Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess Cardiovascular Outcomes Following Treatment With Ertugliflozin (MK-8835/PF-04971729) in Subjects With Type 2 Diabetes Mellitus and Established Vascular Disease, The VERTIS CV Study
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT01986881 
Document Date: 
11-Mar-2016
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,
PARALLEL-GROUP STUDY TO ASSESS CARDIOVASCULAR 
OUTCOMES FOLLOWING TREATMENT WITH ERTUGLIFLOZIN 
(MK-8835/PF-04971729) IN SUBJECTS WITH TYPE 2 DIABETES 
MELLITUS AND ESTABLISHED VASCULAR DISEASE, THE VERTIS CV 
STUDY

Ertugliflozin (MK-8835/PF-04971729)
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CLINICAL PROTOCOL
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO ASSESS CARDIOVASCULAR OUTCOMES 
FOLLOWING TREATMENT WITH ERTUGLIFLOZIN (MK-8835/PF-04971729) IN 
SUBJECTS WITH TYPE 2 DIABETES MELLITUS AND ESTABLISHED 
VASCULAR DISEASE, THE VERTIS CV STUDY
VERTIS:  eValuation of ERTugliflozin effIcacy and Safety
Compound:
MK-8835/PF-04971729
Compound Name:
Ertugliflozin
United States (US) Investigational New 
Drug (IND) Number:
106,447
European Clinical Trial Database 
(EudraCT) Number:
2013-002518-11
Protocol Number:
MK-8835-004-01 (Merck protocol number)
B1521021(Pfizer protocol number)
Phase:
3
Ertugliflozin (MK-8835/PF-04971729) is being co-developed by Merck and Pfizer.  Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA is 
the regulatory Sponsor of this study. 
This document contains confidential information belonging to Pfizer and Merck.  Except as otherwise agreed to 
in writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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Document History
Document
Version Date
Summary of Changes
Amendment 1
11 March 
2016
Added a superiority analysis on the newly-added 
secondary endpoints of cardiovascular death or 
hospitalization for heart failure (composite) and 
cardiovascular death (individual component). 
Changed the non-inferiority analysis plan:  Stage 2 will 
be only based on the results of the current study and 
will not be a meta-analysis across Phase 2 and Phase 3.
Updated event rate assumption for Major Adverse 
Cardiovascular Events (MACE) and timing of interim 
analyses.
Changed number of events required at each stage of the 
analysis and consequently, the amount of alpha to be 
spent, the power to demonstrate non-inferiority and the 
time to reach the approximate number of events 
required at each stage. 
Updated primary analysis plan for non-inferiority to 
censor Stage 2 events occurring more than 365 days 
after last dose of investigational product (IP).
Increased the overall sample size to approximately 
8000 subjects. Updated assumptions to indicate that 
the rate of withdrawal from the study will be 5% per 
year. 
Order of objectives and endpoints has been changed: 
all the study specific end points are listed first followed 
by the primary objective and endpoint for the 
meta-analysis at Stage 1 for which more details are 
now provided in the Statistical Analysis Plan.
Objectives and Endpoints are now called Primary and 
Secondary, there is no distinction between 
cardiovascular and non-cardiovascular.
Changed the secondary objective of time to the first 
occurrence of MACE to time to the first occurrence of 
MACE plus.
Changed the secondary endpoint of:  all MACE plus 
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events (not censored at time of first event) to:  all 
MACE events (not censored at time of first event).
Added secondary end point of:  Change in insulin dose 
from Baseline at Week 18, Week 52 and annually 
thereafter to the overall study and to the insulin with or 
without metformin sub-study (at Week 18 only for the 
sub-study).
Added clarification that secondary endpoint of:  Time 
to the first occurrence of a subject receiving glycemic 
rescue therapy, will only be measured during the first 
18 weeks. 
Added clarification that the analysis of change in 
albuminuria from baseline is stratified by albuminuria 
category at baseline.
Added a glycemic sub-study in subjects receiving 
metformin plus sulfonylurea (SU) at the doses specified 
and clarification regarding inclusion into this sub-study 
which will be done programmatically at the time of the 
analyses for all the sub-studies without changing the 
randomization scheme (only applicable to subjects 
enrolled prior to amendment).
Added inclusion criterion regarding adequate 
documentation of the objective evidence that the 
subject has established vascular disease. Previously 
this wording had only appeared in Section 6.2.1 of the 
protocol.
Modified the exclusion criterion to remove Class III 
heart failure as exclusionary.
Modified laboratory exclusion criteria for screening 
hemoglobin level as well as clarified repeat screening 
laboratory test language for certain laboratory 
parameters. 
Added language to clarify that the final population for 
the insulin with or without metformin and for the SU 
monotherapy sub-studies will be determined via 
programming at the time of the sub-study analyses.
Changed the analysis plan for the SU monotherapy 
glycemic add-on sub-study to conduct hypothesis 
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testing regardless of the number of enrolled subjects in 
this sub-study. 
Included new Section on discontinuation of 
investigational product, withdrawal of consent, and 
avoiding lost to follow-up (Sections 6.6, 6.7.1 and 
6.7.2, respectively) to clarify importance of follow-up 
of subjects after discontinuation of investigational 
product and processes to minimize subjects who are 
lost to follow-up to minimize missing data.
Added clarifying wording in Section 7.8 regarding the 
order of the measurement of postural blood pressure.
Added wording in Section 7.9 to clarify the unblinding 
of fasting plasma glucose (FPG) values of 70 mg/dL or 
less during the first 18 weeks of the study.
Clarified in Section 7.9 that estimated glomerular 
filtration rate (eGFR) is calculated with the Chemistry 
analysis.
Clarified in Section 7.9, footnote, and in Section 7.9.1 
that:  If low density lipoprotein (LDL-C) is measured 
directly on a Day 1 sample, the central laboratory will 
perform direct LDL-C measurements on subsequent 
samples for that subject. 
Corrected in Sections 8.1 and 8.4 the instructions for 
reporting adverse events (AEs) during the screening 
period and for the timing of serious adverse events 
(SAEs) reporting to match Merck´s safety reporting 
requirements.
Added clarification in Section 8.5 that:  All adverse 
events will be reported to regulatory authorities,
institutional review boards/ethics committees
(IRBs/IECs) and investigators in accordance with 
applicable local laws and regulations.
Updated Section 8.7 to follow Sponsor’s instructions 
for the management of subjects with elevated 
ALT/AST.
Updated Section 1.2.2 to match current Investigator 
Brochure (IB) document and deleted wording that is a 
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repeat from the wording in the IB.
Changed the name of the insulin metformin 
sub-study to insulin with or without metformin 
sub-study to increase clarity about entry requirements.
Removed the requirement that for a subject to meet the
criterion of either progression or regression of 
albuminuria, the albuminuria threshold had to be met at 
two consecutive visits.
Clarified in Section 9.7 that only the results of the 
meta-analysis (Stage 1) will be submitted to regulatory 
authorities while the main study is ongoing.
Added a superiority analysis for the composite 
endpoint of renal death, renal dialysis/transplant or
2x increase in baseline serum creatinine.
Original 
Protocol
25 August 
2013
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), or other bodies.
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PROTOCOL SUMMARY
Background and Rationale:
Ertugliflozin (MK-8835/PF-04971729) is a potent inhibitor of Sodium-Glucose 
co-Transporter 2 (SGLT2) and possesses a high selectivity over glucose transport via 
Sodium-Glucose co-Transporter 1 (SGLT) and several other glucose transporters 
(GLUT1-4).  Ertugliflozin inhibits renal glucose reabsorption resulting in urinary glucose 
excretion and thereby reducing plasma glucose and glycated hemoglobin (HbA1c) in subjects 
with type 2 diabetes mellitus (T2DM). Ertugliflozin is being developed as an adjunct to diet 
and exercise to improve glycemic control in patients with T2DM.
Individuals with T2DM are 2 to 4 times more likely to die from cardiovascular disease than 
adults without diabetes1 and coronary heart disease and stroke account for approximately 
two-thirds of deaths in people with diabetes.2  Given the substantial cardiovascular morbidity 
and mortality from T2DM, an understanding of the cardiac safety of a new agent for T2DM
is of paramount importance.  The United States Food and Drug Administration (FDA) has 
revised its approval process and guidelines for all new anti-diabetic therapies requiring that 
acceptable levels of cardiovascular safety are demonstrated at the time of the New Drug 
Application (NDA) filing as well as post-approval.3 The European Medicines Agency 
(EMA) has also updated its guidelines requiring that sponsors of novel diabetes agents 
demonstrate that the new compound does not increase the risk of macrovascular 
complications at the time of the Marketing Authorization Application (MAA).4 Both the 
FDA and EMA guidance documents recommend that an assessment of cardiovascular safety 
needs to include subjects with T2DM and elevated cardiovascular risk.
This trial is primarily intended to assess the cardiovascular safety of ertugliflozin and it has 
two main objectives.  First, to support initial regulatory submission, this trial will contribute 
to a program-wide meta-analysis of cardiovascular endpoints occurring in the ertugliflozin 
Phase 2 and Phase 3 development program.  This meta-analysis is intended to support the 
initial regulatory submission of ertugliflozin and will assess the composite endpoint of 
cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for 
unstable angina (MACE plus).  This trial will continue in the peri-approval and anticipated 
post-approval period with the objective of assessing the cardiovascular safety of ertugliflozin
on the composite endpoint of cardiovascular death, non-fatal myocardial infarction or
non-fatal stroke (MACE).  The objective of MACE will be based solely on this study and 
will not use a meta-analysis approach.  The primary and secondary objectives for the 
assessment of the cardiovascular safety of ertugliflozin are listed below.
Additionally, this trial includes a glycemic sub-study in subjects receiving background 
insulin with or without metformin, another sub-study in subjects receiving background
sulfonylurea (SU) monotherapy and a sub-study in subjects receiving background metformin 
with SU.  Details on the objectives and endpoints for these sub-studies are described in the 
body of the protocol in Sections 2.2, 2.3, 2.4, 2.7, 2.8, 2.9.
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Primary Objective and Hypothesis:

