Clinical trial NCT02532855
Conditions: Type 2 Diabetes Mellitus
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-10-20; Completion date: 2017-10-10
Enrollment: 614 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess the effect of the addition of sitagliptin to metformin with or without a sulfonylurea compared with the addition of dapagliflozin to metformin with or without a sulfonylurea on hemoglobin A1c (A1C) over 24 weeks of treatment as well as the overall safety and tolerability of sitagliptin in comparison to that of dapagliflozin after 24 weeks of treatment. The primary hypothesis is that the change from baseline in A1C in participants treated with the addition of sitagliptin is non-inferior compared to that in participants treated with the addition of dapagliflozin after 24 weeks of treatment.

Detailed description:

Arms: arm 1: Participants receive sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 5 mg once daily for 4 weeks followed by sitagliptin 100 mg once daily plus matching placebo for dapagliflozin 10 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study. arm 2: Participants receive dapagliflozin 5 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 4 weeks followed by dapagliflozin 10 mg once daily plus matching placebo for sitagliptin 100 mg once daily for 20 weeks. Participants continue pre-study metformin (at least 1500 mg daily) alone or in combination with a sulfonylurea agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) throughout the duration of the study.
Interventions: intervention 1: Sitagliptin intervention 2: Dapagliflozin intervention 3: Metformin intervention 4: Matching placebo to sitagliptin intervention 5: Matching placebo to dapagliflozin intervention 6: Sulfonylurea
Intervention descriptions: intervention 1: Sitagliptin 100 mg oral tablet intervention 2: Dapagliflozin 5 mg or 10 mg oral capsule. Up-titration to dapagliflozin 10 mg daily may be delayed if participant is unable to tolerate up-titration in the opinion of the investigator. Dapagliflozin 10 mg daily may be down-titrated to dapagliflozin 5 mg daily if participant is unable to tolerate the higher dose in the opinion of the investigator. intervention 3: This medication is a standard-of-care medication and is administered in an open-label fashion. Supply of background metformin oral tablet(s) (at least 1500 mg daily) will be the responsibility of the participant throughout the duration of the study. intervention 4: Matching placebo to sitagliptin 100 mg oral tablet intervention 5: Matching placebo to dapagliflozin 5 mg or 10 mg oral capsule. Up-titration to matching placebo to dapagliflozin 10 mg daily may be delayed if participant is unable to tolerate up-titration in the opinion of the investigator. Matching placebo to dapagliflozin 10 mg daily may be down-titrated to matching placebo to dapagliflozin 5 mg daily if participant is unable to tolerate the higher dose in the opinion of the investigator. intervention 6: This medication is a standard-of-care medication and is administered in an open-label fashion. The dose of the sulfonylurea agent will be required to be at least 50% of maximum labeled dose, consistent with near maximum efficacy of the sulfonylurea agent.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:  A Phase III, Multicenter, Randomized, Double-Blind, Active-
Comparator Controlled Clinical Trial to Study the Safety and 
Efficacy of the Addition of Sitagliptin Compared with the
Addition of Dapagliflozin in Subjects with Type 2 Diabetes Mellitus 
and Mild Renal Impairment Who Have Inadequate Glycemic 
Control on Metformin With or Without a Sulfonylurea
NCT number: 
NCT02532855  
Document Date: 
15-Mar-2016


Product:  MK-0431 
1
Protocol/Amendment No.: 838-02 
MK-0431-838-02 Final Protocol
15-Mar-2016
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase III, Multicenter, Randomized, Double-Blind, Active-Comparator Controlled Clinical 
Trial to Study the Safety and Efficacy of the Addition of Sitagliptin Compared with the 
Addition of Dapagliflozin in Subjects with Type 2 Diabetes Mellitus and Mild Renal 
Impairment Who Have Inadequate Glycemic Control on Metformin With or Without a 
Sulfonylurea
IND NUMBER:  65,495
EudraCT NUMBER:  2014-005525-13
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 17
Trial Design ........................................................................................................... 17
2.1
Trial Diagram........................................................................................................ 19
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es) .............................................................. 20
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 20
3.2
Other Objectives ................................................................................................... 20
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
4.1
Pharmaceutical and Therapeutic Background .................................................... 21
4.1.1
Rationale................................................................................................................ 22
4.2
Rationale for the Trial and Selected Subject Population .................................... 22
4.2.1
Rationale for Dose Selection/Regimen............................................................... 23
4.2.2
4.2.2.1
Rationale for Sitagliptin Dose...................................................................... 23
4.2.2.2
Rationale for Dapagliflozin Dose ................................................................ 23
Rationale for Endpoints ...................................................................................... 23
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 23
4.2.3.2
Safety Endpoints .......................................................................................... 24
4.2.3.3
Future Biomedical Research........................................................................ 24
Benefit/Risk ........................................................................................................... 24
4.3
5.0
METHODOLOGY ................................................................................................... 25
Entry Criteria........................................................................................................ 25
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 25
5.1.1
Subject Inclusion Criteria.................................................................................... 25
5.1.2
Subject Exclusion Criteria .................................................................................. 27
5.1.3
Trial Treatment(s) ................................................................................................ 32
5.2
Dose Selection/Modification .............................................................................. 33
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 33
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 33
5.2.1.2.1
Dose Modification of Sitagliptin/Matching Placebo to Sitagliptin ...... 33
5.2.1.2.2
Dose 
Modification 
of 
Dapagliflozin/Matching 
Placebo 
to 
Dapagliflozin ........................................................................................ 33
5.2.1.2.3
Dose Modification of Metformin and Sulfonylurea ............................. 34
Timing of Dose Administration .......................................................................... 34
5.2.2
Trial Blinding/Masking....................................................................................... 34
5.2.3
Randomization ...................................................................................................... 35
5.3
Stratification.......................................................................................................... 35
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 35
5.5
Diet/Activity/Other Considerations..................................................................... 37
5.6
Diet...................................................................................................................... 37
5.6.1
Alcohol, Caffeine and Tobacco .......................................................................... 38
5.6.2
Activity ............................................................................................................... 38
5.6.3
Subject Withdrawal/Discontinuation Criteria................................................... 38
5.7
Follow-up for Subjects Who Discontinue Blinded Study Drug ......................... 41
5.7.1
5.7.1.1
Withdrawal of Consent ................................................................................ 41
5.7.1.2
Discontinuation from Blinded Study Therapy............................................. 41
Subject Replacement Strategy............................................................................. 41
5.8
Beginning and End of the Trial ........................................................................... 42
5.9
Clinical Criteria for Early Trial Termination ................................................... 42
5.10
6.0
TRIAL FLOW CHART ........................................................................................... 43
7.0
TRIAL PROCEDURES ........................................................................................... 47
Trial Procedures ................................................................................................... 47
7.1
Administrative Procedures.................................................................................. 47
7.1.1
7.1.1.1
Informed Consent......................................................................................... 47
7.1.1.1.1
General Informed Consent.................................................................... 47
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 47
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 48
7.1.1.3
Subject Identification Card .......................................................................... 48
7.1.1.4
Medical History ........................................................................................... 48
 
 
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7.1.1.5
Prior and Concomitant Medications Review ............................................... 48
7.1.1.5.1
Prior Medications.................................................................................. 48
7.1.1.5.2
Concomitant Medications..................................................................... 48
7.1.1.6
Assignment of Screening Number............................................................... 48
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 49
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 49
7.1.1.8.1
Diet and Exercise Counseling and Monitoring..................................... 49
7.1.1.8.2
Dispense Hypoglycemia Assessment Log and Instruct on 
Hypoglycemia Symptoms and Management ........................................ 49
7.1.1.8.3
Dispense Glucose Meter and SMBG Instructions ................................ 50
7.1.1.8.4
Witness Dosing..................................................................................... 50
7.1.1.8.5
Dispense Single-Blind Placebo Run-in Study Drug............................. 50
7.1.1.8.6
Dispense Double-Blind Study Drug ..................................................... 51
7.1.1.8.7
Medication Compliance Monitoring..................................................... 51
Clinical Procedures/Assessments........................................................................ 51
7.1.2
7.1.2.1
Vital Signs.................................................................................................... 51
7.1.2.2
Postural (Orthostatic) Blood Pressure and Pulse Rate................................. 52
7.1.2.3
Body Weight ................................................................................................ 53
7.1.2.4
Height........................................................................................................... 53
7.1.2.5
Physical Examination................................................................................... 54
7.1.2.6
12-Lead Electrocardiogram (ECG).............................................................. 54
7.1.2.7
Site Fingerstick A1C Measurement ............................................................. 54
7.1.2.8
Fasting Fingerstick Glucose......................................................................... 54
7.1.2.9
Review of SMBG Measurements and Hypoglycemia Assessment Log...... 54
7.1.2.10 Assess Subject for Discontinuation Based on Central Laboratory FPG 
or A1C.......................................................................................................... 55
7.1.2.11 Mixed Meal Tolerance Test (MMTT) ......................................................... 55
7.1.2.12 Adverse Event Monitoring........................................................................... 57
7.1.2.12.1 Hyperglycemia...................................................................................... 57
7.1.2.12.2 Hypoglycemia....................................................................................... 58
7.1.2.12.3 Urinary Tract Infections........................................................................ 58
7.1.2.12.4 Genital Fungal Infections...................................................................... 58
7.1.2.12.5 Reduction in Renal Function ................................................................ 59
 
 
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7.1.2.12.6 Ketoacidosis.......................................................................................... 59
Laboratory Procedures/Assessments .................................................................. 59
7.1.3
7.1.3.1
Laboratory Evaluations (Hematology, Chemistry and Others) ................... 60
7.1.3.2
Future Biomedical Research........................................................................ 61
Other Procedures................................................................................................. 61
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 61
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 61
7.1.4.2
Blinding/Unblinding .................................................................................... 62
7.1.4.3
Calibration of Critical Equipment................................................................ 62
Visit Requirements.............................................................................................. 62
7.1.5
7.1.5.1
Fasting Prior to Scheduled Visits................................................................. 62
7.1.5.2
Scheduling Visits ......................................................................................... 63
7.1.5.3
Visit 1/Screening.......................................................................................... 63
7.1.5.4
Visit 2/Week -2: Single-blind Placebo Run-in ............................................ 64
7.1.5.5
Treatment Period.......................................................................................... 65
7.1.5.5.1
Visit 3/Randomization (Day 1)............................................................. 65
7.1.5.5.2
Visit 4/Week 4 through Visit 7/Week 24:  Double-blind Treatment 
Period.................................................................................................... 65
7.1.5.6
14-Day Post Treatment Telephone Contact................................................. 65
7.1.5.7
Follow-up for Subjects Who Discontinue Blinded Study Drug .................. 65
7.1.5.8
Follow-up for Subjects Who Discontinue Due to Decreased Renal 
Function ....................................................................................................... 66
Assessing and Recording Adverse Events .......................................................... 66
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 67
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 67
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 68
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 68
7.2.3.2
Events of Clinical Interest............................................................................ 69
Evaluating Adverse Events ................................................................................. 70
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 73
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 73
Statistical Analysis Plan Summary ..................................................................... 73
8.1
 
 
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Responsibility for Analyses/In-House Blinding ................................................. 74
8.2
Hypotheses/Estimation ......................................................................................... 75
8.3
Analysis Endpoints ............................................................................................... 75
8.4
Efficacy Endpoints.............................................................................................. 75
8.4.1
Safety Endpoints ................................................................................................. 75
8.4.2
Derivation of Efficacy Endpoints ....................................................................... 76
8.4.3
Analysis Populations............................................................................................. 76
8.5
Efficacy Analysis Populations ............................................................................ 76
8.5.1
Safety Analysis Populations ............................................................................... 77
8.5.2
Statistical Methods................................................................................................ 77
8.6
Statistical Methods for Efficacy Analyses .......................................................... 77
8.6.1
Statistical Methods for Safety Analyses ............................................................. 80
8.6.2
Demographic and Baseline Characteristics ........................................................ 84
8.6.3
Interim Analyses ................................................................................................... 84
8.7
Multiplicity ............................................................................................................ 84
8.8
Sample Size and Power Calculations .................................................................. 85
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 85
8.10
Compliance (Medication Adherence).................................................................. 86
8.11
Extent of Exposure................................................................................................ 86
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 87
Investigational Product ........................................................................................ 87
9.1
Packaging and Labeling Information ................................................................. 87
9.2
Clinical Supplies Disclosure................................................................................. 87
9.3
Storage and Handling Requirements.................................................................. 88
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 88
9.5
Standard Policies................................................................................................... 88
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 88
Confidentiality....................................................................................................... 88
10.1
Confidentiality of Data ....................................................................................... 88
10.1.1
Confidentiality of Subject Records ..................................................................... 89
10.1.2
Confidentiality of Investigator Information........................................................ 89
10.1.3
 
 
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Confidentiality of IRB/IEC Information............................................................. 89
10.1.4
Compliance with Financial Disclosure Requirements....................................... 90
10.2
Compliance with Law, Audit and Debarment ................................................... 90
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 92
10.4
Quality Management System............................................................................... 92
10.5
Data Management................................................................................................. 92
10.6
Publications ........................................................................................................... 93
10.7
11.0
LIST OF REFERENCES......................................................................................... 94
12.0
APPENDICES........................................................................................................... 96
Merck Code of Conduct for Clinical Trials........................................................ 96
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 98
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 104
Management of Subjects with Elevated Liver Function Tests ....................... 115
12.4
Predefined Limits of Change (PDLC)............................................................... 120
12.5
13.0
SIGNATURES......................................................................................................... 122
Sponsor's Representative ................................................................................... 122
13.1
Investigator.......................................................................................................... 122
13.2
 
 
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LIST OF TABLES
    
Table 1  Laboratory Exclusion Criteria .................................................................................. 29
Table 2  Trial Treatments........................................................................................................ 32
Table 3  Timing for the 2-pt MMTT....................................................................................... 56
Table 4  Timing for the 3-pt MMTT....................................................................................... 57
Table 5 Laboratory Evaluations............................................................................................. 60
Table 6  Evaluating Adverse Events....................................................................................... 71
Table 7  Efficacy Endpoints.................................................................................................... 75
Table 8  Analysis Strategy for Key Efficacy Variables.......................................................... 79
Table 9 Analysis Strategy for Safety Parameters .................................................................. 82
Table 10  Product Descriptions............................................................................................... 87
 
 
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LIST OF FIGURES
          
Figure 1 Trial Design.............................................................................................................. 19
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Numbers
Section Titles
Description of Change s
Rationale
1.0 
2.1 
2.2
3.1
3.2
4.2.1
5.1.1
5.1.2
5.1.3
5.2
5.2.1.2.3
5.2.2
5.5
5.7
Protocol Title
Trial Summary
Trial Design
Trial Diagram
Primary Objectives & Hypotheses
Secondary Objectives & Hypotheses
Rationale for the Trial and Selected 
Subject Population
Diagnosis/Condition for Entry into 
the Trial
Subject Inclusion Criteria
Subject Exclusion Criteria 
Trial Treatment
Dose Modification of Metformin and 
Sulfonylurea
Timing of Dose Administration
Concomitant 
Medications/Vaccinations (Allowed 
& Prohibited)
Subject Withdrawal/Discontinuation 
Criteria
Visit 1: expanded the population 
to include subjects on dual 
combination with metformin and 
an SU agent
Since 
both 
sitagliptin 
and 
dapagliflozin are commonly used in 
dual combinations (e.g., add-on to 
metformin) and in triple combinations 
(e.g., add-on to metformin and an SU 
agent), the background allowed AHAs 
will be expanded to include patients on 
either metformin monotherapy or 
metformin in dual combination with 
an SU agent.  This will better reflect 
the breadth of add-on uses of both 
dapagliflozin 
and 
sitagliptin, 
and 
therefore 
allow 
a 
more 
robust 
comparison of these agents. The dose 
of the SU agent will be required to be 
at least 50% of maximum labeled 
dose, consistent with near maximum 
efficacy of the SU agent. 
 
 
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6.0
7.1.2.11
7.1.3.1 
7.1.5.1  
7.1.5.2
7.1.5.3
8.1
8.5.1
8.6.1
8.6.2
8.6.3
Trial Flow Chart
Mixed Meal Tolerance Test (MMTT) 
Laboratory Evaluations (Hematology, 
Chemistry and Others) 
Fasting Prior to Scheduled Visits 
Scheduling Visits
Visit 1/Screening
Statistical Analysis Plan Summary
Efficacy Analysis Populations
Statistical 
Methods 
for 
Efficacy 
Analyses
Statistical 
Methods 
for 
Safety 
Analyses
Demographic 
and 
Baseline 
Characteristics
2.1
5.1.2
Trial Design
Inclusion Criteria
Visit 1: Increased the upper limit 
of the A1C range to 9.5% from 
9.0%
This allows a broader range of patients 
to participate, including patients (i.e., 
those between 9-9.5% A1C values) 
who would often receive the addition 
of 
therapy 
with 
sitagliptin 
or 
dapagliflozin.
5.1.2
Inclusion Criteria
Visit 1:  Added criteria that will 
allow subjects to qualify for a 
repeat test of their Visit 1 eGFR.  
To allow patients with previous eGFR 
values (prior to study entry) within 
protocol-specified ranges, who do not 
meet 
required 
eGFR 
range 
at 
Screening, to have a single repeat.
 
 
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5.1.2
2.2
Inclusion Criteria
Trial Diagram
Visit 2:  Updated the eGFR 
inclusion criteria and expanded 
the criteria required for subjects 
to qualify for a repeat test of 
their Visit 2 eGFR.  
Added the
modified Visit 2 
eGFR inclusion criteria.
To simplify the Visit 2 eGFR entry 
criteria: 
allowing 
patients 
with 
changes in eGFR within the range of 
day-to-day 
variability 
(≤ 
20 
mL/min/1.73 m2 compared to the Visit 
1 qualifying value) to participate, if 
eGFR is still in protocol-specified 
eGFR range (i.e., 60-90 mL/min/1.73 
m2). Also, to allow patients with 
eGFR values slightly outside of the 
range of day to day variability (up to ≤ 
30 mL/min/1.73 m2 compared to the 
Visit 1 qualifying value) to have a 
single repeat to evaluate eligibility.
5.1.3
Exclusion Criteria
Added note to state that subjects 
that were excluded based upon 
Protocol 838-00, but may be 
eligible under Protocol 838-02, 
may be rescreened, one time.
To allow patients who had previously 
been excluded
under the original 
protocol,
an 
opportunity 
to 
be 
rescreened under the amendment.
2.1 
5.7.1
Trial Design
Follow-up 
for 
Subjects 
Who 
Discontinue Blinded Study Drug
Revised text to state that subjects 
who 
discontinue 
study 
medication without withdrawing 
consent should be counseled to 
return to the study site for all 
scheduled safety and efficacy 
evaluations.
To make consistent with the approach 
indicated by some health agencies 
(including the US FDA) that diabetes 
studies attempt to obtain results from 
protocol-specified 
procedures 
in 
patients 
who 
discontinue 
study 
medication (if they agree to remain in 
the study off of study medication).  
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3
Exclusion Criteria
Criteria #22:  Clarified the 
conditions which would, in the 
judgment of the investigator, 
make the subject inappropriate 
for entry into the trial. 
Criteria #37:  Removed text 
regarding thyroid replacement 
therapy
Wording 
clarified 
and 
simplified without changing 
intent of criterion.
Patient must be on a stable dose 
of thyroid replacement therapy 
6 
weeks 
prior 
to 
Visit 
1/Screening, 
not 
Visit 
3/Randomization (Day 1)
5.2.1.2.1
Dose 
Modification 
of 
Sitagliptin/Matching Placebo to 
Sitagliptin
Updated text regarding adverse 
events which would necessitate 
interruption or discontinuation 
of study medication.
To 
make 
consistent 
with 
updates 
to 
the 
sitagliptin 
labeling.
5.2.1.2.2
Dose 
Modification 
of 
Dapagliflozin/Matching 
Placebo to Dapagliflozin
Updated text regarding adverse 
events which would necessitate 
interruption or discontinuation 
of study medication.
To 
make 
consistent 
with 
updates to the dapagliflozin 
labeling.
5.5
6.0
Concomitant 
Medications/Vaccinations 
(Allowed & Prohibited)
Trial Flow Chart
Added details regarding the 
requirements for concomitant 
medication assessments.
Added 
row 
specifying 
the 
review 
of 
any 
prohibited 
medications, including AHAs 
other than the trial treatments.
Added footnote (f) to clarify 
the 
requirements 
for 
concomitant 
medication 
assessments.
To clarify requirements and 
ensure patient adherence to 
protocol.   
Added row and footnote in trial 
flow chart to emphasize the 
importance of reviewing this 
information
 
 
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6.0
Trial Flow Chart
Discontinuation 
Column:  
Updated text to indicate that the 
Discontinuation Visit is only 
for subjects who discontinue 
study medication prematurely. 
Revised footnote (b) to indicate 
that subjects, who discontinue 
study 
medication,
should 
complete procedures for the 
Discontinuation Visit and (if 
consent was not withdrawn)
continue to be followed by the 
investigational site, attending 
scheduled study visits and 
undergoing study procedures.
Added footnote (i) to indicate 
that 
subjects 
who 
are 
continuing in the study off of 
double-blind study medication, 
should 
not 
receive 
study 
medication 
and 
compliance 
should not be assessed.
To 
clarify 
which 
subjects 
should have a Discontinuation 
Visit.
To clarify which procedures 
need to be completed by 
subjects who are continuing in 
the 
trial 
off 
of 
study 
medication.
6.0
Trial Flow Chart
Added “Review of 
Health 
Economic Assessment”
Already 
indicated 
to 
be 
performed 
(stated 
study 
objective); added row in trial 
flow 
chart 
to 
remind 
investigators to collect health 
utilization information.
6.0
Trial Flow Chart
Added footnote (a) to clarify 
the interval required between 
Visit 1 and Visit 2.
Footnote 
added
for 
clarification.
 
