patients 
with type 2 diabetes mellitus 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
, Novartis Trial Statistician 
, 
 Trial Statistician 
Document type: 
RAP Documentation 
Document status: 
Final Addendum 1 
Release date: 
17th Dec 2019 
Number of pages: 
41 
Property of Novartis 
Confidential 


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May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
2.2 
28NOV2018 
Section 2.1.5 - Background and demographic characteristics – 
baseline HbA1c categories were updated to be <7% and >=7%. 
  
  
2.2.1 - Definition of geographic region for efficacy analyses – 
geographic region categories were added as per Novartis decision. 
2.2.2.3 – Rate of loss in glycemic control over time – time (of HbA1c 
measurements, in years) added as random effect to the analysis 
model. 
  
  
2.3.1 - Overall experience of adverse events (AEs) – statement 
added that AEs will be analyzed by study period as well in addition 
to overall (including study events from study period 1, 2 and 3) in line 
with DMC analyses. 
Section 2.3.1.1 – statement added that AEs will be analyzed by 
study period for all subsection of AEs leading to discontinuation. 
  
  
Section 2.3.5 - Hypoglycemic events – statement added that events 
will be analyzed by study period as well in addition to overall in line 
with DMC analyses.  Added new category to plasma glucose level 
list. 
Section 2.8 – Added statement that time will be used as both a fixed 
and random effect in analyses of rate of loss of glycemic control. 
  
  
Section 2.8 - Changes in the conduct of the study or planned 
analyses – it was added that the definition of initial treatment failure 
is changed to regard the date of the second of the two consecutive 
measurements of HbA1c values >=7%. 
 
 
 
3 
06May2019 
Section 1.4 Changed duration derivation from weeks to Months. 
Section 1.6 Added the list of AEs of special interest 
Section 2.1.2 Added information of efficacy parameters to be 
considered for deviation code N02 and N03. 
Section 2.1.5 Removed definition of baseline HbA1c and FPG as it 
was redundant. Baseline is already defined in section 1.1 
Section 2.1.5 redefined age classification based on tertiles 
Section 2.1.6 redefined exposure categories in months instead of 
weeks.  
Section 2.2.1 Added table mentioning grouping for geographical 
regions 
Section 2.2.2 Removed loss of glycemic control as primary endpoint; 
provided additional detail to used confirmation visit for time to initial 
treatment failure; Since we have only one primary endpoint, 
removed multiple testing methods section 
Section 2.2.2.4 Added time to first treatment failure as supportive 
analysis; modified age categories for subgroup analysis; added 
smoking status, region and beta cell functional and insulin resistance 
as subgroups of interest; removed ethnicity 
Section 2.2.3 Added rate of glycemic control over time as secondary 
endpoint; 
 


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Version 
Date 
 
analyzed and it is outside the scope of the SAP 
Section 2.2.3.3 Added the analysis of rate of glycemic control over 
time in this section 
Section 2.3.5 Added clarification on using chi square test to compare 
events only if we have sufficient observed events. 
 
 
Section 2.7 Updated power calculations based on single primary 
endpoint and updated yearly dropout rate. 
 
 
 
Addendum 1 
17Dec2019 
Section 2.2.2.4 Time to second treatment failure endpoint is added 
as a post-hoc analysis 
Section 2.2.2.4 Subgroup analysis for the primary endpoint is added 
as a post-hoc analysis. 
Section 2.7 Updated sample size section based on the protocol 
amendment 4 
 


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Table of contents 
Clinical Development ................................................................................................................. 1 
List of abbreviations ................................................................................................................... 6 
1 
Definitions and general strategy .......................................................................................... 7 
1.1 
Baseline definitions ................................................................................................. 7 
1.2 
Last On-Treatment Observation (Endpoint Observation) ....................................... 7 
1.3 
General data handling strategy ................................................................................ 8 
1.3.1 
Output data precision .............................................................................. 8 
1.3.2 
Efficacy Assessment Window / Week X Measurement ......................... 8 
1.3.3 
Laboratory visit windows ........................................................................ 9 
1.3.4 
Multiple laboratory measurements within same day ............................ 10 
1.4 
Duration of exposure to study medication ............................................................. 10 
1.5 
Treatment-Emergent Adverse Events .................................................................... 10 
1.6 
Other clinically significant events (predefined AE risks) ...................................... 10 
1.7 
Hypoglycemic Event Classifications ..................................................................... 11 
1.8 
Laboratory abnormalities ....................................................................................... 12 
1.8.1 
Clinically Significant Laboratory Abnormalities .................................. 12 
1.8.2 
Hepatic enzyme and CPK elevations .................................................... 12 
1.9 
Notable Vital Sign Abnormalities ......................................................................... 13 
1.10 
GFR formula and definition ................................................................................... 14 
2 
Statistical and analytical plans ........................................................................................... 15 
2.1 
Subjects and treatments ......................................................................................... 15 
2.1.1 
Analysis sets .......................................................................................... 15 
2.1.2 
Protocol Deviations and other criteria leading to exclusion of 
patients in analysis sets ......................................................................... 15 
2.1.3 
Patient Disposition ................................................................................ 16 
2.1.4 
Groupings for analysis .......................................................................... 17 
2.1.5 
Background and demographic characteristics ....................................... 17 
2.1.6 
Study medication ................................................................................... 18 
2.1.7 
Concomitant medication ....................................................................... 19 
2.2 
Efficacy evaluation ................................................................................................ 19 
2.2.1 
Definition of geographic region for efficacy analyses .......................... 19 
2.2.2 
Primary efficacy variables ..................................................................... 20 
2.2.3 
Secondary efficacy variables ................................................................. 22 
2.3 
Safety evaluation ................................................................................................... 29 
2.3.1 
Overall experience of adverse events (AEs) ......................................... 30 


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2.3.2 
Laboratory values .................................................................................. 31 
2.3.3 
Vital signs.............................................................................................. 33 
2.3.4 
Electrocardiograms (ECGs) .................................................................. 33 
2.3.5 
Hypoglycemic events ............................................................................ 33 
 
 34 
 
 35 
 
 35 
 
 35 
 
 36 
2.5 
Interim analyses ..................................................................................................... 37 
2.6 
Other topics ............................................................................................................ 37 
2.7 
Determination of sample size ................................................................................ 38 
2.8 
Changes in the conduct of the study or planned analyses ..................................... 39 
References ................................................................................................................................ 41 


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List of abbreviations   
AE  
adverse event  
ALT  
alanine aminotransferase  
ANCOVA  
analysis of covariance  
AST  
aspartate aminotransferase  
ATC  
anatomical therapeutic chemical classification system  
AUC 
area under the curve 
bid  
bis in die (twice a day)  
BMI  
body mass index  
BUN 
Blood urea nitrogen 
CPK  
phosphocreatine kinase  
CSR 
clinical study report 
ECG  
electrocardiogram  
eCRF 
electronic case report/record form 
EOS 
end of study 
FAS  
full analysis set  
FPG  
fasting plasma glucose  
GFR  
glomerular filtration rate  
HbA1c  
glycosylated hemoglobin  
 
 
 
 
 
 
ISR 
insulin secretion rate 
ISR/G 
insulin secretion rate/glucose 
LOCF  
last observation carried forward  
MDRD  
modification of diet in renal disease  
MedDRA  
medical dictionary for regulatory activities  
OGIS 
oral glucose insulin sensitivity 
PD 
protocol deviation  
PK 
pharmacokinetics 
PPS  
per protocol set 
RAN  
randomized set  
SAE  
serious adverse event  
SAF  
safety set  
SCR  
screened-only set  
SI 
standard international 
SMQ 
standardized MedDRA queries 
SYE 
subject year exposure 
T2DM  
type-2 diabetes mellitus  
ULN  
upper limit of normal  
VAS 
visual analogue scale 
WBC 
white blood cell 
WHO  
world health organization   
 


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1 
Definitions and general strategy 
1.1 
Baseline definitions 
Unless specified otherwise, the baseline will be the measurement obtained on Day 1, or the 
closest sample obtained at an earlier visit (scheduled or unscheduled) to Day 1, if the Day 1 
measurement is missing.   
For derived variables 
 the baseline will be derived using measurements 
obtained on Day 1, or the closest samples obtained at an earlier visit (scheduled or 
unscheduled) to Day 1, if the Day 1 measurements are missing.  Details of imputation 
methods to use if one or more of the individual measurements used in the derivation is 
missing, are detailed in section 2.2.3.1. 
Day 1 will be defined as the first day of study treatment (the earliest vildagliptin/placebo date 
as recorded on the vildagliptin/placebo dosage administration page of the eCRF). 
Vital Signs 
For blood pressure and pulse, baseline will be defined as the average of all pre-treatment 
visits, regardless of being scheduled or unscheduled. For 
, baseline will be 
defined as the day 1 measurement if non-missing, or last non-missing value coming from 
either an earlier scheduled or unscheduled visit. 
Routine ECG Measurements 
ECGs are analyzed and interpreted locally for this study, hence only qualitative ECG 
measurements are recorded. ECGs are scheduled to be measured at screening (and not Day 1). 
Baseline is therefore defined as the measurement obtained at screening, unless there is a later, 
unscheduled measurement on or before Day 1 (in which case the latest of these will be used).   
 