Primary Objective: To demonstrate the non-inferiority of ertugliflozin compared 
with placebo on the time to first occurrence of the composite endpoint of MACE:  
cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. 

Hypothesis: The time to first occurrence of the composite endpoint of MACE in 
subjects treated with ertugliflozin is non-inferior compared to that in subjects treated 
with placebo.
Secondary Objectives and Hypotheses

Objective: To demonstrate the superiority of ertugliflozin compared with placebo on 
the time to first occurrence of the composite endpoint of cardiovascular death or 
hospitalization for heart failure.

Hypothesis: The time to first occurrence of the composite endpoint of cardiovascular 
death or hospitalization for heart failure in subjects treated with ertugliflozin is 
superior compared to that in subjects treated with placebo.

Objective: To demonstrate the superiority of ertugliflozin compared with placebo on 
the time to cardiovascular death.

Hypothesis: The time to cardiovascular death in subjects treated with ertugliflozin is 
superior compared to that in subjects treated with placebo.

Objective:  To demonstrate the superiority of ertugliflozin compared with placebo on 
the time to first occurrence of the composite endpoint of renal death, renal 
dialysis/transplant, or 2x increase in baseline serum creatinine.

Hypothesis:  The time to first occurrence of the composite endpoint of renal death, 
renal dialysis/transplant, or 2x increase in baseline serum creatinine in subjects 
treated with ertugliflozin is superior compared to that in subjects treated with placebo.

Objective: To assess the effect of ertugliflozin as compared with placebo on the time 
to first occurrence of:

MACE plus;

Fatal or non-fatal myocardial infarction;

Fatal or non-fatal stroke;

Hospitalization for heart failure;

Individual components of MACE (cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke). 
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
Objective: To assess the effect of ertugliflozin as compared with placebo on the time 
to:

All-cause mortality;

All MACE events (not censored at time of first event);

All cardiovascular death or hospitalizations for heart failure (not censored at time 
of first event. 
Objective and Hypothesis Across the Ertugliflozin Phase 2 and Phase 3 Development 
Program:

Objective: To demonstrate the non-inferiority of ertugliflozin as compared with a 
non-ertugliflozin comparator group on the time to first occurrence of any of the 
components of the composite endpoint of MACE plus. 

Hypothesis: The time to first occurrence of any of the components of the composite 
endpoint of MACE plus in subjects treated with ertugliflozin is non-inferior 
compared to that in subjects not treated with ertugliflozin.
Further details regarding the meta-analysis across the Ertugliflozin Phase 2 and Phase 3 
Development Program are provided in the Statistical Analysis Plan (SAP) document.
Endpoints
Primary Endpoint

The primary cardiovascular endpoint is time to first occurrence of MACE.
Secondary Endpoints

Time to first occurrence of: 

Cardiovascular death or hospitalization for heart failure;

Cardiovascular death;

MACE plus;

Fatal or non-fatal myocardial infarction;

Fatal or non-fatal stroke;

Hospitalization for heart failure;
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
Individual components of MACE (cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke). 

All-cause mortality.

All MACE events (ie, not censored at the time of the first event).

All cardiovascular death or hospitalizations for heart failure (ie, not censored at the 
time of the first event).

Time to first occurrence of the composite of renal death, renal dialysis/transplant, or 
2x increase in baseline serum creatinine.
Endpoint Across the Ertugliflozin Phase 2 and Phase 3 Development Program:

Time to first occurrence of MACE plus. 
Other secondary objectives and endpoints along with primary and secondary objectives, 
hypotheses and endpoints for the insulin with or without metformin, SU monotherapy and 
metformin + SU glycemic sub-studies are described in the body of the protocol in
Sections 2.1, 2.2, 2.3, 2.4, 2.6, 2.7, 2.8 and 2.9.
Study Population:
Men and women, 40 years of age with T2DM (HbA1c 7.0-10.5% [53-91 mmol/mol]) 
diagnosed in accordance with American Diabetes Association (ADA)5 guidelines and have 
established vascular disease involving the coronary, cerebral and/or peripheral vascular 
systems.
Study Design:
This trial is a multicenter, randomized, double-blind, placebo-controlled, event-driven trial
that includes a main cardiovascular study and three 18 week add-on glycemic sub-studies in 
subjects receiving specific background anti-hyperglycemic treatments. All subjects enrolled 
under the original protocol prior to Amendment 1 will be randomized into the overall study,
and subjects meeting additional inclusion criteria will also be included in the specific 
sub-studies as described below and in Sections 4.1.1, 4.1.2, and 4.2.1.  Subjects enrolled after 
the approval of Amendment 1 will only be randomized into the overall study.  For these 
subjects, the protocol sub-study details described below and in Sections 4.1.1, 4.1.2, and 
4.2.1 are not applicable.
Approximately 8000 total subjects will be enrolled and the randomization ratio will be 1:1:1 
to 5 mg ertugliflozin once daily, 15 mg ertugliflozin once daily or placebo. 
In order to contribute to the program-wide assessment of the cardiovascular safety of 
ertugliflozin, the cardiovascular endpoints from this trial will be combined with the 
cardiovascular endpoints from the rest of the Phase 2 and 3 development program to enable a 
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meta-analysis, provided in the initial registration dossier, to support the cardiovascular safety 
of ertugliflozin.  The endpoint for the meta-analysis will be MACE plus.  The goal of this 
meta-analysis will be to rule out a hazard ratio of 1.8 (an 80% increase in the risk of MACE 
plus relative to a non-ertugliflozin comparator group). 
This trial will continue in the post-approval period to assess the primary endpoint of time to 
the first occurrence of the composite endpoint of MACE as well as other secondary 
endpoints.  The study’s primary hypothesis of non-inferiority of ertugliflozin to placebo will 
be evaluated by excluding a hazard ratio of 1.3 (a 30% increase in the risk of MACE relative 
to placebo).  If non-inferiority at the 1.3 margin is established for the primary MACE 
endpoint, then tests of superiority on the secondary endpoints of cardiovascular death or 
hospitalization for heart failure (composite) and cardiovascular death (individual component) 
will also be performed.  As stated before, this trial is event-driven, with the number of events 
required to occur prior to assessment of the study’s primary endpoint discussed in 
Sections 3.1 and 9.1.
Beyond the effects on cardiovascular endpoints, the trial is also designed to assess the safety 
and tolerability of ertugliflozin and its effects on measures of glycemic control, blood 
pressure, body weight, renal function and albuminuria.
For subjects enrolled under the original protocol, at the time of randomization, subjects will 
be stratified into the main cardiovascular study, the insulin (with or with metformin) 
sub-study or the SU monotherapy sub-study, according to their background 
anti-hyperglycemic treatment as follows.  Subjects receiving background insulin (with or 
without metformin) at doses specified in the protocol are included into the insulin (with or 
without metformin) add-on glycemic sub study; subjects receiving background SU 
monotherapy (at doses specified in the protocol) are included into the SU monotherapy 
add-on glycemic sub-study.  Subjects receiving background metformin with SU at doses 
specified in the protocol are included in the metformin plus SU sub-study.  Unlike the other 
two sub-studies, inclusion in the metformin with SU sub-study will not be determined at the 
time of randomization.  Instead, all subjects randomized into the main cardiovascular study 
who meet the additional eligibility requirements will be considered enrolled in this sub-study.  
Since all the subjects participating in the three sub-studies are enrolled in the main 
cardiovascular study, visit schedules and protocol-required tests and procedures are the same 
for all subjects irrespective of whether or not a subject also participates in a sub study.  The 
glycemic sub-studies will run during the initial 18 weeks of the study.  Following the 
collection of efficacy and safety end points at Week 18 (V5), subjects in the glycemic 
sub-studies will continue participating in the main cardiovascular study. 
Study Treatments:
Subjects will be randomized in a 1:1:1 ratio to receive ertugliflozin 5 mg, ertugliflozin,
15 mg ertugliflozin or matching placebo once daily added to their background therapy. 
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Statistical Methods:
Sample Size
The cardiovascular safety of ertugliflozin will be assessed in two stages.  Stage 1 will consist 
of a meta-analysis of MACE plus events across the Phase 2 and Phase 3 development 
program with the majority of events expected to come from this trial.  Stage 2 will consist of 
an analysis of MACE and secondary endpoints [eg, Cardiovascular (CV) death or 
hospitalization for heart failure (composite), CV death (individual component), and renal 
composite] in this trial.  The two doses of ertugliflozin (5 and 15 mg) will be pooled for the 
purpose of all these analyses. 
The primary objective for the Stage 1 across-program meta-analysis will be addressed by 
testing the hypotheses H0: Hazard Ratio (HR)1.8 versus H1:HR<1.8 for the MACE plus 
endpoint; the primary Stage 2 analysis (assessed within this study) will be addressed by 
testing the hypotheses H0:HR1.3 versus H1:HR<1.3 for the MACE endpoint.  For these 
analyses, the HR represents the risk of ertugliflozin relative to a non-ertugliflozin comparator 
group at Stage 1 and relative to placebo at Stage 2 as measured by the hazard ratio. 
Stage 1 of the trial uses a group sequential design with up to two analyses: an interim 
analysis and a final analysis.  The Stage 1 interim analysis will take place at the later of 1) the 
time at which at least 130 adjudicated MACE plus events have accrued throughout the 
Phase 2 and Phase 3 development program or 2) the approximate time at which all necessary 
data are available to support the filing of ertugliflozin. This analysis will assess the hazard 
ratio for the MACE plus endpoint with respect to the 1.8 non inferiority margin.  If the first 
analysis is conducted with less than 173 MACE plus events, then a second analysis (the final 
analysis for Stage 1) will take place, if necessary (ie, if the non-inferiority margin of 1.8 is 
not met in the first analysis), at the time at which at least 173 MACE plus events have 
accrued, and the appropriate alpha spending will be determined from an O’Brien-Fleming 
type spending function.  If the first analysis is conducted with 173 or more MACE plus 
events, then that will constitute the only analysis for Stage 1, and the full alpha of 0.025 
(1-sided) will be utilized.
For these Stage 1 analyses, using an O’Brien-Fleming type alpha spending function, and 
analyses at 130 and 173 adjudicated MACE plus events, the meta-analysis will have 
approximately 95% power to demonstrate non-inferiority of ertugliflozin to a 
non-ertugliflozin comparator group when there is truly no difference between treatments 
(HR=1.0) using the non-inferiority margin of 1.8 and testing at the overall one-sided alpha 
level of 0.025.
Stage 2 of the trial uses a group sequential design with up to two analyses: an interim 
analysis and a final analysis.  The Stage 2 interim analysis and the final analysis are planned 
to occur when approximately 714 and 939 adjudicated MACE events have accrued in this 
study.  These analyses will assess the hazard ratio for the MACE endpoint with respect to the 
1.3 non-inferiority margin.  If non-inferiority is established for the primary MACE endpoint, 
then tests of superiority on the secondary endpoints of CV death or hospitalization for heart 
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failure (composite), CV death (individual component), and the renal composite will also be 
performed in a sequential manner.  If any of the first three tests in this four step testing 
sequence are unsuccessful at the interim analysis, the study may be continued to the final 
analysis (depending on the result of futility assessment).
For the primary Stage 2 analyses, using an O’Brien-Fleming type alpha spending function 
and analyses at approximately 714 and 939 adjudicated MACE events, the study will have 
approximately 96% power to demonstrate non-inferiority of ertugliflozin to placebo when 