 
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7.1.2.11
6.0
Mixed Meal Tolerance Test
Trial Flow Chart
Added note to clarify that 
subjects who are discontinuing 
study medication but agree to 
continue in the study off of 
study medication should have 
the MMTT conducted at the 
Discontinuation 
Visit. 
However, the final visit (i.e., 
Visit 
7/Week 
24) 
MMTT 
should not be performed.
Modified
footnote
(s) 
to 
indicate that for subjects who 
stop 
study 
medication 
prematurely, but will continue 
in the study off of double-blind 
study medication, the MMTT 
should be performed at the 
Discontinuation Visit (and not 
at Visit 7/Week 24).
To clarify which procedures 
need to be completed by 
subjects who are continuing in 
the 
trial 
off 
of 
study 
medication.
7.1.2.12.4
Genital Fungal Infections
Changed the term from “central 
lab” to “local lab”.
To clarify that the analysis 
should be done at a local lab 
and not by the central lab
7.1.3.1
Laboratory 
Evaluations 
(Hematology, Chemistry and 
Others)
Added guidance for subjects 
who do not fast for at least 10 
hours prior to visits.
Clarify requirement for fasting.
 
 
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7.2.1
Definition of an Overdose for 
This Protocol and Reporting of 
Overdose to the Sponsor
Added 
text 
to 
define 
an 
overdose of dapagliflozin.
In a dose range study of 
dapagliflozin, the safety and 
tolerability profile was reported 
to be generally similar over the 
dose range studied of 5 to 50 
mg per day for 12 weeks in 
patients with T2DM. Given 
these results, doses above 50 
mg per day (>5 times the dose 
of dapagliflozin included in this 
study) will be considered as an 
overdose. 
8.6.1
Statistical Methods for Efficacy 
Analysis
Removed the analyses that use 
LOCF to handle missing data. 
Defined the primary estimands 
for the study.  
To comply with FDA efficacy 
recommendations.
8.6.2
Statistical Methods for Safety 
Analysis
Defined 
the 
primary 
and 
secondary 
approaches 
for 
safety analysis.   
To clarify the handling of data 
collected beyond the 14-day 
follow-up period after the last 
dose of blinded study drug.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Sitagliptin vs. Dapagliflozin As Add-on to Metformin With or 
Without Sulfonylurea in Subjects with Mild Renal Impairment
Trial Phase
Phase III
Clinical Indication
Treatment of Type 2 Diabetes Mellitus (T2DM)
Trial Type
Interventional
Type of control
Active control
Route of administration
Oral
Trial Blinding
Double-blind
(Select Groups)
Sitagliptin 100 mg q.d., dapagliflozin 10 mg q.d.
Number of trial subjects
Approximately 556 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 75 
weeks from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 30 weeks 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  This will include a 2-week screening period 
(Visit 1 to Visit 2); a 2-week single-blind placebo run-in period (Visit 
2 to Visit 3); a 24-week double-blind, active-comparator-controlled 
treatment period (Visit 3 to Visit 7); and a post-treatment telephone 
contact 14 days after the last dose of blinded study drug.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a multicenter, randomized, double-blind, active-comparator-controlled, parallel-group
clinical trial of sitagliptin in subjects with type 2 diabetes mellitus (T2DM) and mild renal 
impairment and who have inadequate glycemic control on metformin monotherapy or dual 
metformin/sulfonylurea (SU) therapy.  This trial will be conducted in conformance with 
Good Clinical Practices.
The duration of the trial will be up to approximately 30 weeks (with 7 clinic visits) for each
subject.  This will include a 2-week Screening Period (Visit 1 to Visit 2); a 2-week single-
blind placebo run-in period (Visit 2 to Visit 3); a 24-week double-blind, active-comparator-
controlled treatment period (Visit 3 to Visit 7); and a post-treatment telephone contact 14 
days after the last dose of blinded study drug.
Approximately 556 men and women ≥25 years of age with T2DM, diagnosed in accordance 
with American Diabetes Association (ADA) guidelines [1] with inadequate glycemic control 
(hemoglobin A1c [A1C] ≥7.0% and ≤9.5% [≥53 mmol/mol and ≤80 mmol/mol]) while on a 
stable dose of metformin (≥1500 mg/day for ≥8 weeks) alone or in dual combination with an 
SU (at a dose of ≥ 50% of maximum labeled dose) with an estimated glomerular filtration 
rate (eGFR) ≥60 and <90 mL/min/1.73m2 as calculated by the CKD-epi equation, and who 
meet all other enrollment criteria will be randomized.   
Randomization Ratio
1:1
 
 
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All subjects will undergo a mixed meal tolerance test (MMTT) at Visit 3/Randomization, 
before their first dose of double-blind study drug, and at the end of the double-blind 
treatment period (Visit 7/Week 24 or Discontinuation Visit).  At the majority of investigator 
sites, all subjects will undergo a 2-point, 2-hour MMTT.  At selected investigator sites, all 
subjects will instead undergo a 2-hour, 3-point MMTT.  It is expected that approximately 316 
subjects will undergo a 2-point, 2-hour MMTT at both time points and approximately 240 
subjects will undergo a 3-point, 2-hour MMTT at both time points.
Management of Subjects Prior to Randomization
Subjects on a stable dose of metformin (≥1500 mg/day for ≥8 weeks) in monotherapy or in 
dual combination with an SU agent (at a dose of ≥ 50% of maximum labeled dose) with an 
A1C ≥7.0% and ≤9.5% (≥53 mmol/mol and ≤80 mmol/mol) at Visit 1/Screening, an eGFR 
≥60 and <90 mL/min/1.73m2 at Visit 1/Screening and Visit 2/Week -2, and who meet all 
other enrollment criteria will be eligible to enter the double-blind treatment period beginning 
at Visit 3/Randomization (Day 1), after completing the 2-week single-blind placebo run-in 
period (Visit 2/Week -2 to Visit 3/Randomization [Day 1]).
Management of Randomized Subjects
At Visit 3/Randomization (Day 1), subjects will enter the 24-week, double-blind, active-
comparator-controlled treatment period and be randomized in a 1:1 ratio to sitagliptin 100 
mg once-daily (q.d.) or dapagliflozin once daily.  Dapagliflozin/matching placebo will be 
initiated at 5 mg and titrated up to 10 mg at Visit 4/Week 4. If, in the opinion of the 
investigator, a subject is unable to tolerate up-titration to 10 mg at Visit 4/Week 4, the subject
may remain on dapagliflozin 5 mg/matching placebo; in this case the investigator should 
continue to assess at subsequent visits whether the subject may be up-titrated to dapagliflozin
10 mg/matching placebo.  Dapagliflozin 10 mg/matching placebo may be down-titrated to 
dapagliflozin 5 mg/matching placebo if subjects demonstrate an inability to tolerate the 
higher dose. Subjects are to remain on their stable doses of metformin and, for subjects 
entering on metformin and SU dual combination, stable doses of their SU agent, while
receiving blinded study drug during the double-blind treatment period.  
Every appropriate effort should be made to support subject study completion on the anti-
hyperglycemic agent (AHA) regimen to which they are randomized.  Subjects may 
discontinue blinded study therapy without withdrawing consent, and remain in the study, off 
of blinded study medication.  These subjects should complete procedures for the 
Discontinuation Visit at the time they discontinue blinded study therapy, and should then be 
counseled to return to the study site for all scheduled safety and efficacy evaluations (per 
Trial Flowchart, see Section 6.0).  If a subject is not willing to return to the investigational 
site for subsequent scheduled study visits, alternative efforts should be made to collect safety 
and efficacy information, as summarized in Sections 5.7.1 and 7.1.4.
Withdrawal of consent will result in discontinuation of all study procedures. Subjects 
withdrawing consent should be encouraged to complete procedures for the Discontinuation 
Visit.  
 
 
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This trial is designed to evaluate, in adult subjects with T2DM and chronic mild renal 
impairment and who have inadequate glycemic control on diet and exercise and metformin,
alone or in dual combination with an SU, the glycemic efficacy, safety, and tolerability of the 
addition of treatment with sitagliptin over a 24-week treatment period in comparison to the
addition of treatment with dapagliflozin.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1 Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In subjects with T2DM and mild renal impairment with inadequate glycemic control on 
metformin alone or in dual combination with an SU agent:
1) Objective:  After 24 weeks, to assess the effect of the addition of sitagliptin
compared with the addition of dapagliflozin on A1C.
Hypothesis:  After 24 weeks, the change from baseline in A1C in subjects treated 
with the addition of sitagliptin is non-inferior compared to that in subjects treated 
with the addition of dapagliflozin.
Note: The non-inferiority margin is 0.3%.  The criterion for determining non-
inferiority can be found in Section 8 (Statistical Analysis Plan).
2) Objective: Over 24 weeks, to assess the overall safety and tolerability of sitagliptin
in comparison to that of dapagliflozin.
Secondary Objective(s) & Hypothesis(es)
3.2
In subjects with T2DM and mild renal impairment with inadequate glycemic control on 
metformin alone or in dual combination with an SU agent, after 24 weeks:
1) Objective: To assess the effect of the addition of sitagliptin compared with the 
addition of dapagliflozin on change from baseline in 2-hour incremental post-prandial 
glucose excursion.
Hypothesis: The addition of sitagliptin provides greater reduction in incremental 
post-prandial glucose excursion compared with the addition of dapagliflozin.
2) Objective:  To assess the effect of the addition of sitagliptin compared with the
addition of dapagliflozin on change from baseline in 2-hour post-prandial glucose 
(PPG).
3) Objective:  To assess, in a subset of subjects, the effect of the addition of sitagliptin 
compared with the addition of dapagliflozin on change from baseline in post-prandial 
insulin AUC, glucagon AUC, and insulin AUC:glucagon AUC ratio.
4) Objective:  To assess the effect of the addition of sitagliptin compared with the
addition of dapagliflozin on the proportion of subjects at the A1C goal of <7.0% (<53
mmol/mol).
5) Objective:  To describe the effect of the addition of sitagliptin compared with the 
addition of dapagliflozin on change in fasting plasma glucose (FPG) from baseline.
Other Objectives
3.3
Over 26 weeks (the 24-week treatment period plus the 2-week safety follow-up period), to 
assess the effect of the addition of sitagliptin compared with the addition of dapagliflozin on 
medical resource utilization (e.g., visits to healthcare providers).
 
 
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4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the approved labeling for detailed background information on sitagliptin and 
dapagliflozin.
Pharmaceutical and Therapeutic Background
4.1.1
There has been a steady increase in the global prevalence of T2DM, largely attributed to 
rising rates of excess body weight and obesity. In 2011, diabetes was estimated to affect 
more than 365 million people worldwide between the ages of 20-79 years, and the prevalence 
of diabetes is projected to reach more than 550 million by the year 2030 [2]. T2DM also 
represents one of the largest medical burdens in the United States, resulting in direct medical 
costs of $176 billion and $69 billion in loss of productivity in 2012 [3]. At present, it is 
estimated that 25.8 million people in the US have diabetes (8.3% of the population), of which 
7 million remain undiagnosed [4]. T2DM accounts for approximately 90-95% of all cases of 
diabetes. Individuals with T2DM have an increased risk of developing both microvascular 
and macrovascular complications, including nephropathy, neuropathy, retinopathy, and 
cardiovascular disease, and are 2 to 4 times more likely to die from cardiovascular disease 
than adults who do not have diabetes [5].
In recent years, diabetes experts have reached a consensus that glycemic targets and glucose-
lowering therapies should be individualized [6]. Important comorbidities and adverse effects 
of anti-hyperglycemic agents (AHAs) are among the subject factors that should be 
considered. Diet, exercise, and education remain the foundation of treatment for T2DM, but 
most patients will eventually require AHA therapy. Hence, it is essential to understand the 
relative efficacy and safety/tolerability of available AHA therapies.
Sitagliptin (Merck, Sharp, & Dohme Corp.) is an orally active and highly-selective dipeptidyl 
peptidase IV (DPP-4) inhibitor indicated for the treatment of patients with T2DM.  The 
therapeutic improvements in glycemic control associated with sitagliptin are mediated by 
increases in the active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-
dependent insulinotropic polypeptide (GIP), which result from inhibition (by sitagliptin) of 
the DPP-4 enzyme responsible for inactivation of these peptide hormones.  GLP-1 and GIP 
are released by enteroendocrine L- and K-cells respectively in response to a meal, and result 
in enhanced glucose-dependent insulin secretion from pancreatic β-cells.  In addition, GLP-1 
suppresses glucagon release from pancreatic α-cells and slows gastric emptying.  These 
effects work in concert to lower both fasting and post-prandial glucose concentrations.  
Clinical studies have shown that sitagliptin (as monotherapy and in combination with other 
AHAs) is generally well-tolerated, effectively reducing blood glucose concentrations in 
patients with T2DM.  In the United States, sitagliptin (JANUVIA™) is approved as an 
adjunct to diet and exercise to improve glycemic control as monotherapy and as combination 
therapy with other AHAs including insulin.  In the European Union (EU), sitagliptin 
(JANUVIA™, TESAVEL™, XELEVIA™) is approved as a restricted first-line oral AHA in 
patients who cannot tolerate metformin or with contraindication to metformin use.  In 
addition, sitagliptin is approved in the EU as add-on therapy in combination with other 
AHAs including insulin.
 
 
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Dapagliflozin (AstraZeneca LP) is an orally active and highly-selective sodium-glucose 
cotransporter 2 (SGLT2) inhibitor indicated for the treatment of patients with T2DM.  
Inhibition of the SGLT2 transporter in the proximal tubule of the nephron results in glucose 
excretion and improved glycemic control. Effects secondary to the glucosuria are an osmotic 
diuresis resulting in blood pressure reduction and calorie loss resulting in weight loss. 
Clinical studies have shown that dapagliflozin (as monotherapy and in combination with 
other AHAs) is generally well tolerated, effectively reducing blood glucose concentrations in 
patients with T2DM and an eGFR ≥60 mL/min/1.73m2.  In the United States, dapagliflozin 
(FARXIGA™) is approved as an adjunct to diet and exercise to improve glycemic control as 
monotherapy and as combination therapy with other AHAs including insulin. In the EU, 
dapagliflozin (FORXIGA™) is approved as a restricted first-line oral AHA in patients who 
cannot tolerate metformin or with contraindication to metformin use.  In addition, 
dapagliflozin is approved in the EU as add-on therapy in combination with other AHAs 
including insulin.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
T2DM is a progressive disease, with pancreatic β-cell function declining with increasing
duration of the disease. Though initiation of metformin therapy continues to be the standard 
first-line pharmacologic intervention for the management of hyperglycemia due to T2DM, 
additional therapies are eventually required to achieve and maintain recommended levels of 
glycemic control (i.e., A1C <7% for most patients), including addition of an SU agent or a 
DPP-4 inhibitor, or an SGLT2 inhibitor. Sitagliptin is a DPP-4 inhibitor and is commonly 
used as add-on to metformin or add-on to metformin/SU to improve glycemic control. 
Dapagliflozin is a member of a recently approved class of anti-hyperglycemic agents (AHAs) 
called SGLT2 inhibitors, which is often used as add-on to metformin or add-on to 
metformin/SU to improve glycemic control. Because the mechanism of action of SGLT2-
inhibitors is via the kidney, this class of compounds has less glycemic efficacy in renal 
impairment and restricted indications for use in patients with moderate and severe renal 
impairment. Some reduction in efficacy in subjects with only mild renal impairment (eGFR 
60 to <90 mL/min/1.73m2) has been demonstrated with dapagliflozin as well as other 
approved compounds in this class [7, 8] but prospectively designed studies comparing 
efficacy, safety and tolerability of this class to other AHAs in subjects with mild renal 
impairment have not been done. Moreover, though sitagliptin clinical trials have included 
subjects who meet eGFR criteria for mild renal impairment, this sub-group has not been 
specifically studied in a dedicated clinical trial of sitagliptin. 
 
 
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Renal impairment is common in patients with T2DM, and 38% of individuals with T2DM 
are estimated to have chronic mild renal impairment [9]. Minimum age for inclusion in this 
trial is 25 years old, in order to provide added assurance that the mild renal impairment is due 
to an underlying chronic condition (e.g., T2DM) rather than due to a primary renal disease 
which may progress rapidly.  This study will evaluate the relative glycemic efficacy (by 
assessment of non-inferiority of A1C reduction) and the relative safety/tolerability profile of 
sitagliptin in comparison to dapagliflozin in subjects with T2DM and mild renal impairment 
who have inadequate glycemic control on a background of metformin alone or dual
combination with an SU in conjunction with diet and exercise.
Rationale for Dose Selection/Regimen
4.2.2
4.2.2.1
Rationale for Sitagliptin Dose
The approved dose for patients with creatinine clearance (CrCl) ≥50 mL/min is sitagliptin 
100 mg once daily. Given that this study will enroll subjects with mildly impaired renal 
function (eGFR 60 to <90 mL/min/1.73m2), sitagliptin 100 mg once daily is appropriate.
4.2.2.2
Rationale for Dapagliflozin Dose
The recommended dose of dapagliflozin is 10 mg once daily.  In accordance with the US 
labeling, the starting dose in this trial will be 5 mg once daily. At Visit 4/Week 4 of the 
treatment period, dapagliflozin will be up-titrated to 10 mg daily in all subjects unless, in the 
opinion of the investigator, the subject is unlikely to tolerate the 10 mg dose. Subjects on the 
10 mg dose who, in the opinion of the investigator, are unable to tolerate the 10 mg dose may 
be down-titrated to the 5 mg dose.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
Glycemic efficacy endpoints will be A1C, FPG, 2-hour post-prandial glucose (PPG), 2-hour 
incremental post-prandial glucose excursion, and post-prandial insulin, glucagon, and 
insulin:glucagon ratio. A1C reflects average glucose concentrations in the past 3-4 months 
and, therefore, provides a useful index of the glycemic control of sitagliptin and dapagliflozin
over that time period. It is a standard efficacy endpoint used to assess the glycemic efficacy 
of AHAs, and improvement in A1C correlates with reduction of risk of diabetic 
complications. Although sitagliptin lowers both the post-prandial rise in glucose and fasting 
glucose levels, a greater effect on the incremental post-prandial glucose is usually observed 
[10].  Some studies have highlighted the role of post-prandial glucose excursions in 
contributing to diabetic complications, and suggested the importance of post-meal glucose 
control [11].  Assessment of incremental post-prandial glucose excursion will provide insight 
into the relative effects of sitagliptin and dapagliflozin on post-prandial glucose control, with 
2-hr PPG evaluating both post-meal and fasting control. Assessment of post-prandial insulin, 
glucagon, and insulin:glucagon will aid in understanding of the relative effects of sitagliptin 
and dapagliflozin on hormonal regulation of glucose. Assessment of FPG will characterize 
the earlier time course of glucose control in this trial.
 