 
 
1.2 
Last On-Treatment Observation (Endpoint Observation) 
For specified efficacy variables, clinical laboratory variables, vital signs and ECG findings, 
the measurement obtained at the last post-baseline study visit will be considered the last on-
treatment (endpoint) observation, regardless of whether it is obtained at a scheduled or 
unscheduled visit, up to the last scheduled visit.   
For specified efficacy variables, clinical laboratory variables and ECG findings, end of Period 
1 and end of Period 2 endpoints will also be of interest. The end of Period 1 endpoint is 
defined as the final available post-randomization assessment obtained at any visit (scheduled 
or unscheduled), prior to or at initial treatment failure, up to the last scheduled study visit. The 
end of Period 2 endpoint is defined as the final available post-randomization assessment 


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obtained at any visit (scheduled or unscheduled), prior to or at the initiation of insulin therapy, 
up to the last scheduled study visit. 
1.3 
General data handling strategy  
1.3.1 Output data precision 
Decimal places to be used in displays of demographic, background and duration of exposure 
variables will be as follows: 
o 3 decimal places (p-values; if p-value is less than 0.001, display <0.001), 
o 2 decimal places (standard errors and standard deviations), 
o 1 decimal place (means, medians), 
o 1 decimal place (minimums, maximums), 
o 1 decimal place (percentages), 
o if percentage = 100, no decimal is required. 
Decimal places for efficacy and other safety summary tables and listings will be as follows: 
o 3 decimal places (p-values; if p-value is less than 0.001, display <0.001), 
o data precision + 2 decimal places (standard errors and standard deviations), 
o data precision + 1 decimal place (means, medians), 
o same as data precision (minimums, maximums), 
o 1 decimal place (percentages), 
o if percentage = 100, no decimal is required. 
Decimal places for the Hematology, Biochemistry and Urinalysis tables will be as follows: 
o 2 decimal places for standard errors and standard deviations (Hematology and 
Biochemistry), 3 decimal places for standard errors and standard deviations (Urinalysis), 
o 2 decimal places for means, medians (Hematology and Biochemistry), 3 decimal places 
for means, medians (Urinalysis), 
o 2 decimal places for minimums, maximums (Hematology and Biochemistry), 3 decimal 
places for minimums, maximums (Urinalysis).  
For vital signs tables of change from baseline, 2 decimal places for mean, median, standard 
deviation, minimum and maximum will be used. 
In outputs containing estimates and p-values for inferential purposes (e.g. ANCOVA), means, 
standard errors, standard deviations and confidence intervals will be output to 2 decimal 
places for all parameters. P-values will be output to 3 decimal places; if a p-value is less than 
0.001, it will be displayed as <0.001. 
1.3.2 Efficacy Assessment Window / Week X Measurement 
For all efficacy variables, the measurements obtained at the scheduled visit corresponding to 
X weeks (e.g. 13, 26, ..., 260 weeks) of treatment as defined in the assessment schedule table 
[Tables 6-1 and 6-2 in the protocol] will be considered as Week X measurement (e.g. Week 
13, 26, ... , 260 measurements) if -28 days < (visit date - Week X date) < 28 days. The Week 
X date is the theoretical date when the visit should have occurred (e.g. if the scheduled visit is 


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visit 5, corresponding to week 26, then the Week 26 date is the treatment start date + 26 
weeks).  
Discontinuation visits will be assigned to the closest unallocated visit. For example, if a 
patient discontinues at visit 4, this discontinuation visit will be re-assigned from visit 777 to 
visit 4 (and not visit 23). This re-assigned visit value will be stored in a separate variable, i.e. 
the original value will not be overwritten. 
Efficacy data obtained at visits outside the above defined window or at unscheduled visits will 
be excluded from the analyses and tabulation of summary statistics by visit.  However, they 
will be displayed in the patient data listings. If the last on-treatment observations of the 
efficacy variables are obtained at a visit outside the above defined windows or at an 
unscheduled visit, they will still be used for the FAS analysis based on the last observation 
carried forward (LOCF) imputed endpoint (see section 1.2).  
Note that prior to implementation of these windows, the remapping of the efficacy laboratory 
parameters will be implemented. 
1.3.3 Laboratory visit windows 
Safety lab data 
The following will be implemented for non-efficacy laboratory data: 
o Safety lab data will be summarized and listed as reported on LRS panel, no additional visit 
windows will be used.  
o Laboratory “Visit dates” from the VIS panel on eCRF will not be listed, instead laboratory 
listings will present the date and day of the sample collection (obtained directly from 
LRS).  
Efficacy laboratory data 
The idea of the visit window is to ensure that as many scheduled visits as possible are 
included in summaries of efficacy parameters over time. 
For all efficacy laboratory summaries over time (tables and figures), a "re-defined scheduled 
visit" will be created as follows: 
o If scheduled visit laboratory sample already exists on database then that sample remains as 
the "re-defined scheduled visit".     
o If scheduled visit laboratory sample is missing, then search for unscheduled sample 
closest to actual scheduled visit date (theoretical date visit should have occurred based on 
treatment start date).  If unscheduled sample closest to actual scheduled visit date is within 
7 days of actual scheduled date then map this unscheduled visit to the scheduled visit 
number in the "re-defined scheduled visit".  If there is a tie between unscheduled samples 
before and after the actual visit, take the later measurement.  Note that the randomization 
visit laboratory measurement will not consider measurements from unscheduled visits 
taken after Day 1. 
All efficacy outputs will include the following footnote:  "In the case of a missing scheduled 
visit sample, the closest unscheduled visit within 7 days of scheduled visit is used."  


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1.3.4 Multiple laboratory measurements within same day 
It is possible that 2 sets of laboratory measurements may be taken with the sample date.  All 
such measurements will be included in the summaries and listings of notably abnormal or 
percent change from baseline summaries.  For the analysis of “persistent” events (where 
consecutive measurements are checked) or for the analysis of parameter over time in the 
following key safety parameters, only the highest within-day value will be included: 
o ALT 
o AST 
o Bilirubin (direct and/or total) 
o CPK 
Specifically, in the case of duplicate measurements with same sample date, only the 
maximum value will be selected.  All samples will be listed along with sample date. 
1.4 
Duration of exposure to study medication 
Treatment start date is defined as the earliest vildagliptin/placebo date as recorded on the 
vildagliptin/placebo dosage administration page of the eCRF).  
Overall duration (in months) on study medication will be computed as follows: 
If a complete last study drug date is available: 
(last study drug date – treatment start date + 1) / 30.4375,  
or if the last study drug date is missing or incomplete: 
(last visit date – treatment start date) / 30.4375, 
or if a patient received no dose of randomized double-blind medication: 
          
overall duration is set to 0. 
The study drug end date is defined as the last treatment date. The last treatment date in the 
study completion panel will be used for this study drug end date. 
1.5 
Treatment-Emergent Adverse Events 
A treatment-emerging adverse event is defined as  
o an undesirable sign, symptom, or medical condition with onset after the first dose of study 
medication or, 
o an increase in severity of an event that is present during the pre-treatment period,   
o all events included on the database will be included in AE summary tables/listings. 
1.6 
Other clinically significant events (predefined AE risks) 
For this project, there are some predefined adverse event risks that are considered of special 
interest defined as below: 
Important identified risks 
• 
Transaminase elevations and Drug-induced liver injury (DILI) 
• 
Angioedema 


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• 
Acute pancreatitis 
• 
Skin lesions (pemphigoids) 
• 
Hypoglycemia  
• 
Lactic acidosis (metformin) 
Important potential risks 
• 
Serious infections 
• 
Cardiac events in CHF (NYHA Functional Class III) patients (adjudication) 
• 
Muscle events/ myopathy/rhabdomyolysis 
• 
Neuropsychiatric events 
• 
Breast cancer 
•      Pancreatic cancer 
1.7 
Hypoglycemic Event Classifications 
Patients were educated to record hypoglycemic symptoms and treatment in a study diary. 
Study diary data were then entered in the Glycemia Study Diary or Adverse Event eCRF, 
respectively according to the following criteria. The Glycemia study diaries were reviewed by 
the study staff at each visit and assessed according to Table 1-1. Note that if glucose is 
recorded as whole blood on the eCRF, rather than plasma, then it will be converted to a 
plasma value in the derived dataset, using a conversion factor of 1.12 (i.e. plasma glucose = 
blood glucose x 1.12). 
Table 1-1 
Recording and classification of glycemia study diary data 
Severity  
Symptoms  
Plasma glucose 
Action taken  
Classification  
Patient able to 
initiate self-
treatment if 
necessary 
Symptoms 
suggestive of 
hypoglycemia 
< 3.1mmol/L 
(56mg/dL) 
Enter in 
Glycemia Study 
Diary eCRF 
Hypoglycemic 
event, grade 1 
Symptoms 
suggestive of 
hypoglycemia 
≥ 
3.1mmol/L(56mg
/dL) 
Enter in 
Glycemia Study 
Diary eCRF 
Adverse Event  
Symptoms 
suggestive of 
hypoglycemia 
Not taken  
Enter in 
Glycemia Study 
Diary eCRF 
Adverse Event  
Asymptomatic  
< 
3.1mmol/L(56mg
/dL) 
Enter in 
Glycemia Study 
Diary eCRF 
Asymptomatic low 
blood glucose 
Patient is unable 
to initiate self-
treatment and 
requires 
assistance of 
another person 
or hospitalization 
Symptoms 
suggestive of 
hypoglycemia  
< 
3.1mmol/L(56mg
/dL) 
Enter in 
Glycemia Study 
Diary eCRF & 
report as SAE 
Hypoglycemic 
event, grade 2 & 
SAE 
Symptoms 
suggestive of 
hypoglycemia  
Not taken  
Enter in 
Glycemia Study 
Diary eCRF & 
report as SAE 
Suspected 
hypoglycemic 
event, grade 2 & 
SAE 