there is truly no difference between treatments (HR=1.0) using the non-inferiority margin of 
1.3 and testing at the overall one-sided alpha level of 0.025.
With two enrollment periods of 19 months each and assuming an event rate of 3.5% per 
annum for MACE, a total of approximately 8000 subjects (about 4000 per enrollment cohort) 
randomized in a 1:1:1 ratio to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo will be 
sufficient to accrue approximately 714 MACE events within approximately 5.0 years and 
approximately 939 MACE events within approximately 6.1 years from the start of this study.  
These calculations assume that subjects will withdraw from the study at a rate of 5% per 
annum. 
Power for Secondary Hypotheses
For the Stage 2 analyses of secondary endpoints, using an O’Brien-Fleming alpha spending 
approach and assuming accrual of at least 442 and 582 composite events of cardiovascular
death or hospitalization for heart failure at the interim and final analysis respectively, the 
study will have approximately 90% power to demonstrate superiority of ertugliflozin to 
placebo on the composite endpoint of cardiovascular death or hospitalization for heart failure 
when the true HR=0.75.  Moreover, assuming accrual of at least 287 and 377 cardiovascular
death events at the interim and final analysis respectively, the study will have approximately 
83% power to demonstrate superiority of ertugliflozin to placebo on cardiovascular death 
when the true HR=0.725.  With accrual of at least 144 and 190 renal composite events at the 
interim and final analysis respectively, the study will have approximately 79% power to 
demonstrate superiority of ertugliflozin to placebo on the renal composite endpoint when the 
true HR=0.65.
Cardiovascular Endpoints Analysis:
The two doses of ertugliflozin will be pooled for the analysis of all cardiovascular endpoints.  
The analyses described below will be performed at each interim analysis and at the end of the 
trial.
The Stage 1 meta-analysis population will include all randomized subjects who have taken at 
least one dose of investigational product across the Phase 2 and 3 development program.  The 
Stage 2 non-inferiority analysis population will include all randomized subjects who have 
taken at least one dose of investigational product in this study.  For both stages, subjects will 
be analyzed in the group to which they were assigned by the Interactive Voice Response 
System (IVRS), regardless of the actual treatment received, and only events confirmed by the 
Endpoint Adjudication Committee will be included in the analysis. For Stage 1, all 
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confirmed MACE plus events will be included in the primary analysis. For Stage 2, 
confirmed MACE events occurring between randomization and 365 days after the last dose 
of study treatment will be included in the primary non-inferiority analysis.
The MACE plus and MACE endpoints will be analyzed using a stratified Cox proportional 
hazards model including treatment group as a covariate.  For the Stage 1 meta-analyses, the 
Cox model will include “Study” as a stratification factor with the following three levels: 
cardiovascular study, placebo-controlled non-cardiovascular studies, and active-controlled 
non-cardiovascular studies.  For the Stage 2 analyses, the Cox model will include “Cohort” 
as the stratification factor with the following levels: Cohort 1 (subjects randomized between 
December 2013 and July 2015) and Cohort 2 (subjects randomized in 2016 and beyond).  A 
test of non-inferiority at the one-sided 0.025 significance level will be performed based on 
the Cox model.  The upper bound of the alpha-adjusted two-sided confidence interval (CI) 
for the hazard ratio (HR) (ertugliflozin to a non ertugliflozin comparator group or placebo) 
will be calculated using an O’Brien-Fleming alpha spending function and compared with the 
appropriate non-inferiority margin (1.8 or 1.3). 
If non-inferiority at the 1.3 margin is established for the primary MACE endpoint based 
solely on this study, then tests of superiority on the secondary endpoints of cardiovascular
death or hospitalization for heart failure (composite), cardiovascular death (individual 
component), and the renal composite will also be performed.  The population for superiority 
testing will include all randomized subjects and all confirmed events, including those 
occurring more than 365 days following discontinuation of investigational product.  
Superiority tests will be implemented by comparing the upper bound of the alpha-adjusted 
two-sided CI to 1.0.
In order to control the Type I error rate across multiple hypotheses in Stage 2, a four-step 
hierarchical testing sequence for the pooled ertugliflozin group versus the placebo group will 
be utilized as follows:
1. Non-inferiority for MACE;
2. Superiority for cardiovascular death or hospitalization for heart failure (composite);
3. Superiority for cardiovascular death (individual component);
4. Superiority for renal death, renal dialysis/transplant, or 2x increase in baseline 
serum creatinine.
Kaplan-Meier curves for the distribution of time to the primary and secondary endpoints will 
also be provided for each of the three treatment groups. 
Subjects without events will be censored at the earliest of the study cut-off date, last contact 
date, or end of the applicable analysis ascertainment window (eg, 365 days after the last dose 
of investigational product for primary Stage 2 non-inferiority analyses).
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Protocol summary information, when provided, is consistent with and does not contain new 
information that is not found in the body of the protocol.
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES and 
ASSESSMENTS for detailed information on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the subject. 
Protocol Activities
Visits During Year 1
Visits Following Year 1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Weeks (Wk) or Months (M) 
Since Randomizationa
Screening
Day 1b
Wk 6
Wk 12
Wk 18
Wk 26
Wk 39
Wk 52
M 16
M20
M24
Recommended Visit Window
7 days 7 days 7 days 7 days
14 days
14 days
1 month
1 month
1 month
Informed Consent
X
Informed Consent for Future 
Biomedical Research 
X
Contact IVRS System
X
X
X
X
X
X
X
X
X
X
X
Assess Eligibility
X
X
Randomization
X
Provide Subject with Study 
Contact Card
X
Demography, Height in 
Duplicate & Medical History 
including Smoking
X
Complete Physical Examination
X
Brief Physical Examinationc
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
X
Sitting Blood Pressure and Pulse 
Rated
X
X
X
X
X
X
X
X
X
X
X
Postural (Orthostatic)Blood 
Pressure and Pulse Ratee
X
X
X
12-Lead ECGf
X
X
X
X
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Protocol Activities
Visits During Year 1
Visits Following Year 1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Weeks (Wk) or Months (M) 
Since Randomizationa
Screening
Day 1b
Wk 6
Wk 12
Wk 18
Wk 26
Wk 39
Wk 52
M 16
M20
M24
Recommended Visit Window
7 days 7 days 7 days 7 days
14 days
14 days
1 month
1 month
1 month
Laboratory
Chemistry Group
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Urinalysisg
X
X
X
X
X
X
Pregnancy Test (women of 
childbearing potential only)h
X
X
X
X
X
X
X
X
X
X
X
Site Fingerstick HbA1ci
X
Fasting Fingerstick Glucose
X
Fasting Triglycerides/TSH
X
HbA1c & FPG
X
X
X
X
X
X
X
X
X
X
X
Lipid Panelj
X
X
X
X
Urinary Albumin/Creatinine 
ratiok
X
X
X
X
Whole blood (DNA) for Future 
Biomedical Researchl
X
Plasma for Future Biomedical 
Researchl
X
X
X
Serum for Future Biomedical 
Researchl
X
X
X
Drug
Dispense Investigational Product
X
X
X
X
X
X
X
X
X
X
Assess Compliance with 
Investigational Product
X
X
X
X
X
X
X
X
X
Prior/Concomitant Medications 
Assessment
X
X
X
X
X
X
X
X
X
X
X
Subject Education/Monitoring
Diet/Exercise Counseling 
(V2)/Monitoring (other visits)
X
X
X
X
X
X
X
X
X
X
Distribute Sponsor-provided 
Glucose meter (V2) and Glucose 
meter Supplies
X
X
X
X
X
X
X
X
X
X
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Protocol Activities
Visits During Year 1
Visits Following Year 1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Weeks (Wk) or Months (M) 
Since Randomizationa
Screening
Day 1b
Wk 6
Wk 12
Wk 18
Wk 26
Wk 39
Wk 52
M 16
M20
M24
Recommended Visit Window
7 days 7 days 7 days 7 days
14 days
14 days
1 month
1 month
1 month
Dispense Hypoglycemia 
Assessment Log and Blood 
Glucose-Self Monitoring logs 
and educate on hypoglycemia 
symptoms and management and 
on symptoms of hyperglycemia
X
Dispense/Review self 
monitoring blood glucose and 
Hypoglycemia Assessment Log
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringm
X
X
X
X
X
X
X
X
X
X
Potential Cardiovascular Event 
Assessmentn
X
X
X
X
X
X
X
X
X
X
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Protocol Activities
Visits Following Year 1 
V12
V13
V14
V15
V16
V17
V18
V19
V20
V21
V22
Months (M) Since Randomizationa
M28
M32
M36
M40
M44
M48
M52
M56
M60o
ETp/
EOSq
2 Week Phone 
Follow Ups
Glycemic 
Rescue Visitt
Recommended Visit Windows
1
month
1
month