 
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Although subjects randomized to dapagliflozin will be on maximum dose for 20 weeks (due 
to the up-titration at Visit 4/Week 4 of the double-blind treatment period) while subjects 
randomized to sitagliptin will be on maximum dose for 24 weeks, this should not bias the 
efficacy assessment in favor of sitagliptin, since both dapagliflozin and sitagliptin are 
expected to achieve maximal glycemic efficacy by 18 weeks of treatment. Therefore, the 
protocol design allows a valid comparison of efficacy between the two treatments.
4.2.3.2
Safety Endpoints
Safety assessment will include collection of adverse events (AEs), a hypoglycemia 
assessment log to collect information on each potential episode (including concurrent 
fingerstick glucose value), physical examination including vital signs and postural blood 
pressure/heart rate.  Laboratory safety studies will include blood chemistry, lipid panel, 
hematology, and urine pregnancy testing (performed in women of childbearing potential).  
Refer to Section 8.0 for further details.
4.2.3.3
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the Informed Consent documents.
 
 
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5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with T2DM and mild renal impairment on metformin alone or in 
combination with an SU agent and who are at least 25 years of age will be enrolled in this 
trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
At Visit 1/Screening
1. Have T2DM in accordance with ADA guidelines [1] and be ≥25 years of age on the 
day of signing the ICF.
2. Have an eGFR ≥60 mL/min/1.73 m2 and <90 mL/min/1.73 m2, as calculated by the 
CKD-epi equation [12].
Note: Subjects with eGFR not meeting this criterion, but with an eGFR value within 
5 mL/min/1.73 m2 of this range (i.e., ≥ 55 and ≤ 95 mL/min/1.73 m2), may have a 
single repeat value, and continue in the study if the repeat value meets the inclusion 
criterion.
3. Be on metformin ≥1500 mg/day alone or in combination with an SU agent (at a dose 
of ≥50% maximum labeled dose in the country of the investigational site) for ≥8
weeks with a Visit 1/Screening A1C ≥7.0% and ≤9.5% (≥53 mmol/mol and ≤80
mmol/mol).
4. Have a body mass index (BMI) ≥18.0 kg/m2.
5. Have personally signed and dated the ICF indicating that he/she has been informed of 
all pertinent aspects of the trial.  The subject may also provide consent for Future 
Biomedical Research.  However, the subject may participate in the main trial without 
participating in Future Biomedical Research.
6. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures.
7. Meet one of the following criteria:
a.
Subject is a male.
b. Subject is a female not of reproductive potential defined as one who:
1) Is postmenopausal (defined as at least 12 months with no menses in 
women ≥45 years of age), or
 
 
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2) Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral 
tubal ligation or occlusion at least 6 weeks prior to Visit 1/Screening.
c.
Subject is a female of reproductive potential and:
1) agrees to remain abstinent from heterosexual activity (if this form of birth 
control is accepted by local regulatory agencies and ethics review 
committees as the sole method of birth control for subjects participating in 
clinical trials), or
2) agrees to use (or have her partner use) acceptable contraception to prevent 
pregnancy while receiving blinded study drug and for 14 days after the last 
dose of blinded study drug.  Two methods of contraception will be used to 
avoid pregnancy.  Acceptable combinations of methods include:

Use of one of the following double-barrier methods:  diaphragm 
with spermicide and a condom; cervical cap and a condom; or a 
contraceptive sponge and condom.

Use of hormonal contraception (any registered and marketed 
contraceptive agent that contains and estrogen and/or a 
progestational agent [including oral, subcutaneous, intrauterine and 
intramuscular agents, and cutaneous patch]) with one of the 
following:  diaphragm with spermicide; cervical cap; contraceptive 
sponge; condom, vasectomy, or IUD.

Use of an IUD with one of the following:  condom; diaphragm 
with spermicide; contraceptive sponge; vasectomy; or hormonal 
contraception (see above).

Vasectomy with one of the following:  diaphragm with spermicide; 
cervical cap; contraceptive sponge; condom; IUD; or hormonal 
contraception (see above).
At Visit 2/Week -2
8. Have an eGFR ≥60 mL/min/1.73 m2 and <90 mL/min/1.73 m2, as calculated by the 
CKD-epi equation and ≤ 20 mL/min/1.73 m2 different from the qualifying Visit 
1/Screening value.   
Note (1): The Visit 1 and Visit 2 eGFR measurements must be at least 2 weeks apart
and should be no more than 6 weeks apart.
Note (2): If the above eGFR criteria is not met, but the eGFR value is ≤ 30 
mL/min/1.73 m2 different than the qualifying Visit 1 eGFR value, a single repeat may 
be performed, and the subject is eligible if the repeat meets the above eGFR inclusion 
criterion.  
 
 
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At Visit 3/Randomization/Day 1
9. Be ≥80% compliant with placebo run-in medication (as determined by site-performed 
pill count).
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
At Visit 1/Screening
Diabetes Diagnosis and Prior Therapy Criteria
1. Has a history of type 1 diabetes mellitus or a history of ketoacidosis or subject 
assessed by the investigator as possibly having type 1 diabetes mellitus confirmed 
with a C-peptide <0.7 ng/mL (0.23 nmol/L).  
Note:  Only subjects assessed by the investigator as possibly having type 1 diabetes 
should have C-peptide measured at Visit 1/Screening.
2. Has a history of secondary causes of diabetes (e.g., genetic syndromes, secondary 
pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, 
and post-organ transplant).
3. Has a known hypersensitivity or intolerance to any DPP-4 inhibitor or SGLT2 
inhibitor.
4. Has been treated with any of the following agents within 12 weeks of Visit 
1/Screening:

Insulin of any type (except for short-term use [i.e., ≤7 days] during 
concomitant illness or other stress)

DPP-4 inhibitors

Pioglitazone or rosiglitazone

GLP-1 agonists 

SGLT2 inhibitors 

Alpha glucosidase inhibitors

Meglitinides

Bromocriptine 

Colesevelam 

Any other AHA with the exception of metformin and for subjects on dual 
combination therapy,  a sulfonylurea
5. Subject intends to initiate weight loss medication during the study period.
6. Subject has undergone bariatric surgery within 12 months of Visit 1/Screening.
 
 
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7. Subject is not weight stable (defined as ≥5% change in body weight in the last 6 
months; this may be per subject report).
8. Subject has started a weight loss medication (such as orlistat, phentermine, or 
sibutramine) or a medication associated with weight changes (e.g., anti-psychotic 
medications) within the prior 12 weeks.
Concomitant Disease of Organs and Systems
9. Has a history of myocardial infarction, unstable angina, arterial revascularization, 
stroke, transient ischemic attack, or NYHA functional class III-IV heart failure 
within 3 months of Visit 1/Screening.
10. Is at high risk for volume depletion, hypotension and/or electrolyte imbalances, in 
the opinion of the investigator.
11. Has a history of malignancy ≤5 years prior to signing the ICF, except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer:
Note (1):  A subject with a history of malignancy >5 years prior to signing the ICF 
should have no evidence of residual or recurrent disease.
Note (2):  A subject with any history of melanoma, leukemia, lymphoma, bladder 
cancer, or renal cell carcinoma is excluded.
12. Has human immunodeficiency virus (HIV) as assessed by medical history.
13. Has

Blood dyscrasias or any disorders causing hemolysis or unstable red blood 
cells, or

Clinically important hematological disorder (such as aplastic anemia, 
myeloproliferative or myelodysplastic syndromes, thrombocytopenia).
14. Has a medical history of active liver disease (other than non-alcoholic hepatic 
steatosis), including chronic hepatitis B or C (assessed by medical history), primary 
biliary cirrhosis, or symptomatic gallbladder disease.
15. Has any clinically significant malabsorption condition.
16. Is currently being treated for hyperthyroidism.
17. Is on thyroid replacement therapy and has not been on a stable dose for at least 6 
weeks prior to Visit 1/Screening.
Note:  Subjects who meet this criterion may be re-screened after being on a stable 
dose of thyroid replacement therapy for at least 6 weeks.
18. Is on or likely to require treatment for ≥14 consecutive days or repeated courses of 
pharmacologic doses of corticosteroids.
Note: Inhaled, nasal, ophthalmic, and topical corticosteroids and physiological 
replacement doses of adrenal steroids are permitted.
 
 
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19. Is on or likely to require treatment for ≥7 consecutive days with non-steroidal anti-
inflammatory drugs.
Note:  Does not apply to chronic aspirin (ASA) therapy (≤325 mg daily).
20. Has undergone a surgical procedure within 12 weeks prior to signing the ICF or has 
major surgery planned during the trial.
Note:  A subject who has undergone minor surgery within the 12 weeks prior to Visit 
1/Screening and is fully recovered or a subject who has planned minor surgery may 
participate. Minor surgery is defined as a surgical procedure involving local 
anesthesia.
21. Has a mean value for duplicate sitting systolic blood pressure >160 mm Hg and/or 
diastolic blood pressure >90 mm Hg (after at least a 5-minute seated rest) and blood 
pressure is considered unlikely to be below these limits by Visit 3/Randomization 
(Day 1) with initiation or adjustment of antihypertensive medication.
Note:  Investigators are encouraged to maximize blood pressure control according to 
current guidelines.  The subject may have blood pressure medication initiated or 
adjusted and be enrolled if repeat blood pressure measurements no longer meet the 
exclusion criterion at Visit 3/Randomization (Day 1).  Subjects on blood pressure 
medication must be on a stable regimen for at least 4 weeks prior to Visit 
3/Randomization (Day 1).
22. Has other medical condition, psychiatric condition, or laboratory abnormality that 
may increase the risk associated with study participation or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would make 
the subject inappropriate for entry into this trial.
Exclusion Criteria Based on Laboratory Abnormalities
23. Has an exclusionary laboratory value as listed in Table 1 below:
Table 1 Laboratory Exclusion Criteria
Parameter1
Population
(if applicable)
Trial Limit for Exclusion
Alanine aminotransferase (ALT)
>2 times Upper Limit of Normal (ULN)
Aspartate aminotransferase (AST)
>2 times ULN
Thyroid-stimulating hormone (TSH)2
Outside central laboratory normal range
Hemoglobin
Male
Female
<12 g/dL (120 g/L)
<11 g/dL (110 g/L)
Triglycerides (TG)3
>600 mg/dL (6.78 mmol/L)
1. Subjects with an exclusionary laboratory value may have one repeat determination performed if the 
investigator considers the Visit 1/Screening result to be inconsistent with prior determinations.  Only the 
laboratory test not meeting entry criterion should be repeated (not the entire panel). The last laboratory 
draw/result should be used for inclusion.
2. Subjects excluded due to the TSH criterion may be re-screened after being on a stable thyroid 
replacement therapy for at least 6 weeks.
3. Subjects with elevated TG levels may have lipid-lowering medication initiated or adjusted and continue 
in the trial if a repeat measurement (at Visit 2/Week -2) no longer meets the exclusion criterion.  
Subjects on lipid-lowering medication must be on a stable regimen for at least 4 weeks prior to Visit 
3/Randomization (Day 1).
 
 
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Other Criteria
24. Has participated in other studies involving investigational drug(s) (Phase I-IV) 
within 30 days prior to Visit 1/Screening or during the pre-randomization period.
25. Has a positive urine pregnancy test.
26. Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 
days following the last dose of blinded study drug.
27. Is planning to undergo hormonal therapy in preparation to donate eggs during the 
trial, including 14 days following the last dose of blinded study drug.
28. Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week or 
engages in binge drinking.
Note (1):  One alcoholic drink is defined as 5 oz. (150 mL) of wine, or 12 oz. (350 
mL) of beer, or 1.5 oz. (50 mL) of 80-proof liquor.
Note (2):  Binge drinking is defined as a pattern of 5 or more alcoholic drinks (male), 
or 4 or more alcoholic drinks (female) in about 2 hours.
29. Has donated blood or blood products within 6 weeks of Visit 1/Screening or who 
plans to donate blood or blood products at any time during the trial.
30. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
At Visit 2/Week -2
31. Has a clinically significant ECG abnormality that requires further diagnostic 
evaluation or intervention (e.g., new, clinically significant arrhythmia or a 
conduction disturbance).
32. Has a FPG consistently (i.e., measurement repeated and confirmed within 7 days) 
>260 mg/dL (14.4 mmol/L).
33. Has a positive urine pregnancy test.
34. Has a fasting TG level >600 mg/dL (6.8 mmol/L).
Note:  This criterion applies to subjects who met the exclusion criterion for TG levels 
at Visit 1/Screening and who required evaluation of TG levels at Visit 2/Week -2 to 
assess eligibility following initiation or adjustment of lipid-lowering medication.
At Visit 3/Randomization (Day 1)
35. Has a site fasting fingerstick glucose (FFSG) <110 mg/dL (6.1 mmol/L) or >260 
mg/dL (14.4 mmol/L).
Note:  If the subject meets this exclusion criterion AND the investigator believes that 
the value is not consistent with the subject’s current SMBG values and Visit 2/Week -
2 FPG value, the subject should not be excluded at this time.  This visit should be 
changed to an Unscheduled Visit and the subject should be rescheduled for Visit 
3/Randomization (Day 1) within 7 days.  Additional single-blind placebo run-in 
medication should be dispensed if needed.
 
 
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If the subject meets this FFSG exclusion criterion at the rescheduled Visit 
3/Randomization (Day 1), the subject MUST be excluded.
36. Has a positive urine pregnancy test.
37. Is on lipid-lowering medication or blood pressure medication and has not been on a 
stable regimen for the 4 weeks prior to Visit 3/Randomization (Day 1).
Note:  The current visit can be changed to an Unscheduled Visit, and the subject 
should be rescheduled for a Visit 3/Randomization (Day 1).  Additional single-blind 
placebo run-in medication should be dispensed if needed.
38. Has a mean value for duplicate sitting systolic blood pressure of >160 mm Hg and/or 
diastolic blood pressure of >90 mm Hg (after at least a 5-minute seated rest).
39. Has developed a new medical condition, suffered a change in status of an established 
medical condition, developed a laboratory or ECG abnormality, or required a new 
treatment of medication during the pre-randomization period which meets any 
previously described trial exclusion criteria or which, in the opinion of the 
investigator, exposes the subject to risk by enrolling in the trial.
Note: Subjects that were excluded based upon eGFR or A1C criteria in Protocol 
838-00, but may be eligible under Protocol 838-02 may be rescreened once 
(returning to the site for a Screening Visit/Visit 1); similarly, subjects on metformin 
and a sulfonylurea, eligible under Protocol 838-02 may be rescreened once 
(returning to the site for a Screening Visit/Visit 1); see site Data Entry Guidelines for 
specific details).
 
 
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Trial Treatment(s)
5.2
Treatments to be used in this trial are outlined below in Table 2.  
Table 2 Trial Treatments
Treatment Group
Drug/Dose
Use
Dose Frequency/ 
Treatment Period
Route of 
Administration
placebo run-in
(all groups)
matching placebo for 
sitagliptin 100 mg
placebo
(trial drug)
q.d. for 2 weeks
oral
matching placebo for 
dapagliflozin 5 mg
placebo
(active-comparator)
sitagliptin
100 mg group
sitagliptin 100 mg
investigational
(trial drug)
q.d. for 24 weeks
oral
matching placebo for 
dapagliflozin 5 mg
placebo
(active-comparator)
q.d. for 4 weeks1
matching placebo for 
dapagliflozin 10 mg
q.d. for 20 
weeks2
dapagliflozin
10 mg group
dapagliflozin 5 mg
active-comparator
q.d. for 4 weeks1
oral
dapagliflozin 10 mg
q.d. for 20 
weeks2
matching placebo for 
sitagliptin 100 mg
placebo
(trial drug)
q.d. for 24 weeks
1 Starting at Visit 3/Randomization (Day 1) through one day prior to Visit 4/Week 4.
2 Starting at Visit 4/Week 4 and for the duration of the double-blind treatment period. Up-titration to 10 mg q.d./matching 
placebo may be delayed if subject is unable to tolerate up-titration in the opinion of the investigator. Dapagliflozin 10 mg 
q.d./matching placebo may be down-titrated to dapagliflozin 5 mg q.d. if subject is unable to tolerate the higher dose in the 
opinion of the investigator.
The first doses of single-blind matching placebo for sitagliptin and matching placebo for 
dapagliflozin will be administered at the trial site as witnessed doses at Visit 2/Week -2.  
The first doses of double-blind sitagliptin/matching placebo and dapagliflozin/matching 
placebo will be administered at the trial site as witnessed doses at Visit 3/Randomization 
(Day 1), after completion of study procedures including MMTT.  Subsequent dosing will be 
performed once-daily by the subject unsupervised at his/her home at approximately the same 
time each day in the morning.
Supply of background metformin (and SU, for subjects on an SU) will be the responsibility 
of the subject throughout the duration of the trial.  
Sitagliptin 100 mg and matching placebo will be administered in a blinded manner as oral 
tablets q.d.  Dapagliflozin 5 mg, dapagliflozin 10 mg, and matching placebos will be 
administered in a blinded manner as oral capsules q.d.  Hence, all subjects will take 1 tablet 
and 1 capsule each day.
Subjects randomized to sitagliptin 100 mg q.d. will take one sitagliptin 100 mg tablet and one 
matching placebo capsule for dapagliflozin 5 mg daily starting at Visit 3/Randomization 
(Day 1) through one day prior to Visit 4/Week 4.  Starting at Visit 4/Week 4, and for the 
duration of the double-blind treatment period, subjects will then take one sitagliptin 100 mg 
tablet and one matching placebo capsule for dapagliflozin 10 mg daily.
 
 
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Subjects randomized to dapagliflozin 10 mg q.d. will take one dapagliflozin 5 mg capsule
and one matching placebo tablet for sitagliptin 100 mg daily starting at Visit 
3/Randomization (Day 1) through one day prior to Visit 4/Week 4.  Starting at Visit 4/Week 
4, and for the duration of the double-blind treatment period, subjects will then take one 
dapagliflozin 10 mg capsule and one matching placebo tablet for sitagliptin 100 mg daily.
If a subject is unable to tolerate up-titration of dapagliflozin (or matching placebo) at Visit 
4/Week 4 from 5 mg to 10 mg, the subject will continue taking the dapagliflozin 5 mg 
capsule (or matching placebo). In this case, the investigator may up-titrate the subject at a 
subsequent study visit if, in the opinion of the investigator, the subject becomes able to 
tolerate the 10 mg dose. If a subject is up-titrated to the dapagliflozin 10 mg capsule (or 
matching placebo) but is unable to tolerate this dose, the investigator should down-titrate the 
subject to the dapagliflozin 5 mg dose (or matching placebo). Any up-titration or down-
titration of dapagliflozin dose will be done via IVRS dispensing of new study medication.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Dose Modification of Sitagliptin/Matching Placebo to Sitagliptin
The dose of sitagliptin or matching placebo cannot be modified throughout the 24-week 
double-blind treatment period.
If a subject is suspected of having pancreatitis, study medications should be interrupted; 
study medications may be re-initiated if pancreatitis is not confirmed.
5.2.1.2.2 Dose Modification of Dapagliflozin/Matching Placebo to Dapagliflozin
The dose of dapagliflozin or matching placebo will be up-titrated at Visit 4/Week 4 from 5 
mg q.d. to 10 mg q.d. If, in the opinion of the investigator, a subject is unable to tolerate up-
titration at Visit 4/Week 4, the subject may remain on the 5 mg dose; in this case, the 
investigator should assess at subsequent study visits whether the subject is now likely to 
tolerate up-titration. For subjects up-titrated to 10 mg, the dose of dapagliflozin or matching 
placebo cannot be modified unless, in the opinion of the investigator, the subject has 
demonstrated an inability to tolerate the 10 mg dose of dapagliflozin. In this case, 
dapagliflozin or matching placebo should be down-titrated to 5 mg q.d.
If a subject is determined to have volume depletion, dapagliflozin (or matching placebo) 
should be interrupted and reinstituted only after volume depletion has been corrected.
 