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1.8 
Laboratory abnormalities 
Laboratory data will be presented in SI units only. 
1.8.1 
Clinically Significant Laboratory Abnormalities  
Notable ranges for selected laboratory parameters of interest as listed in Table 1-2 are the 
basis for the central laboratory to generate notable reports to alert the investigators.  The 
notable ranges will form the basis to evaluate the incidence of clinically significant laboratory 
abnormalities.   
Table 1-2 
Notable ranges (absolute) criteria of laboratory variables of specific 
interest 
 
 
Notable ranges 
 
Lab test description 
 
SI Unit 
Low 
High 
Hematology 
Total leucocytes (WBC) 
10E9/L 
≤ 2.8  
 
Total leucocytes (WBC) 
10E9/L 
 
≥ 16.0 
Platelet count (direct) 
10E9/L 
≤ 75 
 
Platelet count (direct) 
10E9/L 
 
≥ 700 
Hemoglobin 
g/L  
≤115 (m) 
≤ 95 (f) 
− 
Hematocrit 
1  
<0.37 (m) 
≤ 0.32 (f) 
− 
Eosinophils  
% 
− 
≥ 14 
Biochemistry 
Sodium 
mmol/L 
≤ 125  
 
Sodium 
mmol/L 
 
≥ 160 
Potassium 
mmol/L 
≤ 3  
 
Potassium 
mmol/L 
 
≥ 6 
Blood urea nitrogen (BUN) 
mmol/L 
− 
≥ 14.28 
Creatinine 
µmol/L 
− 
≥ 176.8 
1.8.2 
Hepatic enzyme and CPK elevations 
In addition to the notable ranges, the incidence of treatment emergent hepatic enzyme 
elevations is of interest. These are described in Table 1-3.  
Treatment emergent is defined as not meeting the criterion at any pre-baseline visit, but then 
meeting the criterion at a post-baseline visit. Consequently a patient may be classified 
treatment emergent ≥5ULN even though they were not classified as treatment emergent 
≥3ULN  (if had a result ≥3ULN at a pre-baseline visit). 
Table 1-3 
Treatment emergent hepatic enzyme and CPK elevations of interest 
ALT or AST ≥ 3*ULN  


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ALT or AST ≥ 5*ULN 
ALT or AST ≥ 8*ULN 
ALT or AST ≥ 10*ULN 
ALT or AST ≥ 20*ULN 
ALT or AST ≥ 3*ULN and Bilirubin^ ≥ 1.5*ULN 
ALT or AST ≥ 3*ULN and Bilirubin^ ≥ 2*ULN 
Bilirubin^  ≥ 2*ULN                 
Bilirubin^  ≥ 3*ULN                 
CPK ≥ 5*ULN 
CPK ≥ 10*ULN 
ALT ≥ 3*ULN 
ALT ≥ 5*ULN 
ALT ≥ 8 x ULN 
ALT ≥ 10*ULN 
ALT ≥ 20*ULN 
ALT ≥ 3*ULN and Bilirubin^ ≥ 1.5*ULN 
ALT ≥ 3*ULN and Bilirubin^ ≥ 2*ULN 
AST ≥ 3*ULN 
AST ≥ 5*ULN 
AST ≥ 8 x ULN 
AST ≥ 10*ULN 
AST ≥ 20*ULN 
Alkaline Phosphatase ≥ 1.5*ULN 
^ If only direct bilirubin is measured then direct bilirubin will be used for all criteria involving bilirubin. If 
both total and direct bilirubin are measured (i.e. are in the laboratory specifications) throughout a 
study, total bilirubin will be preferred.  The clinical study team has agreed that total bilirubin should be 
used for this study. Note that if at any visit total bilirubin has not been measured then the elevation will 
not be assessed for that visit (even if direct bilirubin has been measured). 
In addition to the overall summary of elevations defined above, the same criteria will also be 
presented, restricted to “persistent elevations” only.  Persistent elevations are those which 
meet the criterion at consecutive on-treatment measurements or at last on-treatment visit (this 
includes assessments within one day of the last dose of study treatment).  The purpose of the 
persistent definition is to remove transient elevations from the summary (i.e. those elevations 
which appeared at one visit but normalized at the next visit). 
1.9 
Notable Vital Sign Abnormalities 
Notable vital sign abnormalities 
 are defined in Table 1-4.  


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Table 1-4 
Notable vital sign abnormalities  
 
 
Notable abnormalities 
Vital signs 
 
Low 
High 
Pulse (beats/min) 
 
either ≤50 + decrease ≥30*  
or < 40  
either ≥120 + increase ≥25*  
or >130 
Blood pressure (mmHg) 
Systolic 
either ≤90 + decrease ≥30*  
or < 75  
either ≥180 + increase ≥30*  
or > 200 
 
Diastolic 
either ≤50 + decrease ≥20*  
or < 40  
either ≥105 + increase ≥20*  
or > 115 
 
 
 
 
 
* Refers to post-baseline value as compared to baseline value 
The notable abnormality of ‘> 120 + increase > 25 or > 130’ will be interpreted as that the 
value in the treatment period is > 120 and the increase from baseline is >25, or the value in the 
treatment period is > 130.  
1.10 
GFR formula and definition  
The following formula is used to estimate Glomerular Filtration Rate (GFR) modification of 
diet in renal disease (MDRD) (Rigalleau 2005): 
GFRMDRD (mL/min) × (1.73/m2) = 
 
 
175 × (serum creatinine {mg/dL}) -1.154 
 
 
× (age {years}) -0.203 
 
 
× 0.742 (if female) 
 
 
× 1.210 (if race is Black) 
GFR will be available in the raw laboratory data (and used to assess inclusion/exclusion 
criteria) but will be re-derived within the derived datasets using this RAP-specified formula. 
This will ensure consistency with other studies within the program. 
Baseline GFR (MDRD) is a derived variable calculated using the baseline serum creatinine, 
 & age value, i.e. the value obtained Day 1, or the sample obtained at an earlier 
visit (scheduled or unscheduled) which is closest to Day 1, if the Day 1 measurement is 
missing.  Hepatic function is categorized as follows: 
   Normal: 
GFR (MDRD) >80 
   Mild: 
GFR (MDRD) ≥50 - GFR (MDRD) ≤80 
   Moderate: 
GFR (MDRD) ≥30 - GFR (MDRD) <50 
   Severe: 
GFR (MDRD) <30 


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2 
Statistical and analytical plans 
Data will be analyzed 
 according to the data analysis section 9 of the study protocol 
which is available in Appendix 16.1.1 of the CSR.  Important information is given in the 
following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR. 
2.1 
Subjects and treatments 
2.1.1 Analysis sets 
Screened-only set (SCR): The SCR consists of all patients who were screen failed after the 
first visit or who entered the run-in phase but were not randomized. Except for the listing of 
individual patients in this SCR with the reasons for not being randomized, and the tabulation 
of patients in this SCR by discontinuation reason, no other analysis will be performed on this 
analysis set. 
Randomized set (RAN): The RAN consists of all randomized patients.  
Full analysis set (FAS): The FAS consists of all randomized patients who receive at least one 
dose of randomized study medication (vildagliptin or placebo) and have at least one post-
randomization assessment of any efficacy parameter. Following the intent-to-treat principle, 
patients will be analyzed according to the treatment approach they are assigned to at 
randomization. 
Safety set (SAF). The SAF consists of all patients who receive at least one dose of 
randomized study medication (vildagliptin or placebo). Patients will be analyzed according to 
the treatment approach received. If a patient receives both vildagliptin and placebo in Period 
1, then the patient will be included in the vildagliptin group. Note that the SAF allows the 
inclusion of non-randomized patients who received the study drug in error. 
Per Protocol set (PPS): The PPS is a subset of FAS and consists of all randomized patients 
who receive at least one dose of randomized study medication (vildagliptin or placebo), have 
at least one post-randomization assessment of any efficacy parameter in Period 1, do not 
discontinue the study prior to Week 26, and have no major protocol deviations occurring 
during Period 1.  
2.1.2 Protocol Deviations and other criteria leading to exclusion of patients in 
analysis sets 
Patients will be excluded from analysis based on the protocol deviations (PDs) in VAP 
Module 3 and other criteria described in Table 2-1. The PDs described in VAP Module 3 will 
be identified manually by field monitors/CTH and/or via PD programming, and will be 
provided in the VIOPTO source dataset, whilst those in (Table 2-1) will be programmed by 
Biostatistics using source data, and stored in the derived dataset NOVIOPTO. The severity 
codes assigned to each deviation as described in VAP Module 3 and Table 2-1 will be used to 
classify patients as described in Table 2-2. Note that other protocol deviations will also be 
identified. However, patients will not be excluded from analysis based on these other 
deviations (with severity code 49) including violations of entry criteria on prior use of anti-