1
month
1
month
1
month
1
month
1
month
1
month
1
month
3 
days
Contact IVRS System
X
X
X
X
X
X
X
X
X
X
Brief Physical Examinationc
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
X
Sitting Blood Pressure and Pulse Rated
X
X
X
X
X
X
X
X
X
X
X
Postural (Orthostatic) Blood Pressure and 
Pulse Ratee
X
12-Lead ECGf
X
X
X
X
Laboratory
Chemistry Group
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
Urinalysisg
X
X
X
X
X
Pregnancy Test (women of childbearing 
potential only)h
X
X
X
X
X
X
X
X
X
X
X
HbA1c & FPG
X
X
X
X
X
X
X
X
X
X
Xu
Lipid Panelj
X
X
X
X
X
Urinary Albumin/Creatinine ratiok
X
X
X
X
Plasma for Future Biomedical Researchl
X
X
Serum for Future Biomedical Researchl
X
X
Drug
Dispense Investigational Product
X
X
X
X
X
X
X
X
X
Assess Compliance with Investigational 
Product
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications Assessment
X
X
X
X
X
X
X
X
X
X
X
Subject Education/Monitoring
Diet/Exercise Monitoring
X
X
X
X
X
X
X
X
X
X
X
Distribute sponsor-provided glucose 
meter supplies. 
X
X
X
X
X
X
X
X
X
Review/Dispense Self- Monitoring Blood 
Glucose and Hypoglycemia Assessment 
Log
X
X
X
X
X
X
X
X
X
Xr
X
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Protocol Activities
Visits Following Year 1 
V12
V13
V14
V15
V16
V17
V18
V19
V20
V21
V22
Months (M) Since Randomizationa
M28
M32
M36
M40
M44
M48
M52
M56
M60o
ETp/
EOSq
2 Week Phone 
Follow Ups
Glycemic 
Rescue Visitt
Recommended Visit Windows
1
month
1
month
1
month
1
month
1
month
1
month
1
month
1
month
1
month
3 
days
Adverse Event Monitoringp
X
X
X
X
X
X
X
X
X
X
X
X
Potential Cardiovascular Event 
Assessmentq
X
X
X
X
X
X
X
X
X
X
X
X
a.
Centers should attempt to schedule each subject’s visits at approximately the same time of day for that subject.  The same visit schedule will be followed by all subjects 
enrolled in the main cardiovascular study and those enrolled in the sub-studies.  Subjects should be fasting for at least 10 hours prior to visits (except water), and must be 
instructed to arrive without having taken the dose of investigational product or any other AHA (if applicable).  Other medications may be administered prior to the clinic visit 
if they can be administered without food.  On clinic visit days, subjects may eat to break their fast after the collection of weight, completion of laboratory procedures and 
blood pressure and pulse rate.  Other AHA therapy should be administered after the subject has consumed a meal, if applicable.
b.
Administer first witnessed investigational product in clinic.  All Day 1 visit (V2) procedures to be completed prior to dosing unless otherwise specified.
c.
Brief physical examination to include assessment of heart, lungs, abdomen, extremities and skin.  Other body systems may be evaluated per the judgment of the investigator 
and as needed to evaluate adverse events as per Section 7.3.
d.
Sitting Blood Pressure and Pulse Rate:  Sitting, triplicate blood pressure and pulse rate measurement to be collected as per Section 7.7.
e.
Duplicate measurements of supine and standing blood pressure and pulse rate as per Section 7.8. 
f.
ECG is reviewed at the investigative site for safety monitoring and submitted for central reading as per Section 7.5.  If a subject experiences a non-fatal myocardial infarction 
after randomization, a new baseline ECG should be performed between 6 and 12 weeks following the myocardial infarction, at an unscheduled visit if necessary.
g.
Routinely collected urinalysis samples will be sent to the central laboratory for dipstick analysis and microscopy if dipstick is positive for blood, nitrites, leukocytes and/or 
protein.  Urinalysis should not be collected for a female subject who is menstruating. 
h.
Urine pregnancy tests will be performed for women of childbearing potential at all time points and if positive may be confirmed with a serum pregnancy test.  Pregnancy tests 
may also be repeated at any time if requested of IRB/IECs or if required by local regulations as per Section 7.1.6.
i.
Site fingerstick HbA1c is not mandatory, but may be used at the discretion of the investigator for screening subjects.  However, a fingerstick HbA1c cannot substitute for a 
central laboratory-measured HbA1c to determine if a subject meets entry criteria.
j.
Includes total cholesterol, HDL-C, LDL-C, non-HDL-C and triglycerides at all time points.  If LDL-C is measured directly on a Day 1 sample, the central laboratory will 
perform direct LDL-C measurements on subsequent samples for that subject.
k.
Samples should not be obtained if the subject is menstruating, has vigorously exercised within 24 hours or had fever or an active infection within 2 days of the visit.
l.
The Future Biomedical Research (FBR) informed consent must be obtained before FBR samples are drawn.  The FBR sample for DNA analysis should be obtained pre-dose, 
at the Day 1 visit (V2) as the last sample drawn, on subjects who qualify for randomization, but 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 Day 1 (pre-dose), Week 18, Week 52 or Early Termination Visit, End of Study Visit and Glycemic 
Rescue Visit (if applicable).  The plasma and serum samples for FBR should be collected at all time points, even if the pre-dose or other time point was not collected.
m.
Assess AEs, SAEs and potential clinical events for adjudication as per Section 8.4.1 and Section 7.1.
n.
Subjects will be instructed to contact the site if they are admitted to the hospital for any reason, or if they experience a cardiovascular event.
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o.
If the trial is deemed not complete by Visit 20 (Month 60), visits will continue on an every 4 month schedule and the list of procedures to be performed are the same as the 
visits for Months 52, 56 and 60 respectively until trial completion (EOS).  Unscheduled visits are allowed at any time as needed for assessment of adverse events, repeat 
laboratory testing, etc. 
p.
ET = Early termination, subjects who discontinue taking investigational product prematurely but remain in the study should complete procedures for the ET visit and have a 
2 week (14 days 3 days) follow-up phone call from their last dose of investigational product.  They will also be contacted via telephone by the investigator/designated 
representative according to the same schedule as if the subject were still taking investigational product through the end of the trial (ie, according to the Schedule of Activities
and Section 6, study assessments).  Subjects will be expected to attend annual visits in person.  See Section 6.3.3 for additional details. 
q.
EOS = end of study.  All EOS procedures should be performed for all randomized subjects when the trial is completed.  EOS procedures should be completed whether or not 
the subject is taking investigational product when the trial is terminated. 
r.
Hypoglycemia Assessment and Blood Glucose Self-Monitoring logs will not be dispensed at ET or EOS visits.
s.
Each randomized subject should have a follow-up phone call 14 days 3 days after the last dose of investigational product to assess for SAEs (Section 8.4.1) and collect 
information on clinical events (Section 7.1).
t.
Subjects who require glycemic rescue therapy during the first 18 weeks of the trial, as per Section 5.5.1, must have rescue therapy initiated at either a scheduled or 
unscheduled visit, and not by a telephone call.  Rescue therapy can also be initiated by a non-study physician as described in Section 5.5.1.
u.
HbA1c should not be obtained if Glycemic Rescue Visit or ET occurs within 6 weeks of randomization.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................26
APPENDICES .........................................................................................................................26
1. INTRODUCTION ...............................................................................................................27
1.1. Indication.................................................................................................................27
1.2. Background .............................................................................................................27
1.2.1. Efficacy of Ertugliflozin.............................................................................28
1.2.2. Safety of Ertugliflozin and SGLT2 Inhibitors............................................28
1.3. Rationale for Study..................................................................................................29
1.4. Rationale for Dose Selection of Ertugliflozin.........................................................30
1.5. Rationale for Future Biomedical Research .............................................................31
2. STUDY OBJECTIVES, HYPOTHESES AND ENDPOINTS ...........................................31
2.1. Objectives and Hypotheses .....................................................................................31
2.1.1. Primary Objective and Hypothesis .............................................................31
2.1.2. Secondary Objectives and Hypotheses.......................................................32