 
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If a subject is suspected of having ketoacidosis, study medications should be interrupted, and
study medications may be re-initiated if ketoacidosis is not confirmed.
5.2.1.2.3 Dose Modification of Metformin and Sulfonylurea
The dose of metformin (≥1500 mg/day) and, for subjects on metformin and an SU agent, the 
dose of the SU agent, should remain stable throughout the 24-week double-blind treatment 
period.
If a subject undergoes an imaging study requiring the use of radiocontrast dye (e.g., an 
intravenous pyelogram or computerized tomography study with contrast), metformin should
be interrupted and reinstituted only after renal function has been evaluated and found not to
have been reduced by the dye study.
Subjects on metformin and an SU agent should have the SU agent downtitrated or 
interrupted, as clinically appropriate, for events of unexplained severe hypoglycemia or 
recurrent hypoglycemia, and the subject continued in the study (see also Section 5.7 Subject 
Withdrawal/Discontinuation Criteria).   
Timing of Dose Administration
5.2.2
At Visit 3/Randomization/Day 1, each subject will be randomly assigned to sitagliptin 100 
mg q.d. or dapagliflozin.  At this visit, subjects will take study medication as instructed after 
the MMTT has been completed (see Section 7.1.2.9 for details).  
On days without clinic visits, subjects should take double-blind study drug (sitagliptin, 
dapagliflozin and matching placebos) orally at approximately the same time of the morning.  
Subjects will be instructed not to take double-blind study drug the morning of the clinic visit.
On the days of clinic visits, subjects will take blinded study drug as well as background 
metformin (and SU, for subjects also on an SU agent) after all study procedures are 
completed, with the exception of Visit 7/Week 24 (or Discontinuation Visit). At Visit 
7/Week 24 (or Discontinuation Visit), subjects will take blinded study drug and background 
metformin (and SU, for subjects also on an SU agent) as part of the MMTT, approximately 1 
hour before consuming the standard meal for the MMTT (see Section 7.1.2.9 for details.)
If a subject misses a dose of blinded study drug during the trial, he/she should be instructed 
to take it as soon as they remember, unless it is time for the next dose.  Subjects should be 
instructed not to "make up" for the missed dose by taking two doses at the same time.
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used. 
Sitagliptin and dapagliflozin will be 
packaged identically relative to their matching placebos so that the blind/masking is 
maintained.
The subject, the investigator and Sponsor personnel or delegate(s) who are 
involved in the treatment or clinical evaluation of the subjects are unaware of the group 
assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
 
 
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Randomization
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to sitagliptin 100 mg q.d. or dapagliflozin.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
AHAs taken by the subject at any time prior to Visit 1/Screening and any other medications 
taken within 8 weeks of Visit 1/Screening should be recorded on the appropriate electronic 
case report form (eCRF).  The site may rely on subject report for this information.  
Concomitant medications taken during the trial must also be recorded. 
Subjects should be questioned about their use of concomitant medications at the time points 
indicated in the Trial Flow Chart – Section 6.0.  Subjects should be instructed to contact the 
study investigator before initiating any prescription or non-prescription medications during 
study participation.  If medical necessity requires initiation of a medication prior to 
discussion with the study investigator, the subject should communicate with the study 
investigator as soon as possible.      
Prohibited Medications
Medications listed below are prohibited while subjects are receiving blinded investigational 
product during the double-blind treatment period:
NOTE: At the time points indicated in the Trial Flow Chart (Section 6.0), investigational 
sites should review the use of any prohibited medications, including AHAs with subjects 
who are on double-blind study medication.  At these time points, subjects should be 
instructed regarding the importance of not taking AHAs other than metformin, 
sulfonylurea (if applicable), and double blinded study medication during study 
participation.    
 
 
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1. Other Antihyperglycemic Medications:

Insulin of any type (except for short-term use [i.e., <7 days] during concomitant 
illness or other stress)

GLP-1 agonists

Pioglitazone or rosiglitazone

DPP-4 inhibitors (except blinded sitagliptin)

SGLT2 inhibitors (except blinded dapagliflozin)

Alpha glucosidase inhibitors 

Meglitinides

Bromocriptine

Colesevelam

Any other AHA with the exception of metformin, and for patients on dual 
combination therapy, a sulfonylurea, and double-blind study drug
2. Corticosteroids:
Treatment for ≥14 consecutive days or repeated courses of 
pharmacologic doses of corticosteroid is prohibited.
Note: Inhaled, nasal, and topical corticosteroids and physiological replacement doses of 
adrenal steroids are permitted.
3. Weight-loss Medications:  Initiation of a weight-loss medication (e.g., orlistat, 
phentermine, topiramate, lorcaserin) is prohibited.
Note: Subjects who are on treatment with a weight-loss medication or other medication 
associated with weight changes (e.g., anti-psychotic agents) and who are weight-stable 
(i.e., <5% change in body weight within 6 months of Visit 1/Screening) at Visit 
1/Screening are eligible to participate in the study and permitted to continue these 
medications during the study.  Subjects who require adjustment or initiation of other 
medications associated with weight changes during the study should be discussed with 
the Sponsor.
4. Cimetidine:  Initiation of cimetidine on a regular or as needed basis is prohibited.  If a 
subject requires an H2 antagonist during the study, an alternate agent should be used.
Note: Subjects who are taking regular (at least daily) and consistent cimetidine at 
Visit1/Screening may continue, but should be instructed not to change the use or dose of 
cimetidine during the study.
 
 
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Guidance for Other Medications
The investigator or subject’s physician/health care provider is permitted to make adjustments 
in the subject’s non-AHA therapies throughout the trial if clinically warranted.  Guidance for 
specific medications which are permitted during the study is provided below.
1. Blood Pressure and Lipid-altering Medications:  Concurrent blood pressure and lipid-
lowering medications are permitted.  Subjects should be on stable doses of these 
medications for at least 4 weeks before Visit 3/Randomization (Day 1) and during the 
study.  Subjects whose blood pressure or lipid-lowering medications are not stable at 
Visit 1/Screening should be scheduled appropriately to ensure these medications are 
stable for at least 4 weeks prior to Visit 3/Randomization (Day 1).
2. Hormonal Replacement Therapy and Birth Control Medications: Hormone replacement 
therapy and birth control medications are permitted, but subjects should be on stable 
regimens, and are expected to remain on their stable regimen while receiving blinded 
study drug during the double-blind treatment period and for 14 days after the last dose of 
blinded study drug.
3. Thyroid Hormone Replacement Therapy:  Thyroid replacement medication (e.g., 
thyroxine) is permitted, but subjects should be on a stable dose for at least 6 weeks prior 
to Visit 1/Screening.  Subjects who meet the TSH exclusion criterion specified in Table 1 
may be re-screened after being on a stable thyroid replacement regimen for at least 6 
weeks.
4. Supplemental and/or Traditional Medicines: The use of herbal supplements and other 
natural products should be discouraged.  Subjects who do not discontinue the use of such 
supplements prior to Visit 2/Week -2 should be instructed not to change the use or dose 
of the supplement during the trial.  Subjects should be instructed not to initiate new 
supplements during the trial.  
Diet/Activity/Other Considerations
5.6
Diet
5.6.1
Subjects will be seen by a dietician or qualified healthcare professional for dietary and 
exercise counseling at Visit 2/Week -2; follow-up at other visits may be done by other 
appropriate site personnel evaluating the subject.
The subject will receive counseling on diet consistent with the local guidelines of the country 
of the investigational site.  At each subsequent visit, the subject will be asked about their diet 
and exercise, and counseling should be provided, as appropriate.  Detailed dietary 
information will not be captured.
 
 
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Alcohol, Caffeine and Tobacco
5.6.2

Subjects will be counseled to limit alcohol use to moderate amounts (i.e., ≤2 drinks 
per day and no more than 14 drinks per week).

Subjects should avoid the ingestion of caffeine for at least 30 minutes prior to 
scheduled ECGs and blood pressure determinations.

Subjects should avoid the ingestion of nicotine-containing products for at least 30 
minutes prior to the scheduled ECGs and blood pressure determinations.
Activity
5.6.3
Subjects will be counseled to maintain a medically appropriate, routine exercise program and 
consistent physical activity level during the trial.  
Subjects should avoid strenuous exercise for 24 hours prior to the MMTT, performed at Visit 
3/Randomization and at Visit 7 (or Discontinuation).
Subject Withdrawal/Discontinuation Criteria
5.7
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject withdraws consent.
Note:  Since follow-up health status information is important to the full evaluation of 
any investigational agent, the investigator should determine if a subject who no 
longer agrees to actively participate (i.e., no longer attend visits at the 
investigational site, take blinded study drug, and have other study-related 
procedures conducted at the investigational site) is agreeable to providing 
additional follow-up information through interval telephone contacts (with the 
site collecting important health status information [e.g., SAEs]).  See Section 5.7.1 for 
additional details about monitoring subjects who discontinue treatment with blinded 
study drug.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:
1. Subject meets protocol-specified hyperglycemia criteria, as specified below:
 
 
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Subjects who have a repeated, confirmed FPG or single A1C value meeting relevant 
glycemic discontinuation threshold (see below) for the specific time point in the trial, 
without a reasonable explanation (e.g., intercurrent illness or medication omission) :

FPG consistently >270 mg/dL (15.0 mmol/L) after Visit 3/Day 1 through 
Visit 4/Week 4.

FPG consistently >240 mg/dL (13.3 mmol/L) after Visit 4/Week 4 through 
Visit 5/Week 10.

FPG consistently >200 mg/dL (11.1 mmol/L) or A1C >8.0% (64 mmol/mol)
after Visit 5/Week 10 through Visit 7/Week 24.
Note:  A consistent value for FPG is defined as a repeat measurement performed 
within 7 days of notification from the central laboratory.  Site should reinforce 
diet/exercise counseling prior to repeat measurement.
2. Hypoglycemia:  Repeated (2 or more episodes since the prior visit) FPG or 
fingerstick glucose

<50 mg/dL (2.8 mmol/L) with or without symptoms of hypoglycemia, or

≤70 mg/dL (3.9 mmol/L) with symptoms of hypoglycemia, and without a 
reasonable explanation (e.g., increased physical activity or skipped meal) or 
with a reasonable explanation and likely to reoccur.
Note: for subjects on an SU agent, the SU agent should be interrupted (see 
Section 5.2.1.2.3) prior to evaluation of the subject for discontinuation due to 
hypoglycemia.
3. Abnormal liver function tests meeting criteria specified below (see Section 12.5 for 
additional details on management and discontinuation of blinded study drug for 
subjects with elevated liver enzymes).

ALT or AST ≥3X ULN with total bilirubin (TBL) ≥2X ULN and alkaline 
phosphatase (ALP) <2X ULN and without an established etiology; or

ALT or AST ≥8X ULN or ≥3X ULN with symptoms consistent with liver 
injury and without an established etiology; or

ALT or AST ≥5X ULN for 2 weeks; or

ALT or AST ≥3X ULN and subject is unwilling or unable to undergo repeat 
ALT and AST testing at the frequency defined in Section 12.5.
4. Reduction of renal function:

eGFR persistently <50 mL/min/1.73m2 (CKD-epi formula) from Visit 3/Day 
1 through one day prior to Visit 5/Week 10.
 
 
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Note:  A persistent value is defined as a repeat measurement, performed 2 to 3 
weeks after notification from the central laboratory, that remains <50 
mL/min/1.73m2 despite correction of potential causative factors (e.g., 
correction of volume depletion, discontinuation of nonsteroidal anti-
inflammatory drugs [NSAIDs]).  If the eGFR value continues to meet the 
discontinuation criterion but demonstrates stability or improvement relative to 
the prior result, an additional repeat may be performed.  

eGFR persistently <60 mL/min/1.73m2 (CKD-epi formula) from Visit 5/Week 
10 through Visit 7/Week 24.
Note:  A persistent value is defined as a repeat measurement, performed 2 to 3 
weeks after notification from the central laboratory, that remains <60 
mL/min/1.73m2 despite correction of potential causative factors (e.g., 
correction of volume depletion, discontinuation of NSAIDs).  If the eGFR 
value continues to meet the discontinuation criterion but demonstrates 
improvement relative to the prior result, an additional repeat may be 
performed.  
See Section 7.1.12.5 for guidance on following subjects who discontinue blinded 
study drug due to decreased renal function or renal-related adverse events.
5. Requirement for one of the prohibited medications listed in Section 5.1.3.
6. Pregnancy.
Note:  A positive urine pregnancy test requires immediate interruption of blinded 
study drug until serum β-hCG can be performed and found to be negative.  Subject 
must be permanently discontinued from blinded study drug, and pregnancy should be 
reported and followed per Section 7.2.2 if pregnancy is confirmed by a positive serum 
pregnancy test. 
7. Any medical condition or personal circumstance which, in the opinion of the 
investigator, exposes the subject to risk by continuing in the trial or does not allow the 
subject to adhere to the requirements of the protocol.
8. The investigator or subject becomes unblinded to the subject’s treatment assignment.
The Sponsor should be notified as soon as possible when a subject is discontinued from 
blinded study drug or blinded study drug is interrupted because of an AE or a laboratory 
safety test abnormality.
A subject may discontinue blinded study drug for any of the reasons listed above but 
continue to participate in the trial, as long as the subject does not withdraw consent.  Follow-
up procedures for subjects who discontinue blinded study drug are described in Section 5.7.1.
 
 
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Follow-up for Subjects Who Discontinue Blinded Study Drug
5.7.1
5.7.1.1
Withdrawal of Consent
If a subject indicates his or her intention to stop active participation in the trial (i.e., chooses 
to no longer attend visits at the investigational site, take blinded study drug, and have other 
study-related procedures conducted at the investigational site) and withdraw consent, the 
subject should be encouraged to complete procedures for the Discontinuation Visit (when 
they discontinue blinded study therapy, and withdraw consent). 
The sponsor may retain and continue to use any data collected before the subject’s 
withdrawal of consent.
5.7.1.2
Discontinuation from Blinded Study Therapy
A subject who discontinues treatment with blinded study drugs for reasons other than 
withdrawn consent or a subject for whom the investigator recommends discontinuation of 
study medication should complete a Discontinuation Visit, and have a post-treatment 
telephone call approximately 14 days after the last dose of blinded study medication.  The 
purpose of the 14-day post-treatment telephone call is to collect information about the 
subject’s health status (e.g., evaluate if the subject experienced any SAEs).  The subject 
should then be counseled to return to the study site for all scheduled safety and efficacy 
visits, completing all trial procedures (other than procedures related to study medication, or 
the MMTT), as indicated in the Trial Flowchart (Section 6.0).  
If the subject who has discontinued study medications is unwilling to return for scheduled 
study visits, alternative efforts should be made to collect safety and efficacy information; this 
may include more limited study visits and/or telephone contacts (to collect information about 
the subject’s health status, including collection of any SAEs) according to the study schedule 
until the end of the trial (Week 24).
Subjects who discontinue treatment with blinded study drugs but who continue to participate 
in the trial by providing follow-up information can receive medical and diabetes management 
by their managing physician or investigator, as appropriate.  These subjects may initiate any 
other therapy as needed (previously prohibited medications will not apply to them).  
Procurement of other AHAs, including background AHA, is the responsibility of the subject.  
If the trial site loses contact with the subject, the site should make at least three attempts for a 
telephone contact.  If the three attempts of telephone contact are unsuccessful, the site should 
make at least one attempt to reach the subject via certified letter.  All attempts to contact a 
subject and information received during contact attempts must be documented in the 
subject’s medical record.  
Subject Replacement Strategy
5.8
A subject who discontinues from the trial will not be replaced.
 
 
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Beginning and End of the Trial
5.9
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.10
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Run-In
Randomization
Double-Blind Treatment
Post-Treatment
Visit Number
1
2 a
3
4
5
6
7
Early
Discontinuation
Follow-up
Scheduled Week
-2
0 (Day 1)
4
10
16
24
At time of 
Discontinuation of 
study medicationb
14-Day Post Treatment 
Telephone Contactc
Visit Window Guideline (days)
±5
±5
±7
±7
±7
±7
Administrative Procedures
Informed Consentd
X
Informed Consent for Future 
Biomedical Researche
X
Assignment of Screening Number
X
Contact IVRS
X
X
X
X
X
X
X
X
Subject Identification Card
X
Assignment of Randomization 
Number
X
Trial Compliance
Inclusion/Exclusion Criteria
X
X
X
Prior/Concomitant Medication 
Reviewf
X
X
X
X
X
X
X
X
Review use of any prohibited 
medications, including AHAs; 
counsel patients on importance of 
not taking other AHAsf
X
X
X
X
X
X
X
X
Diet and Activity 
Counseling/Monitoringg
X
X
X
X
X
X
X
Dispense Hypoglycemia 
Assessment Log (HAL) and 
Instruct on Hypoglycemia 
Symptoms and Management
X
Dispense Glucose Meter and 
Provide SMBG Instruction
X
Study Drug 
Dispense Single-Blind Placebo 
Run-In
X
Witness Dose of Blinded Study 
Drug in Clinich
X
X
 
 
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Trial Period:
Screening
Run-In
Randomization
Double-Blind Treatment
Post-Treatment
Visit Number
1
2 a
3
4
5
6
7
Early
Discontinuation
Follow-up
Scheduled Week
-2
0 (Day 1)
4
10
16
24
At time of 
Discontinuation of 
study medicationb
14-Day Post Treatment 
Telephone Contactc
Visit Window Guideline (days)
±5
±5
±7
±7
±7
±7
Dispense Double-Blind Study 
Drugh
X
X
X
X
Assess Compliance with Blinded 
Study Drugi
X
X
X
X
X
X
Clinical Procedures/Assessments
Demographics and Medical 
History
X
Height
X
Weight
X
X
X
X
X
Vital Signs (Pulse Rate and 
Blood pressure)
X
X
X
X
X
X
X
X
Postural (Orthostatic) Blood 
Pressure/Pulse Rate
X
X
X
X
X
X
Full Physical Examj
X
Brief Physical Examk
X
X
12-Lead ECGl
X
Site Fingerstick A1C 
Measurementm
X
Fasting Fingerstick Glucose in 
Clinic
X
Review of SMBG Measurements 
and HAL
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
X
X
Health Economic Assessment
X
X
X
X
X
X
X
Laboratory Procedures/Assessments
FPG
X
X
X
X
X
X
X
X
A1Cn
X
X
X
X
X
X
Fasting C-peptide
Xo
Lipid Panelp
X
X
X
Chemistry Panel
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
 
 
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Trial Period:
Screening
Run-In
Randomization
Double-Blind Treatment
Post-Treatment
Visit Number
1
2 a
3
4
5
6
7
Early
Discontinuation
Follow-up
Scheduled Week
-2
0 (Day 1)
4
10
16
24
At time of 
Discontinuation of 
study medicationb
14-Day Post Treatment 
Telephone Contactc
Visit Window Guideline (days)
±5
±5
±7
±7
±7
±7
Fasting Triglycerides
X
Xq
TSH
X
Urine Pregnancy Test (Women of 
childbearing potential onlyr )
X
X
X
X
X
X
X
X
2 point- MMTT at selected sites:  
Blood samples at 0 and 120 
minutes sent for glucoses
X
X
X
3 point- MMTT at selected sites:  
Blood samples at 0, 60, and 120 
minutes sent for glucose, insulin, 
and glucagons
X
X
X
Plasma and Serum for Future 
Biomedical Researche
X
X
X
Blood 
(DNA) 
for 
Future 
Biomedical Researche
X
a. The interval between Visit 1 and Visit 2 must be at least 2 weeks and at most 6 weeks.
b. This visit is only for subjects who discontinue study medication prematurely.  Such subjects should complete procedures for the Early 
Discontinuation Visit and (if consent was not withdrawn) they should continue to be followed by the investigational site, attending scheduled study 
visits and undergoing study procedures (other than those related to study medication, or the MMTT), see Section 5.7.1. 
c. Subjects will be contacted 14 days after the final dose of blinded study drug to collect SAEs.
d. A subject ICF must be signed prior to any trial specific procedures being performed and may be signed prior to Visit 1/Screening.
e. The Future Biomedical Research (FBR) informed consent must be obtained before FBR samples for DNA analysis, plasma, and serum are collected. 
The FBR sample for DNA analysis should be obtained pre-dose, at Visit 3/Randomization, as the last sample drawn, on randomized subjects only.  
The sample may be obtained at a later date during the trial after the FBR informed consent is obtained.  The plasma and serum samples for FBR should 
be collected at Visit 3/Randomization (pre-dose), and Visit 7/Week 24 (or Discontinuation Visit).  For the FBR serum and plasma, samples should be 
collected at all time points, even if the pre-dose or other time point was not collected.
f.
Subjects on double-blind treatment should be reminded to not take any other AHA medications other than the trial treatments (background 
metformin and sulfonylurea (if patient is on an SU), and double-blind study drug) during their participation in the study.  They should be counseled 
that if another physician prescribes such a treatment (i.e., any AHA), the subject and/or the prescribing physician should immediately contact the 
investigational site prior to initiation of such therapy.  If medical necessity requires initiation of a medication prior to discussion with the study 
investigator, the subject should communicate with the study investigator as soon as possible.  
g. Subjects will be seen by a dietician or qualified healthcare professional for dietary and exercise counseling at Visit 2; follow-up at other visits may be 
done by other appropriate site personnel evaluating the subject.
 