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diabetic agents and BMI range. The subject classification as specified in Table 2-2, will be 
defined based on severity codes prior to un-blinding the database with respect to treatment.    
Table 2-1 
Other criteria leading to exclusion of patients in analysis sets 
Description of Deviation 
Deviation 
code 
Severity 
code 
Inclusion/ 
Exclusion in 
Analyses 
No dose of randomized, double-blind medication 
(vildagliptin or placebo) taken during Period 1 
N01 
8 
Excluded from 
all efficacy and 
safety 
analyses 
No post-randomization efficacy assessment during 
the treatment period (Periods 1, 2 or 3) 
N02 
0 
Excluded from 
efficacy 
analyses 
No post-randomization efficacy assessment during 
Period 1 
N03 
1 
Excluded from 
PPS analyses 
Patient discontinued from the study prior to Week 
26 
N04 
1 
Excluded from 
PPS analyses 
Subjects with no post-randomization efficacy assessment of Hba1c, fasting insulin, fasting 
glucose, fasting C-peptide and meal-test parameters, will be excluded from efficacy analyses 
(Deviation code N02). Subjects with no post-randomization efficacy assessment of Hba1c, 
will be excluded from PPS analyses (Deviation code N03). 
Table 2-2 
Subject classification 
Deviation Severity Codes 
Analysis set 
 0 
 1 
 8                   49 
Randomized Set (RAN) 
 Yes 
 Yes  
 Yes  
Yes 
Full Analysis Set (FAS) 
 No 
 Yes 
 No 
Yes 
Safety Set (SAF) 
 Yes 
 Yes 
 No 
Yes 
Per Protocol Set (PPS) 
 No 
 No 
 No 
Yes 
Note: yes/no means whether patients with PDs or non-PD criteria of a specific code are included (yes) 
or excluded (no) from an analysis set. 
The number and percentage of patients in the RAN with protocol deviations and other criteria 
leading to exclusion of patients from analysis sets will be tabulated by treatment approach. 
Protocol deviations that do not lead to exclusion from analysis populations will be further 
summarized for the RAN by treatment approach. Summaries will be repeated by Period. 
2.1.3 Patient Disposition 
The number and percentage of randomized patients (RAN) who completed the study and who 
discontinued will be tabulated by treatment approach. Discontinuation will be further broken 
down by reason in the tabulation. Summaries will be repeated by Period, including 
information about the number of patients continuing into the next Period.  
Completion information will be listed for the RAN. 


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Patients who were screened for the trial and entered the run-in phase but were not randomized 
(SCR) will be tabulated and listed with reasons for not being randomized. These summaries 
will include both screen failures and run-in failures (i.e. patients who discontinue within the 
screening period and patients who discontinue within the run-in period). Note that the patients 
will be presented together and not separated out into separate groups for screen failures and 
run-in failures. 
2.1.4 Groupings for analysis 
The number and percentage of patients in each analysis set will be summarized by treatment 
approach. The number and percentage of patients included in the meal test, 
 subsets will also be summarized by treatment approach. Meal 
test 
 count data will be presented as part of the efficacy 
evaluations.
 
 
2.1.5 Background and demographic characteristics 
Demographic, background data and key efficacy variables at baseline will be summarized for 
all randomized patients (RAN) by the treatment approach that patients are assigned to at 
randomization. Categorical variables gender, race, ethnicity, baseline age group, current 
smoking status, baseline GFR (MDRD) category, baseline body mass index (BMI) group, and 
baseline HbA1c group will be summarized by frequency and percentage. The continuous 
variables baseline age, height, 
, baseline BMI, duration of T2DM, baseline 
HbA1c and baseline FPG will be summarized by mean, standard deviation, median, minimum 
and maximum.  
All baseline and background characteristics (except HbA1c, FPG and GFR) will be 
summarized at study entry (screening visit) or at the randomization visit if screening (Week -
5) measurements are not collected.   
Baseline body mass index (BMI) will be calculated (i.e. not taken from the eCRF) from the 
height and weight measured at screening (Week -5), BMI = weight / height2, where weight is 
in kilograms (kg) and height is in meters (m).    
The classification of the baseline HbA1c, BMI, age category and GFR (MDRD) category are 
based on the following definitions:  
o HbA1c category (< 7% and ≥7%) 
o BMI (< 30 kg/m2 and ≥ 30 kg/m2 at Visit 1) 
o Age at Visit 1 by tertiles i.e. <48 years, 48 - < 62 years and ≥ 62 years) 
o GFR (MDRD) category (Normal: >80 mL/min, Mild: ≥50 mL/min - ≤80 mL/min, 
Moderate: ≥30 mL/min - <50 mL/min, Severe: 0 mL/min - <30 mL/min) 
Baseline comparability across treatment approaches for all randomized patients (RAN) will be 
examined in a Section 16.1 listing using a chi-square test for the categorical variables, and a 
two-sample t-test for the continuous variables. The p-values are provided for descriptive 
purposes, and will not to be considered as the formal basis for determining factors to be 
included in the statistical analysis model.  


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In addition, all relevant medical history and history of diabetes and complications will be 
summarized by primary system organ class, preferred term and treatment approach using 
frequency tables in Post-text tables for all RAN patients. 
2.1.6 Study medication 
The study consists of three treatment periods.  
In Period 1 patients will be randomized to metformin + vildagliptin 50mg bid, or metformin + 
placebo. If initial treatment fails to maintain HbA1c < 7.0%, confirmed at two consecutive 
scheduled study visits (after remapping in section 1.3.3 has been applied), starting from Visit 
4 (Week 13), then vildagliptin will be added to metformin in the metformin-only arm in 
Period 2. The Period 1 end date is defined as the date of the second of the two consecutive 
scheduled study visits, i.e. the initial treatment failure date. The Period 2 start date is defined 
as the next day. 
In Period 3, insulin is considered based on local guidelines. Both patients and investigators 
will remain masked to the treatment allocation in Period 1, and the study will compare the two 
different treatment approaches. The Period 3 start date is defined as the date of insulin 
initiation. The Period 2 end date is defined as the previous day. 
Treatments are referred to as ‘Treatment approach’ throughout this analysis plan to 
acknowledge that patients are not on the same treatment for the duration of the study. When 
summaries are detailed for the ‘Treatment Period’, they will include data from Periods 1, 2 
and 3, unless specified otherwise. 
The duration of exposure to study medication (in months) during the treatment period will be 
computed for all patients using the algorithm outlined in Section 1.4 and summarized by 
treatment approach for the RAN both descriptively (i.e., mean, standard deviation, median, 
minimum and maximum) and by 3 - monthly intervals (0 - < 3 months, 3 - < 6 months, ..., ≥ 
60 months). 
The study Period 1 duration (in months) will be also similarly summarized for the RAN. The 
study Period 1 duration is defined as (initial treatment failure date – treatment start date + 
1)/30.4375 for patients who entered study Period 2. The study Period 1 duration is the same as 
overall study duration for patients who did not enter into Period 2. 
The study period from treatment start to the end of Period 2 will be computed for all patients 
who initiate insulin in Period 3 and for patients discontinuing the study in Period 2 due to 
being unable or unwilling to initiate insulin for treatment intensification in Period 3. The 
duration will be defined as (initiation date of insulin – treatment start date)/30.4375 for 
patients who initiate insulin, and (last study drug date – treatment start date +1)/30.4375 for 
patients who do not enter Period 3. 
Total subject year exposure (SYE) will also be summarized by treatment approach for the 
RAN. SYE (years) for each treatment will be calculated as (duration of exposure in days, 
disregarding any treatment interruptions, for all subjects in that treatment approach) / 365.25. 
For patients who did not take any study medication, the exposure is set to zero. This summary 
will be repeated on Period 1 data only, and also on Vildagliptin exposure only. 


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Study medication information will be listed for the RAN, including information about 
vildagliptin, placebo, metformin and insulin use. 
2.1.7 Concomitant medication 
Concomitant therapies taken during the treatment period will be summarized by anatomical 
therapeutic chemical classification system (ATC) class and preferred term according to the 
treatment approach patients are assigned to at randomization in the RAN. The number and 
percentage of randomized patients (RAN) in each class and preferred term will be tabulated 
by treatment approach. This summary will be repeated on period 1 data only, i.e. concomitant 
therapies taken during Period 1. 
Use of anti-diabetic medications prior to study entry (as recorded on the eCRF) will be 
summarized by ATC class, preferred term and treatment approach.   
The duration and average daily dose of metformin taken during the screening and run-in 
period will be summarized descriptively (mean, standard deviation, median, minimum and 
maximum), using data from 35 days prior to screening through to 35 days after 
randomization. This will be based on information collected on the i) Metformin dosage 
administration page of the eCRF (considering only dosages which are at most 35 days after 
randomization); and ii) information collected on the prior anti-diabetic medication eCRF page 
with a preferred term containing ‘METFORMIN’ and a dose of ‘mg’ (considering only 
dosages which are at most 35 days prior to the screening visit). The average daily dose of 
metformin during this window will also be summarized categorically (<2000 mg, ≥2000 mg).  
Listings of concomitant medications and prior anti-diabetic medications will be presented by 
treatment approach and patient number. 
2.2 
Efficacy evaluation 
2.2.1 Definition of geographic region for efficacy analyses 
Centers/countries with a small number of patients will be pooled to create geographic regions. 
Larger centers/countries will be considered as their own geographic region. There are six 
geographic regions planned: Europe, Latin America, South-East Asia, East Asia, Australia 
and Africa. The pooling of centers and/or countries to create geographic regions will be 
confirmed once all patients have been randomized. The allocation of countries to the specific 
geographic regions will be as follows. 
Centers/Countries 
Geographic region 
AUT, BGR, CZE, DEU, ESP, EST, FIN, 
HUN, ISR, ITA, LTU, LVA, NOR, POL, 
ROU, RUS, SVK, TUR 
Europe 
ARG, BRA, COL, DOM, GTM, MEX, PAN, 
PER 
Latin America 
IND, MYS, PHL 
South-East Asia 
HKG, KOR, TWN 
East Asia 