2.2. Insulin with or without Metformin Add-on Glycemic Sub-Study Objectives 
and Hypotheses..........................................................................................................34
2.2.1. Primary Objectives and Hypotheses...........................................................34
2.2.2. Secondary Objectives and Hypotheses.......................................................35
2.3. SU Monotherapy Add-on Glycemic Sub-Study Objectives and Hypotheses.........36
2.3.1. Primary Objectives and Hypotheses...........................................................36
2.3.2. Secondary Objectives and Hypotheses.......................................................37
2.4. Metformin with SU Add-on Glycemic Sub-Study Objectives and Hypotheses .....38
2.4.1. Primary Objectives and Hypotheses...........................................................38
2.4.2. Secondary Objectives and Hypotheses.......................................................38
2.5. Objective and Hypothesis Across the Ertugliflozin Phase 2 and Phase 3 
Development Program...............................................................................................40
2.6. Study Endpoints ......................................................................................................40
2.6.1. Primary Endpoint........................................................................................40
2.6.2. Secondary Endpoints ..................................................................................40
2.7. Insulin with or without Metformin Add-on Glycemic Sub-Study Endpoints.........41
2.7.1. Primary Endpoint........................................................................................41
2.7.2. Secondary Endpoints ..................................................................................42
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2.8. SU Monotherapy Add-on Glycemic Sub-Study Endpoints ....................................42
2.8.1. Primary Endpoint........................................................................................42
2.8.2. Secondary Endpoints ..................................................................................42
2.9. Metformin with SU Add-on Glycemic Sub-Study Endpoints ................................42
2.9.1. Primary Endpoint........................................................................................42
2.9.2. Secondary Endpoints ..................................................................................42
2.10. Endpoint Across the Ertugliflozin Phase 2 and Phase 3 Development 
Program .....................................................................................................................42
3. STUDY DESIGN.................................................................................................................43
3.1. Overview of Study Design (Main Cardiovascular Study and add-on 
Glycemic Sub-Studies)..............................................................................................43
3.2. Insulin with or without Metformin Add-on Glycemic Sub-Study..........................45
3.3. SU Monotherapy Add-on Glycemic Sub-Study......................................................46
3.4. Metformin with SU Add-on Glycemic Sub-Study..................................................46
4. SUBJECT SELECTION......................................................................................................47
4.1. Inclusion Criteria.....................................................................................................47
4.1.1. Inclusion Criteria – Specific to Insulin with or without Metformin 
Add-on Glycemic Sub-Study...........................................................................50
4.1.2. Inclusion Criteria – Specific to SU Monotherapy Add-on Glycemic 
Sub-Study.........................................................................................................50
4.2. Exclusion Criteria....................................................................................................50
4.2.1. Exclusion Criteria – Specific to Insulin with or without Metformin 
Add-on Glycemic Sub-Study...........................................................................54
4.3. Randomization Criteria ...........................................................................................54
4.4. Life Style Guidelines...............................................................................................55
4.4.1. Dietary Restrictions ....................................................................................55
4.4.2. Physical Activity.........................................................................................55
4.4.3. Alcohol, Caffeine and Tobacco ..................................................................55
4.4.4. Contraception..............................................................................................56
4.4.4.1. Females – Non-childbearing Potential ......................................56
4.4.4.2. Females of Childbearing Potential ............................................56
4.5. Sponsor Qualified Medical Personnel.....................................................................57
5. STUDY TREATMENTS.....................................................................................................57
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5.1. Allocation to Treatment ..........................................................................................57
5.2. Breaking the Blind ..................................................................................................57
5.3. Drug Supplies..........................................................................................................58
5.3.1. Formulation and Packaging........................................................................58
5.3.2. Administration............................................................................................58
5.3.3. Compliance.................................................................................................59
5.4. Drug Storage and Drug Accountability...................................................................59
5.5. Concomitant Medication(s).....................................................................................59
5.5.1. Treatment for Glycemic Control for Type 2 Diabetes................................60
5.5.2. Treatment for Secondary Prevention of Cardiovascular Disease...............61
6. STUDY PROCEDURES .....................................................................................................61
6.1. Instructions to Subjects ...........................................................................................61
6.1.1. Dispense Hypoglycemia Assessment Log and Instruct on 
Hypoglycemia Symptoms and Management ...................................................62
6.1.2. Diet and Exercise Counseling.....................................................................63
6.2. Screening.................................................................................................................63
6.2.1. Screening (Visit 1)......................................................................................63
6.3. Double-Blind Treatment Period..............................................................................64
6.3.1. Visits During Year 1...................................................................................64
6.3.1.1. Day 1 (Visit 2) – Randomization Visit......................................64
6.3.1.2. Week 6 (Visit 3) ........................................................................66
6.3.1.3. Week 12 (Visit 4) ......................................................................67
6.3.1.4. Week 18 (Visit 5) ......................................................................68
6.3.1.5. Week 26 (Visit 6) ......................................................................69
6.3.1.6. Week 39 (Visit 7) ......................................................................70
6.3.1.7. Week 52 (Visit 8) ......................................................................71
6.3.2. Visits Following Year 1..............................................................................72
6.3.3. End of Study Visit/Early Termination Visit ...............................................74
6.4. Follow-up Phone Call..............................................................................................75
6.5. Glycemic Rescue Visit (if Applicable) ...................................................................75
6.6. Discontinuation of Investigational Product.............................................................76
6.7. Subject Withdrawal.................................................................................................77
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6.7.1. Withdrawal of Consent...............................................................................77