 
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Trial Period:
Screening
Run-In
Randomization
Double-Blind Treatment
Post-Treatment
Visit Number
1
2 a
3
4
5
6
7
Early
Discontinuation
Follow-up
Scheduled Week
-2
0 (Day 1)
4
10
16
24
At time of 
Discontinuation of 
study medicationb
14-Day Post Treatment 
Telephone Contactc
Visit Window Guideline (days)
±5
±5
±7
±7
±7
±7
h. The witnessed dose will be taken after completion of all procedures for the trial visit, including the collection of all fasting blood samples.
i.
Not applicable to subjects continuing in the study off of double-blind study medication.
j.
Full physical examination may exclude genitourinary and rectal exam.
k. Brief physical examination includes assessment of heart, lungs, abdomen, extremities and skin.
l.
ECGs are read locally at the investigative site. 
m. Site fingerstick A1C is not mandatory, but may be used, at the discretion of the investigator, for screening subjects.  However, a fingerstick A1C 
cannot substitute for a central laboratory measured A1C to determine if a subject meets entry criteria. 
n. A1C should not be drawn if Discontinuation Visit occurs within six weeks after Visit 3/Randomization (Day 1).
o. Fasting C-peptide test at Visit 1/Screening is only for subjects assessed by the investigator as possibly having Type 1 diabetes. 
p. Includes total cholesterol, high-density lipoprotein (HDL-C) cholesterol, low-density lipoprotein (LDL-C) cholesterol, triglycerides and non-HDL.   
q. Only subjects with TG meeting the exclusion criterion at Visit 1 should have a repeat test at Visit 2/Week-2, as described in exclusion criterion #15.
r.
Women of childbearing potential will have a urine pregnancy test (and serum pregnancy test if required by site's Institutional Review Board 
[IRB]/Ethics Committee [EC]).  Subjects with a positive urine pregnancy test during double-blind treatment period will interrupt blinded 
investigational product and undergo a serum pregnancy test.
s. The MMTT will be performed prior to witnessed dose of blinded study drug at Visit 3/Day 1.  At Visit 7/Week 24 (or Discontinuation Visit), subjects 
will take blinded study drug and background metformin and background SU (if applicable) approximately 1-hour before consuming the standard meal 
(T=0 minutes) for the MMTT. At selected sites, a 3-point MMTT will be performed with measurement of glucose/insulin/glucagon. At all remaining 
sites, a 2 point MMTT will be performed with measurement of glucose only.  For subjects who stop study medication prematurely, the MMTT should 
be performed at the Discontinuation Visit (and not at Visit 7/Week 24).
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject prior to participating in a clinical trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature on a consent form along with 
the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial.  The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
 
 
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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The use of 
tobacco should be collected as part of the medical history.  Additionally, for male subjects, 
sites should indicate if the subject is circumcised or uncircumcised.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use.  AHAs taken by the 
subject at any time prior to Visit 1/Screening and any other medications taken within 8 weeks 
of Visit 1/Screening should be recorded on the appropriate eCRF.  The site may rely on 
subject report for this information. 
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial on the appropriate eCRF.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
 
 
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7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Adherence to treatment will be assessed by subject report during the double-blind treatment 
period.  Every effort will be made to maintain adherence as close to 100% as possible.
Interruptions from the protocol specified treatment plan for ≥7 days OR compliance ≤75%
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on subject management.
7.1.1.8.1 Diet and Exercise Counseling and Monitoring
Refer to Section 5.6 for further details.
7.1.1.8.2 Dispense Hypoglycemia Assessment Log and Instruct on Hypoglycemia 
Symptoms and Management
At Visit 2/Week -2 the site will review the symptoms and management of hypoglycemia with 
the subject.  The site will counsel the subject to immediately perform a fingerstick glucose 
measurement if any symptoms occur that may be related to hypoglycemia (e.g., weakness, 
dizziness, shakiness, increased sweating, palpitations, or confusion), but also to avoid delay 
in treating these symptoms.
The subject will be instructed to complete the Hypoglycemia Assessment Log (HAL) for any 
symptomatic episodes he or she believes may represent hypoglycemia.  If a fingerstick 
glucose has been obtained before or shortly (i.e., within a few minutes) after treating, the 
value should be recorded in the log.  In addition, subjects will be instructed to record in the 
log any fingerstick glucose values ≤70 mg/dL (3.9 mmol/L) regardless of the presence of 
symptoms.
Subjects should be instructed to contact the investigational site to report:

any episode of hypoglycemia for which assistance was required (i.e., severe 
hypoglycemia),

any episode of fingerstick glucose ≤70 mg/dL (3.9 mmol/L) with or without symptoms
 
 
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Note:  As indicated, subjects will record symptoms and/or fingerstick glucose measurements 
that they believe are related to hypoglycemia on the HAL.  Each episode should be evaluated 
by the investigator.  For episodes determined to be hypoglycemia (symptomatic or 
asymptomatic), and for all glucose values ≤70 mg/dL (3.9 mmol/L) regardless of whether 
they are considered an adverse event, the Hypoglycemia Assessment (HA)  eCRF must also 
be completed.  Each event of symptomatic hypoglycemia must be reported as an adverse 
event on the adverse event eCRF.  Each episode of asymptomatic hypoglycemia considered 
by the Investigator to be an adverse event should also be reported on the adverse event eCRF 
(see Section 7.1.2.12.2.1 for guidance on reporting).
7.1.1.8.3 Dispense Glucose Meter and SMBG Instructions
Glucose meters will be supplied to all subjects at Visit 2/Week -2 in order to perform SMBG. 
Subjects will be instructed on the procedure to perform fingerstick glucose measurements.  
Subjects will monitor their fingerstick glucose concentrations with a frequency determined 
appropriate by the investigator (based upon his/her assessment of the subject’s risk of 
increasing or decreasing glucose concentrations) with a minimum of two fasting 
determinations per week.  
During the run-in period, subjects should be counseled to contact the trial site if fingerstick 
glucose levels are above 270 mg/dL (15.0 mmol/L) ≥2 times per week.  Subjects will be 
instructed to contact the site if the fingerstick glucose values are ≤70 mg/dL (≤3.9 mmol/L).  
Furthermore, in order to assess for discontinuation from blinded investigational product, 
subjects should be instructed to contact the site for fingerstick glucose values that are >270 
mg/dL (15.0 mmol/L) after Visit 3/Day 1 through Visit 4/Week 4, or >240 mg/dL (13.3 
mmol/L) after Visit 4/Week 4 through Visit 5/Week 10, or >200 mg/dL (11.1 mmol/L) after 
Visit 5/Week 10.  
7.1.1.8.4 Witness Dosing
Administration of blinded study drug will be witnessed by the investigator and/or trial staff at 
Visit 2/Week -2 (start of the placebo run-in) and at Visit 3/Randomization (Day 1) after 
completion of all trial procedures, including the collection of all fasting blood samples and 
performance of the mixed meal tolerance test (MMTT). Additionally, blinded study drug will 
be witnessed at Visit 7/Week 24 (or Discontinuation Visit) as part of the MMTT. 
7.1.1.8.5 Dispense Single-Blind Placebo Run-in Study Drug
Subjects will be dispensed single-blind study drug (matching placebo tablet for sitagliptin 
100 mg and over-encapsulated placebo for dapagliflozin 5 mg) at Visit 2/Week -2 and 
instructed to take one pill orally per day from each bottle at approximately the same time of 
day in the morning.  The last dose of placebo run-in should be taken on the day prior to Visit 
3/Randomization (Day 1). 
Refer to Section 5.2.2 for further details.
 
 
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7.1.1.8.6 Dispense Double-Blind Study Drug
Subjects will be dispensed double-blind study drug (sitagliptin or matching placebo for 
sitagliptin and dapagliflozin or matching placebo for dapagliflozin) at all trial visits from 
Visit 3/Randomization (Day 1) through Visit 6/Week 16 and instructed to take the double-
blind study drug once a day, orally at approximately the same time of day in the morning.  
Refer to Section 5.2.2 for further detail.
7.1.1.8.7 Medication Compliance Monitoring
Subjects will be directed to bring any used and unused bottles to each visit.  The investigator 
must maintain a complete and current accountability record for the blinded study drug.
Compliance with the placebo run-in medications should be monitored by study personnel at 
the site at the end of the placebo run-in at Visit 3/Randomization (Day 1), by comparing the 
returned single-blind study drug with the amount dispensed and the information reported by 
the subject.  The number of pills issued minus the number of pills returned will be used to 
calculate pills taken according to the formula below.
Compliance =
pills dispensed – pills returned
× 100%.
No. of days between visits × No. of pills taken per day
Subjects who are <80% compliant based on pill count with the placebo run-in medication are 
ineligible for randomization.
During the remainder of the trial, compliance will be assessed by subject report (see Section 
8.11).  Every effort will be made to maintain compliance as close to 100% as possible. 
The investigator or designee will counsel subjects who report taking <80% of the prescribed 
blinded study drug following randomization.  The investigator or designee will determine 
factors that resulted in <80% compliance with the blinded study drug and will take steps to 
improve compliance.  Subjects will be counseled on the importance of taking their 
medication as prescribed. Subject counseling will be documented in source documents.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Vital Signs
Vital sign measurements include a duplicate measurement of sitting blood pressure and pulse 
rate.  Blood pressure and pulse rate will be measured using an automated, oscillometric blood 
pressure measuring device at all visits as noted in the Trial Flow Chart - Section 6.0.  Site 
personnel should use the same blood pressure measuring device throughout the study for 
each subject.
 
 
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The following method should be used to record sitting blood pressure and pulse rate for 
subjects in duplicate:

Subjects should refrain from nicotine-containing products and/or ingesting caffeine 
for at least 30 minutes preceding the measurements.

Subjects should be seated in a chair with their back supported, feet flat on the floor 
and arm bared (free of restrictions such as rolled up sleeves) and supported at heart 
level.

Measurements should begin after at least 5 minutes of rest.

The appropriate cuff size must be used to ensure accurate measurement.  Each 
subject’s cuff size should be noted in his/her source file to assure the same cuff size is 
used throughout the trial.

Measurements should be taken on the same arm at each visit (preferably the non-
dominant arm).

Measurements must be taken approximately 2 minutes apart with the duplicate set 
recorded in the source document and eCRFs.

Assessment of pulse rate can be manual (rather than using an automated device); 
however, when done manually, pulse rate must be measured in the brachial/radial 
artery for at least 30 seconds.
Other procedures should not be performed during the time of the blood pressure and pulse 
rate measurements.
7.1.2.2
Postural (Orthostatic) Blood Pressure and Pulse Rate
Supine and standing blood pressure and pulse rate will be taken in order to evaluate postural 
changes in blood pressure and pulse rate at the randomization visit and at all subsequent 
scheduled study visits, as noted in the Trial Flow Chart – Section 6.0.  These measurements 
will be in addition to the sitting blood pressure and pulse rate measurements taken at these 
clinic visits.
Postural blood pressure changes will be measured according to the following procedure:

Subject in supine position for a minimum of 5 minutes.

Measure blood pressure and pulse rate in the supine position in duplicate (at least 1 
minute apart).

Stand subject and measure blood pressure and pulse rate in the standing position in 
duplicate according to the following instructions:  The first measurement of standing 
blood pressure and pulse rate will be measured after at least 1 minute of standing.  
The second measurement of standing blood pressure and pulse rate will be measured 
after the subject has been standing for at least 3 minutes
 
 
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7.1.2.3
Body Weight
Body weight will be measured using a standardized, digital scale (provided by the sponsor) at 
each of the pre-defined nominal time points outlined in the Trial Flow Chart – Section 6.0 as 
follows:

Weight will be taken in duplicate throughout the trial at approximately the same time of 
day, after voiding (i.e., forced void) and while wearing only a gown and underwear (no 
shoes or socks).  Investigator sites without access to gowns should weigh subjects in light 
clothing.

Subjects should be instructed to step gently onto the scale, place both feet together in the 
center of the scale and stand straight with eyes directed ahead.  Subjects should be 
instructed to stand still and not sway.  Measurement will be recorded after the weight has 
stabilized.

Body weight should be reported with precision to one decimal place (e.g., 0.1 kg or 0.1 
lb).  The 2 measurements should be recorded in the source documents.  If the 2 
measurements differ by more than 0.2 kg or by 0.4 lb, (1) check the subject to ensure 
proper positioning as indicated above and/or conduct an accuracy check on the scale as 
instructed below and (2) a different set of duplicate measurements must be obtained, and 
the 2 new measurements should be recorded in the source documents.
A 10-kg certified weight will be purchased by the sponsor and sent to each site.  To assess 
the accuracy of the scale, the trial coordinator or appointed designee will weigh him or 
herself alone, then the weight alone, and finally, the individual together with the weight.  
Deviations of more than one scale division (±0.1 kg) will require corrective action and the 
sponsor must be contacted.  Accuracy checks will be performed monthly and the record of 
scale accuracy must be sent to the sponsor at the end of the trial. 
7.1.2.4
Height
Height will be measured without shoes, using a stadiometer or other appropriate device.
Standing height will be assessed through maximum vertical stature for persons who can stand 
unassisted.  Hair ornaments, barrettes, braids, jewelry, or cornrows should be moved or 
removed from the top of the head before the measurement is taken.
A fixed stadiometer with vertical backboard, fixed floorboard and movable headboard should 
be used.  Subjects should stand with the heels of their feet against the vertical backboard with 
feet pointing outward at approximately a 60-degree angle.  Body weight should be distributed 
evenly with both feet flat on the floor.  The examiner should check several contact points 
with the vertical backboard, including heels, buttocks, shoulder blades, and the back of the 
head.  This may be difficult for subjects with certain body shapes.  However, the head should 
be in the Frankfort plane (an imaginary line from the ear canal to just below the lower orbit 
of the eye should be parallel to the floor).  Subject should be looking straight ahead, and be 
asked to take a deep breath and stand tall.  Once the subject is positioned, the headboard or a 
flat ruler will be placed on top of the head, with sufficient pressure to compress the hair.  The 
measurement is recorded in cm, to the nearest mm.  Measurements will be collected until 2 
consecutive measurements do not differ by more than 2.5 cm from each other.  The final 
 
 
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height measurement must be recorded.  Some people may have physical conditions that may 
limit the ability to measure height accurately (e.g., kyphosis).  In such cases, height should be 
measured to the best of the examiner’s ability, and a note should be made of the condition.
7.1.2.5
Physical Examination
A complete physical examination will be performed at the Visit 2/Week -2; genitourinary 
and rectal examination may be omitted from the complete examination.  A brief physical 
examination including assessment of the heart, lungs, abdomen, extremities, and skin will be 
performed at Visit 7/Week 24 (or Discontinuation Visit).  Abnormalities considered 
clinically significant should be reported as adverse events.  Other body systems may be 
evaluated as per the judgment of the investigator or as needed to evaluate adverse events.
7.1.2.6
12-Lead Electrocardiogram (ECG)
Single, supine 12-lead ECG will be obtained at Visit 2/Week -2, as noted in the Trial Flow 
Chart – Section 6.0.  

Subjects should avoid the ingestion of caffeine and nicotine-containing products for 
at least 30 minutes prior to the scheduled ECGs and blood pressure determinations.

12-lead ECGs should be performed after the subject has rested quietly for at least 10 
minutes in a supine position.
12-lead ECGs should be obtained prior to the nominal time assessment of blood pressure, 
and pulse rate as well as prior to blood collection.
All ECGs performed should be reviewed by the investigator at the investigative site for 
subject safety monitoring.  The investigator is responsible for retaining all copies of the ECG 
reports.
7.1.2.7
Site Fingerstick A1C Measurement
Site fingerstick A1C may be used, at the discretion of the investigator, for screening.  Central 
laboratory A1C MUST be used to assess inclusion criteria.
7.1.2.8
Fasting Fingerstick Glucose
FFSG values performed in the clinic will be used to assess exclusion criteria prior to 
randomization at Visit 3/Randomization (Day 1).  
7.1.2.9
Review of SMBG Measurements and Hypoglycemia Assessment Log
SMBG measurements and the HAL will be reviewed at all clinic visits and telephone 
contacts after Visit 2/Week -2 and will be used to assess for events of hypoglycemia, and to 
determine need for discontinuation from blinded study drug due to hypoglycemia.
 
 
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7.1.2.10 Assess Subject for Discontinuation Based on Central Laboratory FPG or A1C
During the double-blind treatment period, FPG and A1C values obtained at the central 
laboratory will be used to assess if the subject meets discontinuation criteria.  Refer to 
Section 5.7 for further details regarding discontinuation.
7.1.2.11 Mixed Meal Tolerance Test (MMTT)
NOTE: Subjects with hypersensitivity or dietary restrictions to the contents of the 
nutrition drink or bars may enroll in the trial without participation in the MMTT.
Sites will be selected to perform either a 2-point or a 3-point MMTT; the type that a site is 
selected to perform will be based on previous experience in performing MMTTs or other 
similar testing.
Subjects should be instructed to avoid strenuous exercise for 24 hours prior to their MMTT.
At Visit 3/Randomization (Day 1), the MMTT will be performed prior to the first dose of 
double blind study drug and metformin (and SU, for subjects on dual combination 
metformin and an SU agent).  Subjects’ last dose of single-blind placebo run-in medication 
should be taken in the morning of the day before Visit 3/Randomization [Day 1]). 
At Visit 7/Week 24 (or Discontinuation Visit), subjects will take their blinded study drug 
and background metformin (and SU, for subjects on dual combination metformin and 
an SU agent) approximately 1-hour before consuming the standard meal for the MMTT.
Subjects should remain sitting during the MMTT, with the exception of going to the
bathroom. For convenience, an intravenous catheter may be placed in the subject’s arm for
the collection of blood samples. Insertion of the catheter should occur about 30 minutes
before the first scheduled blood draw for the MMTT. The first sample (T=0 minutes) will be 
drawn immediately prior to administration of the standard meal. The subjects will then 
consume a standard meal consisting of two nutrition bars and one nutrition drink. This should 
be ingested within 15 minutes. Blood samples will then be collected as indicated below for 
either the 2-point or 3-point MMTT.  Blood samples collected for the MMTT are separate 
and distinct from the fasting blood samples done as part of the visit laboratory assessments 
(i.e., the fasting laboratory assessments cannot be used as the T=0 blood sample for the 
MMTT).
NOTE 1: The subject should consume the entire meal. If the subject is unable to consume at
least 1 bar and the entire drink at Visit 3/Randomization (Day 1), the subject should not 
complete the MMTT and should not participate in the subsequent MMTT (at Visit 7/Week 
24 or the Discontinuation Visit). If the subject consumes the minimum requirement for 
MMTT participation (i.e., at least 1 bar and the entire drink) at Visit 3/Randomization/Day 1 
but does not consume the entire meal, the amount of the meal consumed should be recorded 
and approximately the same proportion of the meal should be consumed for the MMTT at 
Visit 7/Week 24 (or Discontinuation Visit).
NOTE 2: If the subject is unable to consume approximately the same proportion of the meal 
at Visit 7/Week 24 (or Discontinuation Visit) as they consumed at Visit 3/Randomization 
(Day 1), the subject should not complete the follow-up MMTT.
 