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AUS 
Australia 
ZAF 
Africa 
2.2.2 Primary efficacy variables 
2.2.2.1 Variable definition 
The primary efficacy variable is time to confirmed initial treatment failure. The confirmed 
initial treatment failure is defined as a patient with HbA1c measurements ≥7.0% at two 
consecutive scheduled visits (after remapping in section 1.3.3 has been applied), starting from 
Visit 4 (Week 13). The time to confirmed initial treatment failure is defined as the time from 
randomization until the time when the second of the two HbA1c measurement ≥7.0% was 
determined after at least 13 weeks of treatment (Visit 4), i.e. the end of Period 1. The rationale 
of starting the treatment failures count from Visit 4 is that treatment guidelines consider as 
treatment failure patients who do not achieve HbA1c <7.0% after 3 months of treatment 
(ADA-EASD, 2009). 
The main study conclusion will be based on the analysis of the primary efficacy variable 
using the FAS. Analyses based on the PPS will also be performed to assess the robustness of 
the conclusion. 
2.2.2.2 Handling of missing values/censoring/discontinuations 
In the analysis for the primary efficacy variable of time to treatment failure, patients who 
discontinue the study for any reason during Period 1 (lack of efficacy, lost to follow-up, AE or 
abnormal laboratory values etc.) will be treated as censored values at the time of 
discontinuation. Patients who remain under the threshold (or whose measurement above the 
threshold is not confirmed at next scheduled visit) will be censored at the time of last study 
visit.  
No imputation will be used for missing HbA1c measurements. As detailed in section 1.3.3, re-
defined scheduled visits will be created and so it should be the case that there is always a 
measurement for a scheduled visit, as an unscheduled visit should be carried out to ensure 
there was an HbA1c value available. However, if there is a case where the HbA1c value is 
missing then when looking for consecutive scheduled visits, only visits with non-missing 
HbA1c measurements will be considered (e.g. if Visit 4 HbA1c ≥7.0%, Visit 5 HbA1c is 
missing, and  Visit 6 HbA1c ≥7.0%, then this will be considered treatment failure).  
2.2.2.3 Statistical model, hypothesis, and method of analysis 
Time to initial treatment failure 
The primary statistical hypothesis of time to initial treatment failure will be assessed by a 1-
sided test of superiority of the combination treatment with vildagliptin + metformin versus 
metformin monotherapy with α-level of 0.025 with a null hypothesis that the hazard-ratio 
between the combination treatment vildagliptin + metformin and metformin monotherapy is 
equal or greater than 1, versus the 1-sided alternative hypothesis that the hazard-ratio is less 
than 1: 


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H0: λvildagliptin+metformin/λmetformin ≥ 1 
versus 
Ha: λvildagliptin+metformin/λmetformin < 1 
where λvildagliptin+metformin and λmetformin are the hazard-rates of the initial treatment failure for 
vildagliptin 50mg bid + metformin up to 1000mg bid and metformin up to 1000mg bid 
monotherapy respectively. 
The time to confirmed failure will be derived as the time from randomization to the second of 
two consecutive scheduled visits (after remapping in section 1.3.3 has been applied), at which 
HbA1c ≥7.0% is measured, starting from Visit 4 (13 weeks after randomization).  
The primary efficacy analysis will use a Cox proportional hazard regression model to assess 
the probability of initial treatment failure, with treatment approach and geographic region as 
classification variables and baseline HbA1c as a covariate. The hazard-ratio and associated 
95% confidence interval as well as the p-value estimated from the above model will be 
presented by treatment approach. 
The initial treatment failure rate over time by treatment approach will be summarized using 
estimates and 95% confidence intervals from a Kaplan-Meier analysis. The Kaplan-Meier 
estimates will be plotted, with symbols to indicate censored values.  
The primary analysis for this primary efficacy variable will be performed using the FAS. It 
will be performed in the PPS as supportive analysis as well.  
The model assumptions will be checked by plotting the Schoenfeld residuals for the treatment 
effect obtained from the model against time. A random spread of residuals with no clear 
pattern will indicate that the proportional hazards assumption is valid. The results will be 
presented in CSR Section 16 table(s). 
2.2.2.4 Supportive analyses 
Time to first treatment failure 
The time to first treatment failure will be derived as the time from randomization to the first 
of two consecutive scheduled visits (after remapping in section 1.3.3 has been applied), at 
which HbA1c ≥7.0% is measured, starting from Visit 4 (13 weeks after randomization).  
Time to first treatment failure will be analyzed in the similar way as primary analysis. 
Time to second treatment failure 
The time to second treatment failure will be derived as the time from randomization to the 
second of the two consecutive scheduled visits (after remapping in section 1.3.3 has been 
applied), at which HbA1c ≥7.0% is measured in period 2.  
Patients who discontinue the study for any reason during Period 1 or period 2 without the 
treatment failure are censored at the date of discontinuation. Patients that failed (2 consecutive 
scheduled visits with >=7%) in period 1 and didn’t failed in period 2 are at the end of period 
2. Patients who didn’t failed in period 1 passed to period 3 are censored to last study visit 
prior period 3. 


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Time to the second treatment failure will be analyzed in the similar way as primary analysis. 
Descriptive analysis in HbA1c over time 
Summaries of absolute values and change from baseline to end of Period 1 in HbA1c by 
treatment approach and visit will be presented in the FAS. Figures will be produced showing 
the mean HbA1c and standard error by visit during the study Period 1 for each treatment 
approach. The summary table and figure will be repeated for PPS. 
In addition, the above descriptive analysis (including summary table and figure) will be 
performed for FAS on HbA1c data collected up to the end of Period 2, as well as data 
collected during the entire duration of the study. 
Subgroup analysis 
Summaries of absolute values and changes from baseline to end of Period 1 in HbA1c will be 
presented by treatment approach. The analysis will be performed on FAS. The list of 
subgroups of interest is listed below: 
1. Baseline HbA1c category (<7%, ≥7%). 
2. BMI (<30kg/m2, ≥30kg/m2 at Visit 1). 
3. Age at Visit 1 by tertiles i.e. < 48 years, 48-< 62 years, ≥ 62 years. 
4. Gender. 
5. Race. 
6. Smoking status 
7. Geographical regions 
 
In addition to above mentioned subgroups, following will be analyzed and reported for time to 
confirmed treatment failure endpoint in the same way as defined for the primary analysis. 
• Age (three subgroups per tertiles of baseline age in all patients pooling the two treatment 
groups) (i.e., =< P33 years, >P33 - <= P66 years and > P66 years) 
• Age (< 65 years, ≥ 65 years) 
• Baseline GFR [mL/min/1.73m**2] (<90, >=90), baseline GFR (<60,>=60), baseline GFR 
(<30, 30-<60, 60-<90). 
Other baseline demographic subgroups may be added as appropriate. 
2.2.3 Secondary efficacy variables  
2.2.3.1 Derivation of secondary 
 variables 
Rate of glycemic control over time 
The rate of loss of glycemic control over time will be estimated by an annualized slope of 
HbA1c over time from Visit 5 (Week 26) to the end of Period 1. A mixed effect model 


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including a random coefficient will be used for analysis. The rationale of choosing Visit 5 as 
starting point for estimating the rate (slope) of loss of glycemic control over time is based on 
data from study CLAF237A2307 (Scherbaum W et al, 2008) where the maximal reduction in 
mean HbA1c from baseline was between 24 and 32 weeks, therefore a trend for loss in 
glycemic control is sensible to be estimated from a similar time point. 
In the analysis of the rate of loss in glycemic control over time, data used in analysis will be 
censored at the start of Period 2, i.e. the only data included in the model will be from Visit 5 
(Week 26) to the end of Period 1. 
FPG 
If the FPG value (standard non meal-test parameter) is missing, the -20 min meal-test value 
(obtained on the same day) can be used to impute.  If the -20 min value is also missing, the 0 
min value will be used.   
Calculation of OGIS 
OGIS will be calculated as a function of glucose and insulin (meal-test laboratory 
parameters): 
OGIS = 0.5 * { 
                         [ ( (P5*(G(90)-Gc)) + 1 ) * CI_OGTT ] 
                         + sqrt {  
                                     [ ( (P5*(G(90)-Gc)) + 1 ) * CI_OGTT ] ^2  
                                     + [4 * P5 * P6 * (G(90)-Gc) * CI_OGTT]  
                                    } 
                        } 
where, 


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o CI_OGTT ={ P4 * { (P1*D0) – [V*(G(120)–G(90))]/30 } / G(90) +(P3/G(0)) } 
                           / { I(90) – I(0) + P2 } 
o D0 (g/m2) is the glucose dose included in the standard meal administered to patients who 
participate in the standard meal-test (D0 =(73.2*5.551)/BSA for the standard meal as 
planned in Protocol Section 6.4.3. It will be assumed all patients receive a standard meal),  
o BSA=0.164*(Weight in kg**0.515)*((0.01*Height in cm)**0.422), 
o V =10000 (ml/m2) is the assumed glucose distribution volume,  
o G(0), G(90) and G(120) are glucose concentration values (taken from meal-test laboratory 
data) at timepoints 0, 90 and 120 min,  
o I(0) and I(90) are insulin concentration values (taken from meal-test laboratory data) at 
timepoints 0 and 90 min,  
o P1=6.5, P2=1951, P3=4514, P4=792, P5=0.0118, P6=173, Gc=5 are constants (Mari, et al 
2001). 
If the value of glucose or insulin values at 0 minutes are missing, then the -20 min meal-test 
value (obtained on the same day) can be used to impute.  If the -20 min value is also missing, 
the fasting parameter result (i.e. standard non meal-test parameter) will be used. Both glucose 
and insulin should be imputed using the same timepoint (regardless if one has value 
available).  
No imputation will be used for missing 90 or 120 minute values. 
Calculation of ISR 
Separately for each patient and each meal-test, deconvolution is applied to estimating insulin 
secretion to assess β-cell function. C-peptide, which is co-secreted with insulin in an 
equimolar ratio, is preferred to insulin as a basis for estimating insulin secretion. 
Mathematically, we need to solve for the insulin secretion rate r given the impulse response h, 
and plasma C-peptide c, where 
 
The impulse response is the PK model for an intravenously administered unit bolus dose of C-
peptide when the endogenous C-peptide production has been suppressed, i.e. 
 
where V, f, α, and β are a subject’s parameters, which are generally unknown. However, from 
clinical studies these parameters have been estimated, and are related to a subject’s disease 
status, body surface area, age, and gender. Thus, h becomes known. 