6.7.2. Avoiding Lost to Follow-Up ......................................................................78
6.7.3. Withdrawal From Future Biomedical Research .........................................79
6.7.4. Reasons for Discontinuation from Investigational Product or from 
the Trial............................................................................................................79
7. ASSESSMENTS..................................................................................................................80
7.1. Clinical Event Adjudication....................................................................................81
7.1.1. Cardiovascular Events, Venous Thromboembolic Events, and All 
Deaths ..............................................................................................................81
7.1.2. Fractures .....................................................................................................82
7.1.3. Pancreatitis..................................................................................................82
7.1.4. Liver Injury.................................................................................................82
7.1.5. Acute Renal Failure....................................................................................82
7.1.6. Ketoacidosis................................................................................................83
7.2. Pregnancy Testing...................................................................................................83
7.3. Physical Examinations ............................................................................................83
7.4. Body Weight ...........................................................................................................83
7.5. 12-Lead Electrocardiogram.....................................................................................84
7.6. Review of Self-Monitoring Glucose Logs ..............................................................85
7.6.1. Review of Hypoglycemia Assessment Logs ..............................................85
7.6.2. Management of Hypoglycemia...................................................................85
7.6.3. Definition and Severity Categorization of Hypoglycemic Events .............85
7.6.4. Guidance on Adverse Events Related to Hypoglycemia............................86
7.7. Sitting Blood Pressure and Pulse Rate ....................................................................86
7.8. Postural (Orthostatic) Blood Pressure and Pulse Rate ............................................87
7.9. Laboratory Studies ..................................................................................................87
7.9.1. Lipid Panel..................................................................................................88
7.9.2. Urinary Albumin:Creatinine Ratio .............................................................88
7.10. Assessment of Infections.......................................................................................89
7.10.1. Urinary Tract Infections ...........................................................................89
7.10.2. Genital Fungal Infections .........................................................................89
7.11. Follow-up for Subjects Who Discontinue Due to Decreased Renal Function......89
8. ADVERSE EVENT REPORTING......................................................................................90
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8.1. Assessing and Recording Adverse Events ..............................................................90
8.2. Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor................................................................................................................90
8.3. Reporting of Pregnancy and Lactation to the Sponsor............................................91
8.4. Immediate Reporting of Adverse Events to the Sponsor ........................................91
8.4.1. Serious Adverse Events ..............................................................................91
8.5. Evaluating Adverse Events .....................................................................................92
8.6. Events of Clinical Interest.......................................................................................94
8.7. Management of Subjects with Elevated Liver Enzymes (ALT or AST 
3X ULN) .................................................................................................................95
8.8. Serious Adverse Events Exempt from Expedited Reporting ..................................99
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................100
9.1. Sample Size Determination...................................................................................100
9.1.1. Sample Size for Insulin with or without Metformin Add-on 
Glycemic Sub-Study:.....................................................................................102
9.1.2. Sample Size for SU Monotherapy Add-on Glycemic Sub-Study: ...........102
9.1.3. Sample Size for Metformin with SU Add-on Glycemic Sub-Study.........102
9.2. Primary Cardiovascular Endpoints Analysis.........................................................103
9.3. Secondary Endpoints Analysis..............................................................................103
9.4. Other Secondary Endpoints Analysis....................................................................104
9.5. Analysis of Laboratory and Biomarker Endpoints................................................105
9.5.1. Albuminuria..............................................................................................105
9.6. Safety Analysis......................................................................................................105
9.7. Cardiovascular Endpoints Interim Analyses.........................................................106
9.8. Insulin with or without Metformin, SU Monotherapy Add-on and Metformin 
with SU Glycemic Sub-Study Analyses..................................................................109
9.9. Data Monitoring Committee .................................................................................111
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................112
11. DATA HANDLING AND RECORD KEEPING ...........................................................112
11.1. Case Report Forms/Electronic Data Record .......................................................112
11.2. Record Retention.................................................................................................113
12. ETHICS............................................................................................................................113
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........113
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12.2. Ethical Conduct of the Study ..............................................................................113
12.3. Subject Information and Consent........................................................................114
12.4. Informed Consent for Future Biomedical Research............................................114
12.5. Subject Recruitment ............................................................................................114
12.6. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................114
13. DEFINITION OF END OF TRIAL.................................................................................115
13.1. End of Trial in a Member State...........................................................................115
13.2. End of Trial in all other Participating Countries.................................................115
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................115
15. PUBLICATION OF STUDY RESULTS........................................................................115
15.1. Communication of Results by the Sponsor.........................................................115
15.2. Publications by Investigators ..............................................................................116
16. REFERENCES ................................................................................................................118
LIST OF TABLES
Table 1.
Estimated Percent Maximum Response for Various Endpoints...........................30
Table 2.
Minimum Daily Doses of SU for Entry into Sub-Studies....................................50
Table 3.
Glycemic Rescue Criteria for All Subjects for the First 18 Weeks......................60
Table 4.
Clinical/Safety-Related Laboratory Tests.............................................................88
Table 5.
Evaluating Adverse Events...................................................................................92
Table 6.
Alpha Adjusted Confidence Interval and Power for Primary Analyses.............107
APPENDICES
Appendix 1. Collection and Management of Specimens for Future Biomedical 
Research..............................................................................................................120