 
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NOTE 3: Subjects who are discontinuing study medication but agree to continue in the study 
off of study medication (See Section 5.7.1.2, Discontinuation from Blinded Study Therapy) 
should have the MMTT conducted at the Discontinuation Visit (See Section 6.0, Trial Flow). 
These subjects will be requested to return for subsequent study visits with efficacy and safety 
procedures performed; however, the final visit (i.e., Visit 7/Week 24) MMTT should not be 
performed.
Guidance for sites performing a 2-point MMTT
Blood samples for the MMTT will be drawn for measurement of glucose at T=0 minutes 
(immediately prior to meal administration) and then at T=120 minutes following the start of 
the administration of the meal.
Collect blood samples for the 2-pt MMTT as described in Table 3 below.
Table 3 Timing for the 2-pt MMTT
Timing Relative to Meal Consumption
-60 mins
0 mins
(immediately 
before meal)
120 mins
Visit 3/Randomization (Day 1)
Blinded Study Drug Dosing
None
None
None
Glucose sample collection
X1
X
Start Eating Standard Meal2
X
Visit 7/Week 24 (or Discontinuation)
Blinded Study Drug Dosing
X
Glucose sample collection
X1
X
Start Eating Standard Meal2
X
1 Samples should be collected immediately before the subject begins to eat the standard meal.
2 The subject should completely eat the standard meal over a period of 15 minutes or less.
Guidance for sites performing a 3-point MMTT
Blood samples for the 3-pt MMTT will be drawn for measurement of glucose, insulin, and
glucagon at T=0 minutes (immediately prior to meal administration) and then at T=60
minutes and T=120 minutes following the start of the administration of the meal.
Collect blood samples for the 3-pt MMTT as described in Table 4 below.  
 
 
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Table 4 Timing for the 3-pt MMTT
Timing Relative to Meal Consumption
-60 mins
0 mins
(immediately 
before meal)
60 mins
120 mins
Visit 3/Randomization (Day 1)
Blinded Study Drug Dosing
None
None
None
None
Glucose collection
X1
X
X
Insulin collection
X1
X
X
Glucagon collection
X1
X
X
Start Eating Standard Meal2
X
Visit 7/Week 24 (or Discontinuation)
Blinded Study Drug Dosing
X
Glucose collection
X1
X
X
Insulin collection
X1
X
X
Glucagon collection
X1
X
X
Start Eating Standard Meal2
X
1 Samples should be collected immediately before the subject begins to eat the standard meal.
2 The subject should completely eat the standard meal over a period of 15 minutes or less.
Standard Meal
2 nutrition bars
1 nutrition drink
Approximate total nutrient content: (~660 kcal; 96 g carbohydrate, 20 g fat, 28 g protein)
Note:  The standard meal for the MMTT will be provided or approved by the Sponsor 
(depending on the country).  Please refer to the trial investigator binder for details.
7.1.2.12 Adverse Event Monitoring
7.1.2.12.1 Hyperglycemia
A subject should be considered to have an adverse event of hyperglycemia if the subject has 
one or more symptoms (e.g., increased thirst, polyuria) typically associated with an increased 
glucose level.  At the discretion of the investigator, this may be captured as an adverse event 
of "hyperglycemia."  This diagnosis may be supported by, but does not require, results from a 
glucose meter or the trial central laboratory.  Further, at the discretion of the investigator, an 
elevated blood glucose value without associated symptoms that is considered to be an 
adverse event may be reported as an adverse event of "blood glucose increased." General 
guidance regarding the determination as to whether an event is considered to be an adverse 
event should be followed (see Section 7.2).
 
 
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7.1.2.12.2 Hypoglycemia
All episodes considered as likely to represent symptomatic hypoglycemia by the investigator 
must be captured as an adverse event of "symptomatic hypoglycemia."  This diagnosis may 
be supported by, but does not require, confirmatory blood glucose results (such as those 
measured using a fingerstick or from a clinical laboratory sample).  Further, at the discretion 
of the investigator, an asymptomatic blood glucose value ≤70 mg/dL (3.9 mmol/L) may be 
reported as an adverse event of "asymptomatic hypoglycemia."  General guidance regarding 
the determination as to whether an event is considered to be an adverse event should be 
followed (see Section 7.2).
Regardless of whether an episode is considered an adverse event, the HA eCRF must be 
completed for the following:
all episodes determined by the investigator to be hypoglycemia (symptomatic or
asymptomatic).
all glucose values ≤70 mg/dL (3.9 mmol/L).
7.1.2.12.3 Urinary Tract Infections
Any subject presenting with symptoms considered to be a urinary tract infection should be 
recorded as having an adverse event with the term as considered appropriate by the 
investigator (e.g., cystitis, pyelonephritis, urinary tract infection). The site should collect 
urine for culture performed by their local laboratory, but urine dipstick should not be 
performed by the site or local laboratory (since a urinary glucose measurement may provide 
information suggestive of treatment group assignment). If a urinalysis is clinically necessary, 
a microscopic urinalysis ONLY and not a dipstick urinalysis should be performed. If 
symptoms are reported outside of a routine scheduled study visit, clinical assessment and 
urine testing should be done promptly at an unscheduled visit. The investigator or treating 
physician should initiate antibiotic treatment as considered clinically appropriate; if possible, 
a locally obtained culture and sensitivity should be obtained prior to initiating antibiotics.  
The choice of antibiotic agent and duration of treatment is left to the investigator’s or treating 
physician’s discretion.
Additionally, if a subject reports a urinary tract infection treated by another physician, this 
episode should be captured as an adverse event. The site should attempt to obtain information 
from the treating physician regarding diagnostic tests performed (excluding urine dipstick 
results) and treatment provided, and this information should be recorded.
7.1.2.12.4 Genital Fungal Infections
Subjects who suspect that they have a genital fungal infection should be encouraged to report 
this to investigators.  The investigator or treating physician can initiate antifungal treatment 
either empirically as per local practice or following results from genital swab collected and 
analyzed by a local laboratory.  The choice and duration of antifungal agent used is left to the 
investigator or treating physician’s discretion.
 
 
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7.1.2.12.5 Reduction in Renal Function
The investigator should implement an appropriate evaluation for eGFR that may meet 
discontinuation criteria (as described in Section 5.7) or for events of clinically significant 
reduction in eGFR (e.g., >30% reduction from baseline values).  Such an evaluation should 
include detailed review of any associated symptoms, thorough review of concomitant 
medications (including “over the counter” agents) to determine if the subject had any change 
(new initiation or change in dose) in his or her medication regimen with agents associated 
with decreases in eGFR (e.g., non-steroidal anti-inflammatory agents, fenofibrate, 
angiotensin-converting enzyme (ACE) inhibitors, diuretic agents, etc.), and clinical 
assessment of volume status (e.g., measurement of orthostatic HR and BP, and physical 
examination focused on assessment of volume status). Additional evaluations, including 
renal ultrasound, microscopic urinalysis (with culture and sensitivity if infection is 
considered possible), and urine creatinine and electrolytes should be performed, as clinically 
appropriate. Any reduction in eGFR that the investigator considers to meet criteria for an 
adverse event should be reported as an adverse event. 
7.1.2.12.6 Ketoacidosis
In May 2015, the US Food and Drug Administration (FDA) issued a Drug Safety 
Communication warning that the approved SGLT2 inhibitors, including dapagliflozin, may 
lead to ketoacidosis. As of the time of approval of this protocol, this issue is still under 
investigation.
Factors cited by the FDA as potentially triggering the ketoacidosis include major illness and 
reduced food/fluid intake. According to the FDA communication, patients with ketoacidosis 
reported in association with SGLT2 inhibitor use had blood glucose levels that were only 
slightly elevated, compared to typical cases of diabetic ketoacidosis where blood glucose 
levels are much higher. Investigators should use their clinical judgment to determine if a 
subject may have signs or symptoms of ketoacidosis and manage as clinically indicated.
Laboratory Procedures/Assessments
7.1.3
All laboratory tests outlined in the Trial Flow Chart - Section 6.0 will be performed by the 
central laboratory.  The optional site fingerstick A1C at Visit 1/Screening, the fasting
fingerstick glucose measurement at Visit 3/Randomization, and all urine pregnancy tests will 
be performed at the investigational site.
Laboratory test results for chemistry, hematology, and lipids will not be masked.  Glycemic 
measurements (e.g., FPG, A1C) will be masked from Visit 3/Randomization (Day 1).  
However, in order for the investigator to perform an evaluation for discontinuation from the 
blinded study drug, the central laboratory will report to the investigator in an unmasked 
manner if an FPG or A1C value meets criteria for discontinuation from blinded study drug 
criteria (see Sections 5.7).
 
 
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In addition, the central laboratory will flag the following safety measurements potentially 
meeting specific criteria for discontinuation from blinded study drug:

eGFR <60 mL/min/1.73 m2;

elevations ≥3X ULN in liver transaminases (i.e., ALT and AST) (see Section 12.5 for 
guidance on retesting);

elevations in ALT and/or AST ≥3-times the ULN with concurrent total bilirubin ≥2-
times the ULN and alkaline phosphatase <2-times the ULN;

fasting glucose potentially meeting hyperglycemia discontinuation criteria or 
hypoglycemia discontinuation criteria (see Section 5.7)

positive serum pregnancy test
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Refer to the Trial Flow Chart - Section 6.0 for specific laboratory tests performed at each 
trial visit.
7.1.3.1
Laboratory Evaluations (Hematology, Chemistry and Others)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.  
Table 5 Laboratory Evaluations
Hematology
Chemistry
Others

Hemoglobin

Hematocrit

RBC Count

Platelet Count

WBC Count

Neutrophils

Eosinophils

Monocytes

Basophils

Lymphocytes

BUN

Serum Creatinine (eGFR 
calculated using the 
CKD-epi formula)

Calcium (total)

Sodium

Potassium

Chloride

Total Carbon Dioxide 
(Bicarbonate)

Magnesium

Phosphate

Uric Acid

AST (SGOT)

ALT (SGPT)

Alkaline Phosphatase

Total Bilirubin

Direct (conjugated) 
Bilirubina

Indirect (unconjugated) 
Bilirubina

Albumin

Total Protein

TSH

Fasting C-peptide

A1C

FPG

Pregnancy Tests (where 
applicable)

Lipid Panel (i.e., Total 
Cholesterol, HDL-C, 
non-HDL-C, LDL-C, and
Triglycerides)

Insulin, glucagon (as part 
of 3-point MTT only)
a Both direct and indirect bilirubin measured only when total bilirubin is greater than ULN.
 
 
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Laboratory tests will be performed after at least a 10-hour fast (i.e., no food, double-blind 
study drug, background AHA medication [metformin, sulfonylurea], or drink except water 
and non-AHA non-study drug as prescribed).  Subjects who do not fast before a scheduled 
visit will be required to return fasting for a study visit within three days.  Subjects who have 
not fasted prior to Visit 1/Screening should obtain a fasting TG and FPG at or prior to Visit 
3/Day 1 rather than Visit 1/Screening.
7.1.3.2
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Plasma for future biomedical research

Serum for future biomedical research
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Discontinuation Visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
, and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
 
 
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7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed,   their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Digital scale 
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Fasting Prior to Scheduled Visits
Subjects should be counseled to fast (i.e., no food, double-blind study drug, background
AHA medication [metformin, sulfonylurea], or drink except water and non-AHA non-study 
drug as prescribed) for at least 10 hours prior to all study visits.  Subjects who do not fast 
before a scheduled visit will be required to return fasting for a study visit within three days.  
Subjects who have not fasted prior to Visit 1/Screening should obtain a fasting TG and FPG 
at or prior to Visit 2/Week -2 rather than Visit 1/Screening.
 
 
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7.1.5.2
Scheduling Visits
At the end of each trial visit, the next trial visit should be scheduled.  Every effort should be 
made to adhere to the visit schedule (see Section 6.0), and in general visits during the double-
blind treatment period should be scheduled within +/-7 days (Visit 3/Randomization [Day 1] 
through Visit 7/Week 24).  If unavoidable, a visit may be scheduled at a time outside of this 
recommended range, but the schedule for subsequent visits must be adjusted so that the total 
duration of the double-blind treatment period is as close as possible to 24 weeks.  Visits 
should be scheduled relative to the date of Visit 3/Randomization (Day 1).  If a visit is 
scheduled at a time other than the protocol-designated time, careful consideration must be 
given to the amount of blinded study drug the subject has available.
Trial sites should telephone the IVRS at each of the scheduled subject visits for purposes of 
enrollment tracking.
Visit 2/Week -2 may be scheduled as soon as it is confirmed that the subject meets all Visit 
1/Screening trial criteria, including laboratory criteria, ensuring that the interval between 
Visit 1 and Visit 2 is at least 2 weeks (with a maximum interval of approximately 6 weeks).  
The double-blind treatment period begins at Visit 3/Randomization (Day 1).  All subsequent 
double-blind treatment period visits should be scheduled relative to Visit 3/Randomization 
(Day 1).
Visit Reminders-Telephone Contacts
Prior to each visit, subjects should be called to be reminded of:
-
The date and time of appointment.
-
The requirement to fast for at least 10 hours prior to the clinic visit.
-
The requirement not to take metformin (or the SU agent, for subjects on metformin and 
an SU agent) and blinded study drug the morning of the clinic visit.  Non-study 
medications that are not AHA medications should be taken as directed by the prescribing 
physician.
-
The requirement to bring blinded investigational product, open-label metformin, (and the 
SU agent, for subjects on an SU agent), the blood glucose meter, the HAL and any 
collected SMBG information to the clinic.
-
Prior to MMTT visits only (Visit 3/Randomization and Visit 7 (or Discontinuation): to 
avoid strenuous exercise for 24 hours prior to the visit.
7.1.5.3
Visit 1/Screening
Subjects must be on a stable metformin dose of ≥1500 mg for at least 8 weeks at the time of 
screening alone or in dual combination with an SU (at a dose of ≥50% of maximum labeled 
dose).
 
 
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Subjects will be consented and screened according to Visit 1/Screening Inclusion/Exclusion 
Criteria and will receive a screening number and a Subject Identification Card. The subject’s 
medical history and prior/concomitant medications will be reviewed, and vital signs, body 
weight, and height will be measured.  For subjects assessed as eligible to participate in the 
trial, fasting blood samples will be obtained.  Women of childbearing potential will have a 
urine pregnancy test performed (and serum pregnancy test if required by site's IRB/EC).  
At the site, the investigator may choose to screen subjects with fingerstick A1C 
measurements (prior to drawing blood samples for the central laboratory screening 
measurements) to evaluate the likelihood of the subject subsequently meeting trial glycemic 
inclusion criteria.  If, based upon the fingerstick A1C value, the investigator believes the 
subject is an unlikely candidate for the trial, the subject may be excluded prior to undergoing 
additional trial procedures.  Investigators should be aware that the site-fingerstick A1C is a 
tool to evaluate a subject’s glycemic status and that a central laboratory measured A1C is still 
required to assess A1C entry criterion at Visit 1/Screening.
Note (1):  A subject excluded due to the TSH criterion may be re-screened after being on a 
stable thyroid replacement therapy for at least 6 weeks.
Note (2):  Subjects with elevated TG levels may have lipid-lowering medication initiated or 
adjusted and continue in the trial if a repeat measurement at Visit 2/ Week -2 no longer meets 
the exclusion criterion.  Subjects on lipid-lowering medication must be on a stable regimen 
for at least 4 weeks prior to Visit 3/Day 1.
Note (3):  Subjects with elevated systolic and/or diastolic blood pressure levels may have 
blood pressure medication initiated or adjusted and continue in the trial if repeat blood 
pressure measurements no longer meet the exclusion criterion at Visit 3/Randomization 
(Day 1).  Subjects on blood pressure medication must be on a stable regimen for at least 4 
weeks prior to Visit 3/Randomization (Day 1).
7.1.5.4
Visit 2/Week -2: Single-blind Placebo Run-in
All subjects will be evaluated according to Visit 2/Week -2 Inclusion/Exclusion criteria.  The 
subject’s prior/concomitant medications and adverse events will be reviewed; a 12-lead ECG 
and a full physical exam, including routine vital signs, will be performed; and fasting blood 
samples obtained.  Women of childbearing potential will have a urine pregnancy test 
performed (and serum pregnancy test if required by site's IRB/EC).
All subjects will (1) have diet/exercise counseling, (2) receive glucose meters and training in 
performing SMBG, and (3) receive instruction on hypoglycemia symptoms, hypoglycemia 
management, and completion of the HAL.
Subjects will be instructed to monitor their fingerstick glucose concentrations with a 
frequency determined appropriate by the investigator (based upon his/her assessment of the 
subject’s glycemic control) but with a minimum of two fasting determinations per week.  
Subjects are to contact the site if they experience any episodes of hypo- or hyperglycemia.
 
 
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The first dose of single-blind placebo run-in (matching placebo tablet for sitagliptin and 
over-encapsulated dapagliflozin placebo) must be taken as a witnessed dose in the clinic visit 
after completion of all Visit 2/Week -2 procedures, including the collection of all fasting 
blood samples.  Subjects will take their single-blind placebo pills for approximately two 
weeks prior to randomization.  Subjects should be reminded to withhold single-blind study 
drug on the day of Visit 3/Randomization (Day 1).
7.1.5.5
Treatment Period
7.1.5.5.1 Visit 3/Randomization (Day 1)
At Visit 3/ Randomization (Day 1), subjects who meet all trial enrollment criteria will have 
all baseline laboratory tests and trial procedures performed and will be randomized in a 1:1 
ratio to sitagliptin 100 mg q.d. or dapagliflozin 10 mg q.d.
Each subject will be assigned only one randomization number; assignment of a 
randomization number will occur only at Visit 3/Randomization (Day 1).  
The MMTT (either 2-point or 3-point) will be performed as described in Section 7.1.2.11.
Double-blind study drug will be dispensed at Visit 3/Randomization (Day 1).  The first dose 
of double-blind study drug should be taken as a witnessed dose after completion of all trial 
procedures, including the collection of all fasting blood samples and completion of the 
MMTT.
7.1.5.5.2 Visit 4/Week 4 through Visit 7/Week 24:  Double-blind Treatment Period
Subjects will be dispensed double-blind study drug at Visit 4/Week 4, Visit 5/Week 10, and 
Visit 6/Week 16.
Blinded study drug should be taken orally at approximately the same time each morning.  If a 
subject misses a dose of blinded study drug during the trial, they should be instructed to take 
it as soon as they remember unless it is time for the next dose.  Subjects should be instructed 
not to "make up" for the missed dose by taking two doses at the same time.  Compliance with 
the daily dosed medication during this period will be determined by subject self-report.
7.1.5.6
14-Day Post Treatment Telephone Contact
A telephone contact will be performed 14 days after the last dose of blinded study drug to 
collect SAEs.
7.1.5.7
Follow-up for Subjects Who Discontinue Blinded Study Drug
Subjects who prematurely discontinue blinded study drug should be followed according to 
Section 5.7.1.
 