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Insulin secretion rates are modeled by a piecewise continuous linear function with knots at the 
actual sampling time. Changes in slopes are penalized through a single regularization 
parameter that is determined by a root finding method to produce similar residual standard 
deviation for fitted C-peptide concentrations as would be expected from assay error standard 
deviations given in the kit instructions. 
The IMMULITE 2000 C-peptide kit instructions were used to model intra-assay SD as a 
function of the true C-peptide concentration C1 expressed in conventional units of ng/mL by 
simple linear regression as: 
SD = 0.04056C1 + 0.06311ng/mL. 
With concentration of C-peptide expressed alternatively in SI units, i.e., C2 expressed in nM 
(1ng/mL C-peptide = 0.331nM C-peptide) the equations for SD becomes: 
SD = 0.04056 C2 + 0.331 × 0.06311nM. 
The following ln-transformation with a shift parameter of observed and fitted C-peptide 
values is used to stabilize the variance in performing the deconvolution: 
ln(C1 + 0.06311/0.04056) or ln(C2 + 0.331 × 0.06311/0.04056). 
Nonlinear least squares with ISR constrained non-negative using PROC IML function 
NLPLM in SAS® is used to solve for ISR at the sampling time points using actual sampling 
times. The bisection method is used to iteratively determine the regularization parameter such 
that the sum of squares of the observed C-peptide minus the fitted C-peptide expressed in 
either units equals 0.040562n where n is the number of non-missing C-peptide concentrations 
in the meal-test. 
Validated macros (ISR and ISR_IML2) have been provided by Novartis and will be used to 
derive the ISR in 
 production and validation programs. 
Calculation of AUC 
AUC of ISR/G is defined as ISR relative to glucose 0-2h (pmol/min/m2/mM) = AUC0-2hr of 
ISR/AUC0-2hr of glucose. (Glucose is taken from the meal-test laboratory data).  
For the patients participating in the meal-test, the laboratory parameters glucose, insulin and 
C-peptide are also to be measured at the following 7 time-points (minutes in relation to the 
meal time): -20min, 0min  (immediately prior to meal ingestion), 15min, 30min, 60min, 
90min, 120min. Let L1, L2, …., L7 denote the lab measurements at these 7 time-points (i.e., L1 
is the value measured at 20min pre-meal, L2 is the value measured at 0min pre-meal, …, L7 is 
the value measured at 2h after the meal) and T1, T2, .., T7 be the corresponding times (actual 
times in units of h), the AUC0-2hr is calculated (using the trapezoidal rule) as: 
AUC0-2h = 
[(L2 + L3) × (T3 – T2) + (L3 + L4) × (T4 – T3) + (L4 + L5) × (T5 – T4) + (L5 + L6) × (T6 – T5) + 
(L6 + L7) × (T7 – T6)] / 2. 


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Note for above calculation:  
1) L1 and T1 are not used in the calculation. However, if L2 (the value at 0 min) is missing, the 
L1 (the value at –20 min) will be used in its place, but T2 should still be used in the 
calculation (i.e., no substitution of T2 with T1 is allowed). If the -20 min AND 0 min values 
are missing, the fasting value (i.e. the standard non meal-test value) will be used to impute 
the 0 min value. If the 0 minute ISR is missing due to missing 0 minute c-peptide, then the 
missing c-peptide value should be imputed using this approach, in order to obtain a non-
missing 0 minute ISR value. 
2) If Li (a lab value) is not missing, but the corresponding time Ti is missing, Ti will be 
imputed by the planned time (or scheduled time). 
3) If Li is missing at a timepoint Ti, the next available value Li+1 and timepoint Ti+1 will be 
used for calculating AUC.  
4) AUC0-2h will only be calculated for patients for whom there are at least 3 timepoints 
(including one of the first two timepoints (i.e., 0 or -20 min pre-meal), the last timepoint 
(i.e., 2 hours post-meal), and a timepoint in between) where the actual laboratory values are 
known. 
2.2.3.2 Variable definition 
The following secondary 
 efficacy variables will be analyzed. They are grouped 
by type of analyses for the convenience of describing the related analysis methods. 
Variables related to time to event method 
• Time to insulin initiation. 
Variables related to the rate of change of β-cell function and insulin sensitivity 
• Rate of loss of β-cell function (assessed using the AUC of ISR/G) from Visit 4 (week 13) to: 
i) end of Period 1; ii) end of Period 2; iii) EOS. 
• Rate of change in insulin sensitivity (assessed using the OGIS) from Visit 4 (week 13) to:  i) 
end of Period 1; ii) end of Period 2; iii) EOS. 
Variables related to the rate of loss in glycemic control over time 
• Rate of loss in glycemic control in HbA1c from 26 weeks after the start of Period 2 to end of 
Period 2. 
• Rate of loss in glycemic control in FPG, i) from Visit 5 (week 26) to: i) end of Period 1; ii) 
from 26 weeks after start of Period 2 to end of Period 2.  
Variables related to change from baseline to endpoint 
• Change in AUC of ISR/G (as an assessment of β-cell function) from baseline to: i) end of 
Period 1; ii) end of Period 2; iii) EOS. 
• Change in OGIS (as an assessment of insulin sensitivity) from baseline to: i) end of Period 
1; ii) end of Period 2; iii) EOS. 
 


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2.2.3.3 Statistical analysis methods 
Rate of loss in glycemic control over time 
The rate of loss in glycemic control over time will be estimated by the slope of HbA1c over 
time (in years) as a random coefficient in a linear mixed effect model: the model will be fitted 
to HbA1c data collected from Week 26 and onwards, up to and including the end of the 
Period 1 visit, i.e. up to and including the initial treatment failure date. It includes treatment 
approach, geographic region, baseline HbA1c, time (of HbA1c measurements, in years) and 
the interaction of treatment approach by time as the fixed effects, and time and intercept as a 
random effects. Treatment approach and geographic region will be considered as 
classification variables while baseline HbA1c and time are the covariates. The unstructured 
covariance will be used as the covariance structure within patients. The actual hypothesis will 
be tested using the treatment approach by time interaction term. Note that it is not an issue 
that patients who ‘fail’ at Week 26 will only contribute one data point to the analysis, as this 
is expected in only a few patients. 
The mean slopes within each treatment approach and the difference in mean slopes between 
two treatment approaches as well as the p-value obtained from the test using the above model 
will be presented. Graphical representation will also be produced as required. 
The analysis will be performed using the FAS. It will be performed in the PPS as supportive 
analysis as well. 
The assumptions for inference using the model as described above (i.e., errors are 
independently normally distributed with constant variance) will be checked using CSR 
Section 16 table(s) by subjective examination of the presented residual plots: normal 
probability plot and residuals versus fitted values plots.  


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Variables related to the rate of change of β-cell function and insulin sensitivity 
over time 
The rate of change of β-cell function and insulin sensitivity (assessed using the AUC of ISR/G 
and OGIS respectively) from Visit 4 (week 13) to the end of Period 1, or from Visit 4 (week 
13) to the end of Period 2, or from Visit 4 (week 13) to the end of study will be assessed using 
a similar random coefficient linear mixed effect model used in the primary efficacy endpoint 
‘rate of loss in glycemic control in HbA1c from Visit 5 (Week 26) to the end of Period 1’.  
This analysis is performed in the FAS only. Data collected up to the end of Period 1, or the 
end of Period 2, or to the end of the study will be used in the analysis for assessing the rate of 
change from Visit 4 to end of Period 1, or from Visit 4 to end of Period 2, or from Visit 4 to 
the end of the study respectively.  
A general downward trend from Visit 4 to the end of study can be assumed for these 
parameters. 
Variables related to the rate of loss in glycemic control over time 
The rate of loss in glycemic control in HbA1c or FPG from 26 weeks after the start of Period 
2 to the end of Period 2 will be assessed for patients who start insulin therapy in Period 3 (i.e. 
for treatment intensification) or discontinue the study during Period 2 due to not being able or 
unwilling to initiate insulin therapy in Period 3. The random coefficient linear mixed effect 
model used in the primary efficacy endpoint ‘rate of loss in glycemic control in HbA1c from 
Visit 5 (Week 26) to the end of Period 1’ will be used in this secondary variable. Only data 
collected between initiation of Period 2 to insulin initiation on patients who take insulin 
therapy in Period 3 (i.e. for treatment intensification) or who discontinued the study in Period 
2 due to not being able or unwilling to initiate insulin therapy in Period 3 will be included in 
this model. Patients who complete the study in Period 1 or Period 2 will not be included in the 
analysis. The analysis will be performed in the FAS only. Note that it is not known how many 
patients will proceed into Period 3, so may need to later review whether the planned analysis 
for the subgroup of patients entering Period 3 (or being unable/unwilling to) is sensible. 
The rate of loss in glycemic control in FPG from 26 weeks to the end of Period 1 will be 
assessed using the same random coefficient linear mixed effect model used in the primary 
efficacy endpoint ‘rate of loss in glycemic control in HbA1c from Visit 5 (Week 26) to the 
end of Period 1’. This analysis is performed in the FAS only. 


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Variables related to change from baseline to endpoint 
An analysis of covariance (ANCOVA) model with treatment approach, geographic region as 
classification variables and baseline value as a covariate will be used to assess all secondary 
efficacy variables related to change from baseline to endpoint. The least squares mean 
(“adjusted mean”) change from baseline for each treatment approach, the difference in the 
least squares mean changes between the two treatment approaches, and the two-sided adjusted 
95% confidence interval along with the p-value for the difference will be obtained from this 
analysis model and presented. 
 
 
 
 
 
Supportive descriptive analysis for secondary 
 variables over 
time 
Summaries of absolute values and change from baseline to: i) end of Period 1; ii) end of 
Period 2; iii) EOS; in secondary 
 (including FPG, 
, AUC 
of ISR/G, OGIS, 
) by treatment approach 
and visit will be presented in the FAS. 
 
 
2.3 
Safety evaluation 
The safety and tolerability of vildagliptin 50mg bid as add-on to metformin over 5-years of 
treatment will be compared to placebo as add-on to metformin based on data collected during 
the treatment period in SAF. All analyses will use all available data collected during the entire 
study. In addition, key safety analyses will be performed on data obtained during Period 1 
only. Patients will be analyzed according to the treatment approach they received (vildagliptin 
50mg bid + metformin, placebo + metformin).  
The incidence of treatment emergent adverse events (events started after the first dose of 
randomized study medication or events present prior to start of randomized treatment but 
increased in severity) will be summarized by primary system organ class, preferred term, 
severity and relationship to study drug. Any event captured on the database will be included in 
AE summary tables/listings. 
In order to assess safety and tolerability of vildagliptin as compared to placebo, key safety 
variables (overall AEs, SAEs, AEs leading to study drug discontinuation or study drug 
interruption, incidence of hypoglycemia, predefined AE risks, predefined categories of liver 
enzyme (ALT/AST) and CPK and persistent elevations) will also be summarized by treatment 
approach for the SAF. 
The number and percentage of run-in failures reporting any adverse events, serious adverse 
events or adverse events leading to study drug discontinuation will also be summarized. Note 


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these events will not be included in other AE outputs, as these patients will not be included in 
SAF. 
2.3.1 Overall experience of adverse events (AEs) 
The number and percentage of patients reporting any adverse event during the treatment 
period of the study will be summarized by primary system organ class, preferred term and 
treatment approach overall (including study periods 1, 2 and 3) and by study period.  
Percentages will be based on the number of patients in the SAF per treatment approach and 
study period. An AE will be assigned to a period if its start date is after or on the start date but 
not later than the end date of that period. All AEs will be assigned to a specific study period – 
if it is not possible to assign an AE into a specific study period of the patient based on the AE 
start date, then the event will be assigned to the last study period started by the patient. This 
will ensure that all AEs will be categorized to a specific study period   
The most common adverse events reported (≥2 % in any group) during the treatment period of 
the study will be presented in descending frequency starting from the most common event in a 
Text Table.  A complete table of all events reported in descending frequency will be 
prepared.. 
Adverse events that were suspected to be related to study drug will be summarized. Note that 
if the relationship to study drug is missing for any adverse event, then that adverse event will 
be assumed to be related to study drug.   
The maximum severity of all adverse events during the treatment period of the study will be 
summarized. Note that if the severity is missing for any adverse event, then that adverse event 
will be assumed to be severe.  
An overall summary of the number and percentage of patients with drug-related AEs, severe 
AEs, AEs with outcome of death, SAEs and adverse events leading to permanent 
discontinuation of treatment will be presented by study period and  treatment approach. 
The number and percentage of patients reporting any adverse event during the treatment 
period of the study will be summarized by standardized MedDRA query (SMQ) level and 
treatment approach as well. 
In addition, the number and percentage of patients reporting any adverse event during the 
treatment period will also be summarized by primary system organ class, preferred term, 
treatment approach and age group (as defined in section 2.1.5) ) overall and by treatment 
period.. 
Note that there will be no AE adjudication for this study. 
2.3.1.1 Deaths, other serious and other significant adverse events 
An overall summary of the number and percentage of deaths, serious adverse events (SAEs), 
and adverse events (including laboratory abnormalities) leading to discontinuation, study drug 
interruption or considered to be clinically significant will be presented by study period and 
treatment approach.  


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Deaths 
The number and percentage of deaths will be summarized by study period and treatment 
approach and the principal cause in primary system organ class and preferred term.   
Serious adverse events (SAEs)  
The number and percentage of patients with serious adverse events (SAEs) will be 
summarized by primary system organ class, preferred term, study period and treatment 
approach.  
Other significant adverse events – adverse events leading to discontinuations 
The number and percentage of patients with adverse events that lead to discontinuation will be 
summarized by primary system organ class, preferred term, study period, and treatment 
approach.  
Other significant adverse events – adverse events leading to dose adjustments 
or study drug interruptions  
The number and percentage of patients with adverse events that lead to dose adjustments or 
study drug interruptions will be summarized by primary system organ class, preferred term, 
study period, and treatment approach.   
Other significant adverse events – predefined adverse event risks 
The number and percentage of patients with adverse events that were predefined risks (see 
Section 1.6 for definitions) will be summarized by preferred term, predefined risk category, 
maximum severity, study period, and treatment approach.     
2.3.2 Laboratory values 
The details of laboratory parameters collected, SI units (note, only SI units will be reported), 
and normal ranges will be listed in Section 16 of CSR. Note that lipid parameters are 
summarized along with other biochemistry laboratory parameters. Meal test laboratory 
parameters (glucose, insulin and c-peptide) are for use in efficacy analyses only and so should 
not be included in safety laboratory outputs. 
Notable ranges (absolute) criteria of selected laboratory variables are defined in Section 1.8 
above. The laboratory values to be considered for notable ranges or relevant changes will 
include all post-baseline values up to the final scheduled visit, including values at 
unscheduled visits prior to the last visit. Only treatment emergent notable abnormalities will 
be considered (i.e. notably abnormal measurements which were not present at any pre-
baseline visit).  In addition to summary tables, a listing of patients with any treatment 
emergent notable laboratory results during the treatment period will be provided by treatment 
approach and patient number, along with their values at all visits, including repeated, 
unscheduled and follow-up laboratory values.  In the listing, all abnormal values outside of 
normal range and notable values will be flagged, e.g., L/H for a value being below/above 
normal range, LN/HN for a value being in notable low/high range.  


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For each numerical laboratory parameter, the laboratory values will be reported in listings to 
the same precision as that for the unit in UNITCONV dataset. The precision to use in tables is 
as per Section 1.3.1. 
For continuous variables with a value <lower limit, these will be imputed as being half of the 
lower limit. For continuous variables with a value >upper limit, these will be imputed as being 
equal to the upper limit. 
2.3.2.1 Hematology 
The values of hematology laboratory test results at baseline and endpoints (End of Period 1, 
End of Period 2, End of Study) will be summarized, as well as the changes from baseline to 
each endpoint.  
The maximum/minimum value obtained during the treatment period, and the change from 
baseline to maximum/minimum value will be summarized by treatment approach for each 
hematology parameter. 
The number and percentage of patients with abnormal hematology test results meeting notable 
criteria post-baseline, which were not present prior to randomization, will be tabulated. This 
summary will be repeated for abnormalities occurring in Period 1. 
2.3.2.2 Biochemistry 
The values of biochemistry laboratory test results at baseline and endpoints (End of Period 1, 
End of Period 2, End of Study) will be summarized, as well as the changes from baseline to 
each endpoint.   
The maximum/minimum value obtained during the treatment period, and the change from 
baseline to maximum/minimum value will be summarized by treatment approach for each 
hematology parameter. 
The number and percentage of patients with abnormal biochemistry test results meeting 
notable criteria post-baseline, which were not present prior to randomization, will be 
tabulated. This summary will be repeated for abnormalities occurring in Period 1. 
The number and percentage of patients with hepatic enzyme elevations (defined in Table 1-3), 
and persistent hepatic enzyme elevations will be presented, and the patients meeting any of 
the criteria will be listed. Note that for this study total bilirubin will be used for all criteria 
involving bilirubin. If at any visit total bilirubin has not been measured then the elevation will 
not be assessed for that visit (even if direct bilirubin has been measured). 
The liver panel A testing data for patients with hepatic enzyme elevations will be listed at 
patient level. Liver panel B testing data will not be considered as part of the RAP, but will be 
included in narratives if applicable. 
2.3.2.3 Urinalysis 
The baseline and endpoints (End of Period 1, End of Period 2, End of Study) values of 
categorical urinalysis test results will be summarized in number and percentage by treatment 
approach.  The baseline and endpoints (End of Period 1, End of Period 2, End of Study) 