 
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7.1.5.8
Follow-up for Subjects Who Discontinue Due to Decreased Renal Function
Subjects who discontinue blinded study drug for eGFR discontinuation criteria (see Section 
5.7) or renal-related adverse events should have a repeat eGFR performed within 
approximately 1 week after the last dose of blinded study drug.  This may be done as part of 
the Discontinuation Visit (if the Discontinuation Visit occurs within approximately 1 week 
after the last dose of study drug) or at an unscheduled visit.  The out of range test should 
continue to be repeated at intervals considered appropriate (e.g., weekly or every other week) 
until the value returns to baseline (pre-randomization value) or a new baseline is established.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
An overdose must be reported if either of the following occurs during the conduct of this 
trial: (1) Dosing of >400 mg/day of sitagliptin or matching placebo or (2) >200 mg/day of 
sitagliptin or matching placebo for more than 28 days or (3) dosing of >50 mg/day of 
dapagliflozin or matching placebo.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial.
 
 
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Pregnancies and lactations of subjects and female partners of male subjects from the time the 
consent form is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.  Pregnancies and lactations of subjects 
and female partners of male subjects that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported. All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
 
 
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For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
 
 
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Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 6. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 6 for instructions in evaluating adverse events.
 
 
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Table 6 Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.  Separate analysis plans (i.e., separate documents from the sSAP) will be developed 
to detail other planned analyses (i.e., future biomedical research).
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 - 8.12.  
Study Design Overview
Sitagliptin vs. dapagliflozin as add-on to metformin alone or in dual 
combination with an SU agent in subjects with mild renal impairment
Treatment Assignment
Subjects will be randomized in a 1:1 ratio to sitagliptin or
dapagliflozin.
Stratification factors: No stratification factors
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
A1C – change from baseline at Week 24
Key Secondary Endpoints
Change from baseline at Week 24 in each of the following:

Post-prandial glucose excursion (PPGE) (increment in glucose 
from T=0 to T=120 minutes)

Post-prandial glucose (PPG) (glucose value at T=120 minutes)

Glucagon Area Under the Curve (AUC)

Insulin AUC

Insulin AUC to Glucagon AUC ratio

FPG
Proportion of subjects with A1C <7% at Week 24
 
 
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Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary efficacy analysis will compare the efficacy of sitagliptin 
relative to dapagliflozin in change from baseline in A1C at Week 24.  
The mean change from baseline in A1C at Week 24 with sitagliptin 
will be compared to that of dapagliflozin via a cLDA model. 
For the primary hypothesis, sitagliptin will be considered non-inferior 
to dapagliflozin if the upper bound of the two-sided 95% confidence 
interval (CI) of the between-group difference in LS mean change from 
baseline in A1C (sitagliptin minus dapagliflozin) is less than 0.3% (the 
non-inferiority margin).
If the non-inferiority hypothesis is rejected, and if the upper bound of 
the two-sided 95% CI of the between-group difference in LS mean 
change from baseline in A1C (sitagliptin minus dapagliflozin) is less 
than 0, sitagliptin will be considered superior to dapagliflozin in 
lowering A1C.
Statistical Methods for Key 
Safety Analyses
No tier 1 safety endpoints are pre-specified in this study.  For Tier 2 
endpoints, 95% confidence intervals will be provided for between-
group differences in the percentage of subjects with events; these 
analyses will be performed using the Miettinen and Nurminen method 
[15]
Interim Analyses
No interim analysis is planned.
Multiplicity
The study-wise type I error rate will be controlled at =0.025 (one-
sided) using an ordered testing procedure.  
The study will first test for non-inferiority for A1C.  If the success 
criterion for non-inferiority is met, superiority for A1C will be 
assessed. If the test for superiority is successful, the secondary 
hypothesis for post-prandial glucose excursion will be tested. All 
three tests will be conducted at =0.025 (one-sided).  
Sample Size and Power 
The planned sample size is 278 subjects per treatment group.  The trial 
has >99% power to establish that sitagliptin is non-inferior to 
dapagliflozin in lowering A1C at an overall one-sided, 2.5% α-level, if 
the underlying treatment difference is 0%.
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
 
 
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Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Sections 3.1 and 3.2.  A non-inferiority 
margin of 0.3%, which is regarded as a minimum clinically important difference between 2 
treatments, will be used for testing of the primary hypothesis for A1C.  Non-inferiority will 
be declared if the upper bound of the two-sided 95% CI for the treatment effect (sitagliptin 
minus dapagliflozin) is less than 0.3%.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
Efficacy Endpoints
8.4.1
The descriptions of the efficacy measurements and time points at which they are measured 
are described in Section 4.2.3.1 and Section 6.0 (Trial Flow Chart), respectively.  The 
efficacy endpoints to be analyzed are listed in Table 7.  These endpoints will be analyzed at 
Week 24.
Table 7 Efficacy Endpoints
Primary Endpoint
Change from Baseline in A1C at Week 24
Secondary Endpoints
Change from Baseline in PPGE (increment in glucose from T=0 to T=120 minutes)  at Week 24
Change from Baseline in 2- hour PPG (glucose value at T=120 minutes) at Week 24
In a subset of subjects who undergo the 3-point MMTT
Change from Baseline in Glucagon AUC0-120 min at Week 24
Change from Baseline in Insulin AUC0-120 min at Week 24
Change from Baseline in Insulin AUC0-120 min to Glucagon AUC0-120 min Ratio at Week 24
Proportion of subjects with A1C < 7.0% at Week 24
Change from Baseline in FPG at Week 24
Safety Endpoints
8.4.2
The descriptions of the safety measurements and time points at which they are measured are 
described in Section 4.2.3.2 and Section 6.0 (Trial Flow Chart), respectively.  The safety
endpoints to be analyzed are listed in Table 9 in section 8.6.2.  These endpoints will be 
analyzed over 24 weeks.
 
 
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Derivation of Efficacy Endpoints
8.4.3
Computation details for endpoints listed in Table 7 are provided below

Post Prandial Glucose Excursion = Glucose at 120 minutes – glucose at 0 minutes
from the start of the meal.  PPGE will be considered missing if measurement at one 
time point is missing.

AUC endpoints will be derived via the trapezoidal rule using the 0-, 60-, and 120-
minute measurements from the start of the meal during the 3-point MMTT. AUC will 
be considered missing if any of those 3 measurements is missing.
Analysis Populations
8.5
Summaries of subject disposition will include all randomized subjects.  Summaries of 
baseline characteristics will be performed in the All Subjects Treated (AST) population, 
consisting of all randomized subjects who received at least one dose of study treatment.  
Subjects will be included in the treatment group to which they were randomized.
Efficacy Analysis Populations
8.5.1
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all randomized subjects who:

receive at least one dose of study treatment,

have at least one observation for the analysis endpoint, at baseline or subsequent to at
least one dose of study treatment 
A secondary population for analyzing primary and key secondary efficacy endpoints at Week 
24 will be the Per-Protocol (PP) population. All randomized subjects who take at least one 
dose of study medication, with a measurement of the analysis endpoint at both baseline and 
the time point of interest (Week 24), without any of the following protocol deviations will be 
included in this population:

Drug compliance <75%, using the compliance definition provided in Section 8.11.

Use of prohibited antihyperglycemic medications (found in Section 5.5) after 
randomization for a total of ≥14 days or ≥7 consecutive days

Use of pharmacologic doses of corticosteroids for ≥2 consecutive weeks after 
randomization

Incorrect double-blind study drug, or a change in metformin dose or SU dose (if 
applicable) after randomization, for ≥14 consecutive days.
Data after the last dose of study medication plus an offset of 5 days will be excluded from all 
efficacy analyses, with the exception of selected sensitivity analyses to be described in the 
sSAP.
 
 
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These protocol deviations are not just a repetition of the exclusion and inclusion criteria in 
the protocol, but a clinical assessment of deviations from the protocol-specified criteria that 
will either affect or confound the measures of efficacy. Any subject meeting any of the above 
criteria during the trial will be excluded from the PP population.
The final determination on major protocol deviations, and thereby the composition of the PP
population, will be made prior to the final unblinding of the database and will be documented 
in a separate memo.  Subjects will be included in the treatment group to which they are 
randomized for the analysis of efficacy data using both the FAS and Per-Protocol 
populations.  Details on the approach to handling missing data are provided in Section 8.6
Statistical Methods.
Safety Analysis Populations
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  This will be the randomized treatment group for all subjects except those who 
take incorrect study treatment for the entire treatment period. Such subjects will be included 
in the treatment group corresponding to the study treatment actually received.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 Statistical Methods.
Statistical Methods
8.6
Statistical testing and inference for safety analyses are described in 8.6.2. Efficacy results 
that will be deemed to be statistically significant after consideration of the Type I error 
control strategy are described in Section 8.8, Multiplicity. All statistical tests will be 
conducted at α=0.025 (one-sided) level.
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives.
The primary estimands for the study consist of the following elements:

Target population: Patients with T2DM and mild renal impairment who have 
inadequate glycemic control on metformin alone or in dual combination with an SU 
agent

Endpoint: Mean change from baseline (in A1C, in incremental post-prandial glucose 
excursion) at Week 24

Measure of intervention effect: Difference in the effect of randomized treatments on 
the endpoint if all subjects remained on treatment through Week 24
 
 
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For the analysis of change from baseline in A1C, a constrained longitudinal data analysis 
(cLDA) method proposed by Liang and Zeger [13] will be used. This model assumes a 
common mean across treatment groups at baseline and a different mean for each treatment at 
each of the post-baseline time points. In this model, the response vector consists of baseline 
and the values observed at each post-baseline time point. Time is treated as a categorical 
variable so that no restriction is imposed on the trajectory of the means over time. The 
analysis model will also adjust for treatment, time, background AHA (metformin alone, or 
metformin in combination with an SU agent), the interaction of time by background AHA, 
and the interaction of time by treatment. The treatment difference in terms of mean change 
from baseline at Week 24 will be estimated and tested from this model. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements.
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups. Of note, in the event that there are no missing data, the estimated treatment 
difference from the above cLDA model will be identical to that from a traditional 
longitudinal ANCOVA model which uses the baseline value as a covariate. However, unlike 
longitudinal ANCOVA, the cLDA model accounts for variability in the baseline values, thus 
providing more accurate standard errors and confidence intervals for individual treatment 
effects. Moreover, this model allows the inclusion of subjects who are missing either the 
baseline or post-baseline measurements, thereby increasing efficiency. Details of the model 
specification, assumptions, and SAS implementation codes are given in the sSAP.
Analyses of the change from baseline in other continuous efficacy endpoints at Week 24 will 
be performed using the cLDA model as described above.
An ANCOVA model as described above will also be used in the PP population as an 
additional sensitivity analysis for the primary and key secondary endpoints at Week 24. By 
definition, there will be no missing outcome data in the PP population.
For the analysis of percentages of individuals at the A1C goal of <7.0% (53 mmol/mol) at 
Week 24, the cLDA model that is used for the analysis of A1C will also be used to impute 
the missing data on A1C.  Imputations of the missing data will be based on the marginal 
univariate normal distributions with means equal to the predicted values and variances equal 
to the squared standard errors for the predicted values from the cLDA model. Ten sets of 
imputations of each missing value will be constructed from the cLDA model.  Observed data 
will not be imputed.  Subjects will be categorized as subjects at the A1C goal (satisfying the 
A1C specific goal of <7.0% [53 mmol/mol]) or subjects not at the goal at Week 24 after 
imputations.
To estimate the between-group rate difference, each of the 10 imputed data sets will be 
summarized to obtain the proportion of subjects at the goals within each group.  The 
estimated proportions of subjects at the goals from the 10 imputed data sets will be combined 
using standard multiple imputations (MI) techniques proposed by Rubin [14] to yield an 
overall estimate of the response rate and associated variance for each group. The estimated 
response rates and adjusted effective sample sizes [15] will then be used to obtain the 
confidence interval for between-group rate difference via M&N method.  
 
 
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A sensitivity analysis for the A1C goal of <7.0% will also be performed, with imputation of 
“Missing=Not at Goal”. The percentages of subjects at target A1C control at Week 24 will be 
analyzed assuming that all missing Week 24 A1C values were not at target.
Table 8 summarizes the key efficacy analyses.
Table 8 Analysis Strategy for Key Efficacy Variables
Endpoint
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint/Primary Hypothesis
Change from baseline in A1C 
at Week 24
P
S
cLDA
ANCOVA
FAS
PP
Model-based
N/A
Secondary Endpoint/Secondary Hypothesis
Change from baseline in PPGE 
(increment in glucose from 
T=0 to T=120 minutes) at 
Week 24
P
S
cLDA
ANCOVA
FAS
PP
Model-based
N/A
Other Secondary Endpoints
Change from baseline in 2-hr 
PPG (glucose value at T=120 
minutes) at Week 24
P
S
cLDA
ANCOVA
FAS
PP
Model-based
N/A
Change from baseline in 
glucagon AUC0-120min at Week 
24
P
S
cLDA
ANCOVA
FAS
PP
Model-based
N/A
Change from baseline in insulin 
AUC0-120min at Week 24
P
S
cLDA
ANCOVA
FAS
PP
Model-based
N/A
Change from baseline in the 
insulin AUC0-120min to 
glucagon AUC0-120min ratio at 
Week 24
P
S
cLDA
ANCOVA
FAS
PP
Model-based
N/A
Proportion of subjects with 
A1C < 7.0% at Week 24
P
S
M&N
M&N
FAS
FAS
MI
Missing=Not at 
Goal
Change from baseline in FPG 
at Week 24
P
S
cLDA
ANCOVA
FAS
PP
Model-based
N/A
 †P=Primary approach; S=Supportive approach.
  A1C=Glycosylated hemoglobin; ANCOVA=Analysis of covariance; cLDA=Constrained longitudinal data analysis; 
FAS=Full analysis set; =Fasting plasma glucose; N/A=Not applicable; P=Primary; PPG=Post-Prandial Glucose; 
S=Supportive; M&N= Miettinen and Nurminen; MI=Multiple Imputations
 
 
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Missing Data Handling
The cLDA method assumes that data are missing at random (MAR).  In this study, it is 
expected that Missing at Random and Missing Completely at Random (MAR/MCAR) 
mechanisms will underlie most of the missingness, and the proportion of data missing not at 
random (MNAR), driven solely by unobserved values of the study endpoints, will be small.  
Reasons for discontinuation from the study may include lack of efficacy, clinical or 
laboratory adverse experiences, relocation, withdrawal of consent, protocol deviations, 
and/or data processing issues. Missing data caused by relocation and data processing issues 
are likely to be MCAR. On the other hand, missing data caused by discontinuation due to 
lack of efficacy may belong to MAR because the discontinuation may depend on the 
observed efficacy outcomes. The MAR or MNAR mechanisms might each underlie the other 
reasons to some extent. If treatment in large part determines the loss of data for these other 
reasons (such as clinical or laboratory adverse experiences), the mechanism may be close to 
MAR because treatment assignment is an observed variable and included in the analysis 
model. Based on prior study results, missing data due to other reasons is relatively 
infrequent. 
For the analysis of change from baseline in A1C, additional analyses will be performed, with 
specific details for these models provided prior to unblinding:
o
Analyses that assume that the distribution of the missing data differs from the 
distribution of the observed data will be run.  Different assumptions for the missing 
data distribution will be considered, including MNAR.
o
If >5% of the subjects in any treatment group were <75% compliant with study 
medication (using the definition in Section 8.11), at least one model will account for 
compliance.
Details describing the sensitivity analyses will be provided in the sSAP.  Further 
investigation will be performed if the results from these sensitivity analyses are not 
consistent with results from the primary analyses.
The strategy to address multiplicity issues with regard to multiple hypotheses is described in 
Section 8.7 Interim Analyses and in Section 8.8 Multiplicity.
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
The following analysis approaches will be used:

The primary analysis approach will consider all on-treatment data and data up to and 
including the 14-day post-treatment follow-up.

A secondary approach that applies only to AE summary measures, specific AEs, and 
serious AEs will include all data in the database after the first dose of double-blind 
study medication, with no exceptions.
 
 
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The analysis of safety results will follow a tiered approach (Table 9).  The tiers differ with 
respect to the analyses that will be performed.  No safety parameters have been identified as 
“Tier 1” safety endpoints. Therefore all safety endpoints will be considered Tier 2 or Tier 3.  
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory and vital signs parameters will be classified as belonging to 
"Tier 2" or "Tier 3", based on the number of events observed.  Membership in Tier 2 requires 
that at least 4 subjects in any treatment group exhibit the event; all other adverse experiences 
and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs will be 
considered Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, and 
change from baseline values will be provided by treatment group in table format.  Mean 
change from baseline over time will be plotted with the corresponding standard errors.  
The broad clinical and laboratory AE categories consisting of the percentage of subjects with 
any AE, a drug-related AE, a serious AE, an AE which is both drug-related and serious, and 
who discontinued due to an AE, documented hypoglycemia AEs will also be considered Tier 
2 endpoints.  The 95% confidence intervals will be provided for between-treatment 
differences in the percentage of subjects with events; these analyses will be performed using 
the Miettinen and Nurminen method [15], an unconditional, asymptotic method.
 
 
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Table 9 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
There are no pre-determined Tier 1 endpoints
Tier 2
Any AE†
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
AEs of hypoglycemia
X
X
AEs of documented hypoglycemia
X
X
AEs of severe hypoglycemia
X
X
       Any
X
X
      Requiring medical assistance
X
X
       Not requiring medical assistance
X
X
Specific AEs†, SOCs, or PDLCs (incidence ≥4 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of 
subjects in all of the treatment groups)
X
Additional hypoglycemia endpoints
X
Change from Baseline Results (Laboratory 
measurements, Vital Signs)
X
† Adverse Experience references refer to both Clinical and Laboratory AEs.
‡ Includes only those endpoints not already pre-specified as Tier-2 endpoints.
SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
Analysis of Hypoglycemia
The analysis of hypoglycemia will be performed separately by background AHA, i.e., for 
patients on metformin alone or metformin in combination with an SU agent.
The Tier 2 analysis for hypoglycemia will include the numbers and percentages of subjects
experiencing one or more of each of the following:

Adverse events of hypoglycemia (symptomatic or asymptomatic), regardless of 
biochemical documentation.

Adverse events of documented hypoglycemia, defined as adverse events of symptomatic 
hypoglycemia with a concurrent glucose measurement of 70 mg/dL (3.9 mmol/L).

Adverse events of severe hypoglycemia, defined as adverse events of symptomatic 
hypoglycemia that required assistance, either medical or non-medical, regardless of 
whether such assistance was obtained, and regardless of biochemical documentation.  
These events will be further sub-classified as:
o
Those that required medical assistance.  Adverse events of symptomatic 
hypoglycemia that included a markedly depressed level of consciousness, loss of 
consciousness, or seizure will be classified as having required medical assistance, 
whether or not medical assistance was obtained
 
 
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o
Those that did not require medical assistance (i.e., those episodes that required non-
medical assistance to treat).
The Tier 3 summary of hypoglycemia will include the following, based on episodes 
classified by the investigator as adverse events:

The numbers and percentages of subjects with each of the following, overall and by 
lowest reported glucose category (<50 mg/dL [<2.8 mmol/L], ≤70 mg/dL [≤3.9 mmol/L], 
>70 mg/dL [>3.9 mmol/L], or unknown).  A subject's lowest glucose category will be 
classified as unknown only if no glucose measurements are available for that subject.
1. any episodes (symptomatic or asymptomatic)
2. symptomatic episodes
3. asymptomatic episodes

The numbers and percentages of subjects with episodes having precipitating factors

The number of episodes per subject

The number of each of the following (summed across all subjects).  The overall summary 
will include an indication of whether precipitating factors were present.
1. all episodes (symptomatic or asymptomatic)
2. symptomatic episodes
3. asymptomatic episodes
Categorization of episodes by glucose level will be performed based on the units (mg/dL or 
mmol/L) in which the glucose measurements were recorded.
A summary of subjects with episodes that were reported on the hypoglycemia assessment 
(HA) eCRF but were not classified by the investigator as adverse events will also be 
provided.  If a substantial number of subjects had episodes that were not classified as adverse 
events, then additional summaries may be provided for the Tier 3 endpoints above, including 
all episodes reported on the HA eCRF (i.e., not restricted to adverse events).  It is expected 
that all symptomatic hypoglycemia episodes will be classified by the investigator as adverse 
events and, thus, any episodes that are not classified as adverse events will be asymptomatic 
episodes.
 