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values of continuous urinalysis test results will be summarized by treatment approach using 
descriptive statistics. 
2.3.3 Vital signs 
Baseline and endpoint values for blood pressure (sitting), and pulse (sitting) will be presented.  
Summary statistics for vital signs data will be presented by study visit. The summary by study 
visit will include only values obtained at the scheduled visit. 
The number of patients with notably abnormal vital signs 
 post-baseline will be 
presented. This summary will be repeated for abnormalities occurring in Period 1. The criteria 
for notable abnormalities (see Section 1.9) will be listed.   
2.3.4 Electrocardiograms (ECGs)  
Overall interpretation and details of abnormalities are collected at Screening and selected 
visits. 
Change from the baseline ECG result to the endpoint (End of Period 1, End of Period 2, End 
of Study) ECG result will be summarized by a shift table. The number of patients with 
clinically significant abnormalities or not at baseline and at each endpoint ECG assessment 
will be tabulated. 
2.3.5 Hypoglycemic events 
Hypoglycemic events will be characterized by event profile, such as ability to self-treat, self 
monitoring of plasma glucose level, precipitating event, time from last meal, time from last 
dose, and time of the day.  
The incidence of hypoglycemic events (coded as hypoglycemia) and asymptomatic low blood 
glucose (coded as Blood Glucose Decreased), entered into the Glycemia study diary eCRF 
and meeting the event criteria defined in Table 1-1 (Section 1.7), are included in all of the AE 
summaries in Section 2.3.1.  
In addition, patients reporting at least one hypoglycemic event, the subgroup of reporting 1 
event, 2 events, and >2 events, patients discontinued due to hypoglycemic events, patients 
reporting grade 2 events, and patients reporting suspected grade 2 events will be summarized 
by numbers and percentages for each treatment approach overall (including study periods 1, 2 
and 3) and by study period. The summary will be repeated by age group (as defined in section 
2.1.5).   
The hypoglycemic events will further be summarized by event profile as follows: 
• plasma glucose level ≤2.2, >2.2–≤2.8, >2.8–<3.1 and ≥3.1 mmol/L, or Not recorded; note 
that if a patient is unable to initiate self-treatment and plasma glucose is not recorded, this 
is graded as a suspected grade 2 event) 
• grade (grade 1, grade 2 or suspected grade 2) 
• symptom (in preferred term) 
• precipitating event (None, Missed/delayed meal, Strenuous exercise, Alcohol 
consumption, Other or Not recorded) 


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• severity (Mild, Moderate, Severe) 
• relationship to study drug (Not suspected, Suspected) 
• action taken (Study drug dosage adjusted / temporarily discontinued, Study drug 
permanently discontinued, Concomitant medication taken, Non-drug therapy given 
(includes oral carbohydrates), Hospitalization / prolonged hospitalization, no action taken) 
• time interval between last meal and event (0–4, >4–6, >6 hours, not recorded), 
• time interval between last dose and event (0–4, >4–6, >6 hours, not recorded), 
• 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),  
Asymptotic blood glucose events will be similarly summarized by event profile and the 
number of patients with at least one asymptomatic low blood glucose measurement will also 
be summarized.  
A listing of hypoglycemic events and asymptomatic low blood glucose events will be 
presented by treatment approach and patient number. 
Note: As defined in Table 1-1, for patients who are able to initiate self-treatment (where 
necessary) symptoms suggestive of hypoglycemia which are not confirmed by glucose 
measurements will be recorded in the Glycemia diary eCRF.  Since these are not confirmed 
hypoglycemia events, these symptoms will not be reported in the hypoglycemia summary 
tables and listings, these symptoms will appear only in the AE tables and listings. For patients 
unable to initiate self-treatment (where necessary) symptoms suggestive of hypoglycemia that 
were not confirmed by glucose measurements will be classed as suspected hypoglycemic 
events and will therefore be reported in the hypoglycemia summary tables and listings, as well 
as the AE listings.   
Note: Self-monitoring glucose can be recorded in the database as either plasma or whole 
blood. However, only plasma glucose will be reported in the tables and listings. Thus blood 
glucose values will be converted into plasma glucose equivalent, which can be done by 
multiplying a conversion factor of 1.12, i.e., plasma glucose = blood glucose ×1.12. 
The incidence of hypoglycemia and severe hypoglycemia during Period 1 will be compared 
for the SAF using a chi-square test between the two treatment approaches for all patients 
provided that the incidence such these events is more than 5 in each treatment approach. 
 
 


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2.5 
Interim analyses 
No interim analyses are planned for this study.  
2.6 
Other topics  
No other topics will be studied.  


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2.7 
Determination of sample size 
A total sample size of 1000 randomized patients per treatment arm (in 1:1 allocation ratio to 
vildagliptin + metformin and metformin monotherapy) is planned. 
The sample size calculation assumed that all randomized patients are to be followed up for 5 
years unless patients dropped out from the study for various reasons (lack of efficacy, AEs, 
abnormal labs, lost to follow-up etc.), and that the yearly dropout rate is 11% (estimate based 
on ADOPT data (Kahn S et al, 2006). 
The existing vildagliptin study data suggest that approximately 10% of vildagliptin patients 
will have an HbA1c >7.0% after the first 3 months of the study (initial response phase), since 
those patients who are randomized with an HbA1c measurement above the failure threshold 
(7.0%) may never have an HbA1c measurement below the required threshold during the study 
and will therefore be counted as failures during the first 13 weeks. A similar proportion is 
assumed for the comparator arm. Hence it is expected that the difference in failure rate is 
likely to be small early in the study, but will diverge as the study progresses. The power 
calculations have been adjusted to take this assumption into account using statistical 
simulations. 
The simulations showed that assuming an annual initial treatment failure rate of 7.1% in the 
metformin monotherapy arm (estimated based on ADOPT data), incorporating a 10% initial 
failure rate after 13 weeks in each treatment arm (due to some patients with baseline HbA1c 
≥7.0%), 1000 patients per treatment arm would be sufficient to detect a hazard-ratio of 0.75 
between vildagliptin + metformin and metformin alone (corresponding to a risk reduction rate 
of 25% in vildagliptin + metformin group versus metformin alone) with approximate 75% 
power and a 1-sided significance level of 0.025 (corresponding to a 2-sided test at 0.05). 
 


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2.8 
Changes in the conduct of the study or planned analyses 
The following change in the analysis is proposed in protocol amendment 3 (4th Oct 2016) 
which defers with the analysis proposed in this document. These proposed changes have come 
about through development of the RAP modules and discussions around the analyses. 
• Treatment start date to be defined as the earliest vildagliptin/placebo date, as recorded on 
the DAR page of the eCRF (i.e. do not use visit 3 date). Consistently use this definition for 
day 1 and durations related to day 1.  
• ‘+1’ should be included in duration of exposure calculation when last study drug date is 
available. 
• ‘+1’ should not be included in duration of exposure calculation when last study drug date 
is missing/incomplete. 
• Further detail added to better define the analysis sets. 
• Geographic region to be included as a classification variable in the analysis of time to 
initial treatment failure (and all similar analyses).  
• In the analysis of rate of loss in glycemic control over time, time will be included as a 
fixed effect and as a random effect. 
• In the analysis of time to insulin initiation, patients who complete the study in Period 1 or 
Period 2 will be censored at their last study visit. 
• OGIS formula revised as per 23135 study. 
• Due to the large number of patients (patients will be recruited until we have the required 
amount) and the robustness of analyses methods we can assume we will have sufficient 
patients data for the beta-cell function, insulin sensitivity, AUC of ISR/G and OGIS 
analyses. 
 
 
 
 
 
• The definition of initial treatment failure is revised to be the date of the second of the two 
consecutive measurement of HbA1c value >=7%. The rationale of this change is that this 
will be consistent with the Period 1 end date definition. The decision of this definition 
update is documented in the RAP II meeting minutes in RAP Module 1. 
• Main analysis approach includes only one primary endpoint in this SAP. As the 
probability and risk of time to initial loss of glycaemic control as primary efficacy variable 
is presented as a hazard ratio and failure rate over time, the statistical approach and power 
calculations (including the impact of the known retention) was updated accordingly while 
moving the assessment of the rate of loss of glycaemic control by an annualised slope of 
mean HbA1c over time from week 26 to the end of period 1 to be a key secondary 
analysis instead. 


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• Baseline characteristics driving the pre-planned sub-analyses to a previously unpredictable 
direction, is clearly documented in the SAP to ensure transparency and external validity of 
the study 
 
 
• Time to second treatment failure and the subgroup analysis of the primary endpoint is 
added as a post-hoc analysis which is to be included in the CSR. 


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References 
ADA-EASD Consensus Statement (2009) Medical management of hyperglycaemia in type 2 
diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. 
Diabetologia; 52:17-30. 
Hochberg and Tamhane (1987) Multiple Comparison Procedures. Wiley Series. 
Mari A, Ludvik B, Pacini G, et al (2001) A model-based method for assessing 
insulinsensitivity from the oral glucose tolerance test. Diabetes Care; 24: 539-548. 
Rigalleau V, Lasseur C, Perlemoine C, et al (2005) Estimation of glomerular filtration rate in 
diabetic subjects. Cockcroft formula or modification of diet in renal disease study equation?  
Diabetes Care 28:838-843.   
 
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Scherbaum W, et al. (2008) Evidence that vildagliptin attenuates deterioration of glycaemic 
control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. 
Diabetes Obes Metab; 10:1114–1124. 
 
SAS/STAT User’s Guide, version 9.2, SAS Institute, Inc., Cary, North Carolina.