 
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Demographic and Baseline Characteristics
8.6.3
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.  The following demographic/anthropometric, diabetes-related, and 
baseline efficacy variables will be summarized by treatment either by descriptive statistics or 
categorical tables.  Depending on the variable of interest, statistics such as sample size, mean, 
SD, median, range and proportion will be provided.

Continuous baseline demographic variables: age (years), weight (kg), height (cm), and 
body mass index (BMI; kg/m2).

Categorical baseline demographic variables: age (<35 years, ≥35 and <45 years, ≥ 45 and 
<55 years, ≥55 and <65 years, ≥65 and <75 years, ≥75 years), gender (male, female), and 
race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or Other 
Pacific Islander, or Multi-Racial), ethnicity (Hispanic/Latino or not).

Baseline A1C, and distribution of A1C at baseline (A1C levels <8%, and ≥8%)

Baseline FPG

Baseline eGFR

Time since diagnosis of diabetes mellitus (years)

Geographic region (Americas, Europe, Asia, Other)

Background AHA (metformin alone, or metformin in dual combination with an SU 
agent)
The above summaries will be provided for all subjects who received at least one dose of 
study therapy.
Interim Analyses
8.7
No interim analyses are planned for this study.
Multiplicity
8.8
The study-wise type I error rate will be controlled at =0.025 (one-sided) using an ordered 
testing procedure.  
The study will first test for non-inferiority for A1C.  If the success criterion for non-
inferiority is met, superiority for A1C will be assessed. If the test for superiority is 
successful, the secondary hypothesis for post-prandial glucose excursion will be tested. All 
three tests will be conducted at =0.025 (one-sided).  
 
 
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Sample Size and Power Calculations
8.9
This study will randomize approximately 556 subjects (in a 1:1 ratio) into the sitagliptin 
group and dapagliflozin group and has >99% power to establish that sitagliptin is non-
inferior to dapagliflozin in lowering A1C at an overall one-sided, 2.5% α-level, if the 
underlying treatment difference is 0%.
The power and sample size are based on the following assumptions derived using data from 
MK-0431 Protocol 020 and published data for dapagliflozin: 
1) The cumulative attrition rates for each group at Weeks 6, 12, 18, and 24 are 0.03, 0.05, 
0.08, and 0.11.
2) The conditional correlation matrix (correlation matrix of the post-randomization 
measurements conditional on the baseline value) at Weeks 6, 12, 18, and 24 is 
1.00 0.67 0.56 0.50
0.67 1.00 0.86 0.76
0.56 0.86 1.00 0.90
0.50 0.76 0.90 1.00
3) The conditional standard deviation is 0.7%
The non-inferiority margin is regarded as a minimum clinically important difference between 
the 2 treatments.  The calculation is based on the two-sample t-test with an effective sample 
size of 261 subjects per group and was carried out using SAS v9.3. The minimum criterion 
for success is that the upper bound of the two-sided 95% CI of difference is < 0.3%. Given 
the assumed SD of changes from baseline in A1C, the half-width of the 95% CI for the 
between-group difference (sitagliptin minus dapagliflozin) is expected to be 0.12% (based on 
the assumptions used in the power computation); thus, if the observed between-group 
difference is less than 0.18%, the success criterion of non-inferiority will be met.
If the non-inferiority null hypothesis is rejected, superiority for A1C will be tested.
If the A1C superiority test is rejected, superiority for PPGE (increment in glucose T=0 to 
T=120 minutes) will be tested. This study has 82% power to demonstrate the superiority of 
sitagliptin over dapagliflozin in lowering PPGE at a one-sided, 2.5% α-level, if the 
underlying treatment difference in PPGE is 12.0 mg/dL and an assumed standard deviation of 
45.0. These results are based on MK-0431 P020 and canagliflozin study 3006.
A sample size of approximately 120 subjects/group for the subset of subjects who will 
undergo the 3-point MTT will provide approximately 90% power to detect a treatment 
difference of 20.0 pg-h/ml for glucagon AUC.
Subgroup Analyses and Effect of Baseline Factors
8.10
No subgroup analyses are planned for this study.
 
 
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Compliance (Medication Adherence)
8.11
The computation of compliance in the All Subjects Treated (AST) set will be based on the 
study medication case report form. Both the assigned treatment and any matching placebo 
pills will be included in the compliance calculation.
For each subject, percent compliance will be calculated using the following formula:
Compliance =
Number of Compliant Days
× 100%.
Number of Days in the Double-blind Treatment Period
A day within the Double-blind Treatment period will be considered a compliant day if the 
subject was compliant with study medication on that day, defined as follows:

For the sitagliptin group, a subject is compliant if the subject took exactly one 1 tablet
of sitagliptin 100 mg and 1 capsule of matching placebo to dapagliflozin 

For the dapagliflozin group, a subject is compliant if the subject took:
o
1 capsule of dapagliflozin 5 mg and 1 tablet of matching placebo to sitagliptin 
from Visit 3/Day 1 through one day prior to Week 4/Visit 4
o
1 capsule of dapagliflozin 10 mg (or 5 mg if the patient was unable to tolerate 
dapagliflozin uptitration) and 1 tablet of matching placebo to sitagliptin from 
Week 4/Visit 4.
If the study medication eCRF indicates general compliance problems with any blinded 
therapy, the subject will be considered non-compliant for that day regardless of the number 
of tablets reported.
The "Number of Days in Double-blind Treatment Period" is defined for each subject as the 
total number of days from the first dose of double-blind study medication to the last day of 
study medication for dapagliflozin or sitagliptin. 
Summary statistics will be provided on percent compliance by treatment group.
Extent of Exposure
8.12
The extent of exposure to double-blinded study treatment will be evaluated by summary 
statistics (N, mean, median, standard deviation and range) and frequencies for the "Number 
of Days on Therapy" by treatment group, based on daily dosing records on the study 
medication eCRF.
Summary statistics (N, proportion) of subjects who could not tolerate dapagliflozin 10 mg 
will also be provided.
 
 
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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 10 Product Descriptions
Product Name & Potency
Dosage Form
Sitagliptin 100mg
Tablet
Dapagliflozin 5mg
Capsule
Dapagliflozin 10mg
Capsule
Placebo to match Sitagliptin 100mg
Tablet
Placebo to match Dapagliflozin 5 & 10mg
Capsule
All placebos were created by the Sponsor to match the active product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive single blind supplies for two weeks in finished good bottles which 
contain 21 tablets or capsules.  Subjects will receive double blind supplies for intervals of 4 
weeks, 6 weeks or 8 weeks throughout the 24 week period of double blind treatment in 
finished good bottles containing 35 or 63 count of tablets or capsules or the matching 
placebo.
Clinical Supplies Disclosure
9.3
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
 
 
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Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
 
 
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Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
 
 
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Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
 
 
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Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
 
 
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According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
 
 
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
 
 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1. American Diabetes Association. Standards of medical care in diabetes–2014. 
Diabetes Care. 2014;37(Suppl 1):S14–80.
2. Danaei G, Finucane MM, Lu Y, et. al. National, regional, and global trends in fasting 
plasma glucose and diabetes prevalence since 1980: systematic analysis of health 
examination surveys and epidemiological studies with 370 country-years and 2.7 
million participants. Lancet 2011; 378(9785):31-40.
3. American Diabetes Association.  Economic costs of diabetes in the U.S. in 2012.  
Diabetes Care 2013: 1-14.
4. Centers for Disease Control and Prevention. National diabetes fact sheet: national 
estimates and general information on diabetes and prediabetes in the United States, 
2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for 
Disease Control and Prevention, 2011.
5. Cade, WT. Diabetes-Related Microvascular and Macrovascular Diseases in the 
Physical Therapy Setting. Phys Ther. 2008 Nov; 88(11): 1322–1335.
6. American Diabetes Association. Glycemic Targets. Diabetes Care. 2015;38(Suppl 
1):S33-S40.
7. US FDA Center for Drug Evaluation and Research Advisory Committee Meeting for 
dapagliflozin, 
November 
4, 
2013 
BMS 
Briefing 
Document. 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/D
rugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378079.pdf.
8. US FDA Center for Drug Evaluation and Research Advisory Committee Meeting for 
canagliflozin, 
January 
10, 
2013 
Janssen 
Briefing 
Document. 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/D
rugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334551.pdf.
9. Bailey RA, Wang Y, Zhu V, Rupnow MF. Chronic kidney disease in US adults with 
type 2 diabetes: an updated national estimate of prevalence based on Kidney Disease: 
Improving Global Outcomes (KDIGO) staging. BMC Res Notes 2014; 7:415.
10. Herman GA Bergman A, Stevens C et al. Effect of single oral doses of sitagliptin, a 
dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral 
glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006 
Nov;91(11):4612-9.
 
 
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11. Brownlee M, Hirsch IB.  Glycemic variability: A Hemoglobin A1c–Independent Risk 
Factor for Diabetic Complications. JAMA. 2006;295(14):1707-1708.
12. Levey AS, Stevens LA, Schmid C H et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med 2009; 150:604-612.
13. Liang KY, Zeger S. Longitudinal data analysis of continuous and discrete responses 
for pre-post designs. Sankhyā: The Indian Journal of Statistics 2000, Series B 62, 
134–148.
14. Rubin DB. Multiple Imputation for Nonresponse in Surveys. 1987; Wiley, New York.
15. Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985;4:213-226.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.2 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
 
 
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b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
 
 
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At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
 
 
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Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
 and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
 
 
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8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
 
 
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11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Management of Subjects with Elevated Liver Function Tests
12.4
Section I: Identification and Management of Subjects with ALT or AST Results ≥3X ULN
Increases in ALT or AST ≥ 3X the upper limit of normal (ULN) will be assessed in this study 
according to the procedures described below.  The central laboratory report will alert the 
investigator if a subject meets this threshold.  When a randomized subject who is receiving 
blinded study drug has an ALT or AST elevation ≥ 3X ULN, the investigator should determine 
which set of criteria the subject meets from the table below, based upon the following factors: (1) 
the magnitude of the subject’s ALT or AST elevation, (2) the presence or absence of signs and 
symptoms, and (3) whether there is a corresponding increase in total bilirubin (TBL) ≥2X ULN. 
The investigator should monitor the subject and determine whether to interrupt study drug, in 
accordance with the instructions relevant to the specific criterion met.
Investigator Instructions for Management of Subjects with ALT or AST ≥3X ULN
A) Subject has: 

ALT or AST ≥3X ULN with TBL ≥2X ULN and alkaline phosphatase 
<2X ULN
1. The subject should interrupt blinded study drug.  
2. Refer to the “Event of Clinical Interest (ECI) Guidance for Potential DILI (Drug-
Induced Liver Injury) in Clinical Trials” (located in the Investigator Trial File 
Binder or equivalent) and perform procedures accordingly.  
3. If an etiology for the elevated ALT or AST and TBL levels is established and the 
abnormalities resolve, blinded study drug may be restarted with approval by the 
Sponsor.  Otherwise, the subject should discontinue treatment with blinded study 
drug.
Note: Laboratory assessments prescribed in the Event of Clinical Interest (ECI) 
Guidance for Potential DILI (Drug-Induced Liver Injury) in Clinical Trials may be 
sent locally in emergent cases and to support subject compliance with the necessary 
evaluations.  Subjects unwilling or unable to undergo the prescribed testing should be 
discontinued from treatment with blinded study drug.   
 
 
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B) Subject has: 

ALT or AST ≥8X ULN  
OR

ALT or AST ≥3X ULN and <8X ULN, with signs or symptoms of a 
drug reaction consistent with liver injury (e.g., fever, eosinophilia, 
right upper quadrant pain, dark urine, fatigue, etc.)
1. The subject should interrupt blinded study drug.  
2. Perform repeat ALT and AST within 3 days of receipt of the laboratory report.  
3. Initiate evaluation for potential causes.  See Section II below.  
4. Repeat ALT and AST tests at appropriate intervals, initially approximately 2-times 
per week, until resolution or return to baseline.     
5. If an etiology for the elevated liver enzymes is established (e.g., active hepatitis 
with specific etiology demonstrated, cholecystitis, biliary obstruction), blinded 
study drug may be restarted with approval by the Sponsor.  Otherwise, the subject 
should discontinue treatment with blinded study drug.
Note: Local laboratory assessments can be used to support compliance with the repeat 
testing procedure described above if required.  Subjects unwilling or unable to 
undergo repeat ALT and AST testing at the frequency recommended above should be 
discontinued from treatment with blinded study drug.    
 
 
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C) Subject has:

ALT or AST ≥3X and <8X ULN, without associated signs or symptoms
 
 
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In summary, subjects should be discontinued from blinded study drug for any of the 
following reasons:

ALT or AST ≥3X ULN with TBL ≥2X ULN and alkaline phosphatase <2X ULN and 
without an established etiology

ALT or AST ≥8X ULN or ≥3X ULN with symptoms consistent with liver injury and 
without an established etiology

ALT or AST ≥5X ULN for 2 weeks
Section II: Guidance for Assessment of Potential Etiology
Questions to Assess Etiology
Investigate potential causes for the subject’s elevated liver enzymes using the questions below.    
Answers to the questions should be recorded in the subject’s source documents and appropriate 
eCRFs.   
1. Has the subject recently:

Had a change in his/her pattern of alcohol use?  Investigate historic pattern of 
alcohol use as well.

Administered an illegal drug(s) (including intravenous drugs)?

Been exposed to a chemical agent or other environmental toxin?

Consumed any unusual foods (e.g., mushrooms), seasonal foods, or initiated 
treatment with new herbal/nutritional supplements?

Initiated a new diet regimen, started a rigorous exercise program, or 
experienced any form of severe physical exertion? 

Traveled to another country or region?
2. Does the subject have a relevant concomitant illness (e.g., cholelithiasis, hepatitis, 
etc.) or has the subject had potential exposure to viral hepatitis (transfusion, tattoo, 
new sexual partner)?
3. Does the subject have a relevant medical history (e.g., autoimmune disorder, cancer, 
Gilbert’s syndrome, obesity, Wilson’s disease, NASH, alcoholic or infectious 
hepatitis, biliary tract disease, hypoxic/ischemic hepatopathy, etc.)?
 
 
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4. Has the subject recently been treated with a concomitant medication(s) with 
demonstrated or suspected effects on the liver (e.g., acetaminophen; amiodarone; 
aspirin; chlorpromazine; dantrolene; erythromycin; halothane; isoniazid; methyldopa; 
nitrofurantoin; oxyphenisatin; perhexiline maleate; phenytoin; propylthiouracil; 
rifampin; sulfonamides; tetracyclines) or initiated treatment with another new 
medication(s)?
Additional Laboratory/Imaging Evaluations
In subjects for whom an etiology for the abnormal liver enzymes is unknown or whose elevated 
liver enzymes persist for more than 1-week:
1. Consider performing serologic tests including: (a) Hepatitis A (IgM); (b) Hepatitis B 
(surface antigen and core IgM); (c) Hepatitis C (antibody); (d) Hepatitis E (IgG and 
IgM).  Obtain consent prior to testing, if required locally.  Additional evaluations may 
be performed at the discretion of the investigator.  
2. Consider an ultrasound of the subject’s right upper quadrant and additional scans 
(endoscopic retrograde cholangiopancreatography [ERCP] or magnetic resonance 
cholangiopancreatography [MRCP]) if needed. 
Note: Subjects may also be referred to a gastroenterologist or hepatologist for an additional 
work-up if considered necessary by the investigator.  
 
 
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Predefined Limits of Change (PDLC)
12.5
The following predefined limits of change will be assessed in the statistical analysis, as described 
in Section 8.6.2.
Laboratory Test
Predefined Limits of Change† Criterion
Categories Assessed for Each 
Criterion
At Least One 
Value
Last On-
Treatment Value
Laboratory – Hematology
Hemoglobin (g/dL)
1.  Decrease ≥1.5 g/dL
Y
Y
2.  Increase >2.0 g/dL 
Y
Y
3. Increase >2.0 g/dL and value > ULN
Y
Y
WBC Count (103/microL)
1.  Decrease ≥50% and value < LLN
Y
Y
2.  Increase ≥20% and value > ULN
Y
Y
Neutrophil Count (103/microL)
1.  Decrease ≥20%  and value < LLN
Y
Y
2. Increase ≥20% and value > ULN
Y
Y
Lymphocyte Count (103/microL)
1.  Decrease ≥20% and value < LLN
Y
Y
2.  Increase ≥20% and value > ULN
Y
Y
Platelet Count (103/microL)
1.  Decrease ≥25% and value < LLN
Y
Y
2.  Increase  ≥100% and value > ULN
Y
Y
Laboratory – Chemistry
BUN (mg/dL)
1.  Increase ≥50% and value > ULN
Y
Y
eGFR
1. Decrease > 30% 
Y
Y
2. Decrease > 50% 
Y
Y
Total Bilirubin (mg/dL)
1.  Value >2x ULN
Y
Y
AST (IU/L)
1.  Value ≥3x ULN
Y
Y
2.  Value >5x ULN
Y
Y
3.  Value >10x ULN
Y
Y
4.  Value >20x ULN
Y
Y
ALT (IU/L)
1.  Value ≥3x ULN
Y
Y
2.  Value >5x ULN
Y
Y
3.  Value >10x ULN
Y
Y
4.  Value >20x ULN
Y
Y
AST (IU/L) or ALT (IU/L)
1. Value ≥3x ULN
Y
Y
2.  Value >5x ULN
Y
Y
3. Value >10x ULN
Y
Y
4.  Value >20x ULN
Y
Y
AST (IU/L) or ALT (IU/L)+ Total 
Bilirubin (mg/dL)
1.  ALT ≥3× ULN or AST ≥3× ULN with 
concurrent Bilirubin >2× ULN
Y
Y
Alkaline Phosphatase (IU/L)
1.  Value >1.5x ULN
Y
Y
Serum Uric Acid (mg/dL)
1.  Increase ≥50% and value > ULN
Y
Y
Serum Sodium (mEq/L)
1.  Decrease ≥10 mEq/L and value < LLN
Y
Y
2.  Increase ≥10 mEq/L and value > ULN
Y
Y
3.  Value > 155 mEq/L
Y
Y
Serum Potassium (mEq/L)
1.  Decrease ≥1.0 mEq/L and value < LLN
Y
Y
2.  Increase ≥1.0  mEq/L and value > ULN
Y
Y
3. Value >5.4 mEq/L and value increased by 
15%.above baseline
Y
Y
4. Value ≥ 6.0 mEq/L
Y
Y
Serum Calcium (mg/dL)
1.  Increase ≥1.0 mg/dL and value > ULN
2.  Decrease ≥1.0 mg/dL and value < LLN
Y
Y
Y
Y
 
 
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ECG
Serum Magnesium
1.  Increase ≥1.0 mg/dL and value > ULN
2.  Decrease ≥1.0 mg/dL and value < LLN
Y
Y
Y
Y
Serum Phosphate
1.  Increase ≥0.5 mg/dL and value > ULN
2.  Decrease ≥0.5 mg/dL and value < LLN
Y
Y
Y
Y
† Increases and decreases are relative to baseline.
‡ LLN = Lower limit of normal.
§ ULN = Upper limit of normal.
“At Least One Value” will include results meeting the PDLC criterion at any time during the 
Treatment Period (defined as the period from randomization up to 5 days after the final dose of 
study medication).  “Last On-treatment Value” will include only the last available result during 
the Treatment Period.  A listing of all post Treatment Period values that meet PDLC criteria will 
also be provided.
 
 
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Product:  MK-0431 
122
Protocol/Amendment No.: 838-02 
MK-0431-838-02 Final Protocol
15-Mar-2016
Confidential
13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
04D0QD


 
 
04KLZB
PPD
PPD