Appendix 2. Biomarker Brochure..........................................................................................126
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1. INTRODUCTION
1.1. Indication
Use in patients with T2DM to improve glycemic control with once daily dosing with the 
SGLT2 inhibitor, ertugliflozin. 
1.2. Background 
There has been an 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 it is projected to reach 
more than 550 million individuals by the year 2030.6  T2DM accounts for approximately 
90-95% of all cases of diabetes.  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.  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.7  Approximately 
85% of patients with T2DM are overweight or obese, a key factor underlying the 
development and maintenance of insulin resistance.8,9 Individuals with T2DM have an 
increased risk of developing both microvascular and macrovascular complications, including 
nephropathy, neuropathy, retinopathy, and cardiovascular disease. Coronary heart disease 
and stroke account for approximately two-thirds of deaths in people with diabetes2 and adults 
with T2DM are 2 to 4 times more likely to die from cardiovascular disease than those who do 
not have diabetes.1
The sodium glucose co-transporter family (SLC5A) consists of 12 known members, 
including 6 gene products named SGLTs.10  SGLT1, a low capacity, high-affinity transporter 
with a sodium:glucose stoichiometry of 2:1 transports D-glucose as well as D-galactose and 
is primarily distributed in the intestine; it is also found in the S3 segment of the proximal 
tubule of the kidney where it is responsible for approximately 10% of glucose reabsorption.  
In contrast, SGLT2 is primarily located in the S1/S2 segments of the proximal tubule of the 
kidney and is responsible for the reabsorption of approximately 90% of the glucose from the 
urine.  SGLT2 utilizes a sodium ion gradient to actively transport glucose in a 1:1 
stoichiometry and has been characterized as a high capacity, low affinity glucose 
transporter.11
Ertugliflozin (MK-8835/PF-04971729) is a potent inhibitor of Sodium-Glucose 
co-Transporter 2 (SGLT2) and possesses a high selectivity over glucose transport via 
Sodium-GLucose co-Transporter 1 (SGLT1) and several other glucose transporters 
(GLUT1-4).  Ertugliflozin inhibits renal glucose reabsorption resulting in urinary glucose 
excretion and thereby reducing plasma glucose and glycated hemoglobin (HbA1c) in subjects 
with T2DM.  Ertugliflozin is being developed as an adjunct to diet and exercise to improve 
glycemic control in patients with T2DM. 
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1.2.1. Efficacy of Ertugliflozin
In Phase 2 clinical studies, subjects received ertugliflozin for up to 12 weeks in duration.  
Phase 2 results demonstrated that ertugliflozin significantly lowered HbA1c, blood pressure 
and body weight without increasing the risk of hypoglycemia.  In study B1521006 involving 
adult subjects with T2DM the following placebo-adjusted mean (80% CI) reductions in 
HbA1c (%) were observed for the 5 mg, 10 mg and 25 mg daily doses after 12 weeks of 
treatment: -0.69 (-0.89 to -0.49), -0.62 (-0.82 to -0.42) and -0.72 (-0.93 to -0.52),
respectively.  The placebo-adjusted mean (80% CI) reductions in body weight (%) for the 
5 mg, for the 10 mg and for the 25 mg doses were: -1.75 (-2.35 to -1.14), -2.15 (-2.76 to 
-1.54) and -1.91 (-2.52 to-1.30) respectively.  The placebo-adjusted mean reductions in 
systolic blood pressure (mmHg) seen with doses of 5 mg, 10 mg and 25 mg were: 
-3.69 (-6.44 to -0.93), -2.77 (-5.59 to 0.05) and -2.77 (-5.56 to 0.02) respectively; and the 
results for diastolic blood pressure for the 5 mg, 10 mg and 25 mg doses were: -2.03 (-3.68 to 
-0.37), -4.12 (-5.81 to -2.42) and -2.40 (-4.08 to -0.73) respectively.
1.2.2. Safety of Ertugliflozin and SGLT2 Inhibitors
The SGLT2 inhibitors dapagliflozin, canagliflozin and empagliflozin are approved in the US
and in the European Union.  Based on available clinical trial data with dapagliflozin, 
canagliflozin and empagliflozin, several potential risks from SGLT2 inhibition have been 
identified.  In clinical trials, the rate of genital fungal infections in males and females has 
consistently been higher in subjects receiving SGLT2 inhibitors as compared to placebo or 
other diabetes medications.  Therefore, the increased risk of genital fungal infections can be 
considered a class effect of SGLT2 inhibitors.  Glucosuria can potentially result in increased 
risk of urinary tract infection (UTI) and this adverse drug reaction was commonly reported in
clinical trials with marketed SGLT2 inhibitors.  Most infections were mild to moderate in 
severity and infections were reported more frequently in females than in males.  There have 
also been postmarketing reports of serious UTIs including urosepsis and pyelonephritis 
requiring hospitalization in patients receiving marketed SGLT2 inhibitors. 
SGLT2 inhibition results in an osmotic diuresis, which may lead to reductions in 
intravascular volume and a small decrease in blood pressure. In clinical trials with marketed
SGLT2 inhibitors, treatment was associated with an increase in the incidence of adverse 
events related to volume depletion (eg, dehydration, hypovolemia, hypotension, orthostatic 
hypotension, syncope, postural dizziness). These events occurred at higher frequency and 
were more pronounced in some populations.  As SGLT2 inhibition can lead to volume 
depletion, there is a concern for potential adverse renal effects. In clinical trials with 
marketed SGLT2 inhibitors, early declines in the estimated glomerular filtration rate (eGFR) 
were seen, although there was a return toward baseline levels over time during treatment and 
upon discontinuation of therapy.  This early eGFR decline is believed to be related to 
dehydration and not due to progressing renal insufficiency. However, the pattern of eGFR 
decline appeared to be different in subjects with varying degrees of baseline renal function, 
with greater persistence of eGFR decline in subjects with moderate renal impairment. In 
addition, in subjects with moderate renal impairment there was a slightly higher incidence of 
renally-related adverse events reported in subjects receiving SGLT2 inhibitors than in 
controls. 
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Reports of ketoacidosis have been identified in postmarketing surveillance in patients 
receiving other marketed SGLT2 inhibitors.  In many of these reports, the presence of 
ketoacidosis was not immediately recognized and institution of treatment was delayed, 
because blood glucose levels were below those typically expected for diabetic ketoacidosis 
(often less than 250 mg/dL [13.9 mmol/L]).
Routine safety monitoring for these adverse events will be performed in this study. 
The safety of ertugliflozin has been assessed in the clinical development program in healthy 
subjects as well as in subjects with T2DM. 
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigators’ Brochure for ertugliflozin 
(MK-8835/PF-04971729).
1.3. Rationale for Study
Given the substantial cardiovascular morbidity and mortality from T2DM, an understanding 
of the cardiac safety of a new agent for patients with T2DM is of paramount importance.
The FDA has revised its approval process and guidelines for all new anti-diabetic therapies 
requiring that acceptable levels of cardiovascular safety are demonstrated at the time of the 
NDA filing as well as post-approval.3  The FDA guidance requires that sponsors must rule 
out an upper 95% CI of the HR for cardiovascular events of 1.8 before approval and 1.3 after 
approval.
The EMA has also updated its guidelines requiring that sponsors of novel diabetes agents 
exclude that the new compound increases the risk of macrovascular complications at the time 
of the MAA.4 In contrast to the FDA guidance, the EMA does not specify thresholds of 
excess cardiovascular risk that must be excluded.  Both the FDA and EMA guidance 
documents recommend that an assessment of cardiovascular safety needs to include subjects 
with T2DM and high cardiovascular risk.
The primary objective of this trial is to support the assessment of cardiovascular safety of 
ertugliflozin. 
Additionally, after the publication of the results of the EMPA-REG OUTCOME 
(EMPA-REG) trial with empagliflozin,13 a superiority analysis for the secondary end point of 
cardiovascular death or hospitalization for heart failure (composite) and cardiovascular death 
(individual) has been included in the analysis plan.  In the EMPA-REG trial, which showed a 
significant effect in reducing the risk of MACE; HR (95% CI) 0.86 (0.74-0.99), there was 
also a statistically and robust reduction in cardiovascular death; HR (95% CI) 0.62 
(0.49-0.77) and in hospitalization for heart failure; HR (95% CI) 0.65 (0.50-0.85), with no 
significant reductions in the risk of non-fatal myocardial infarction and non-fatal stroke.13  
The fact that the reduction in MACE was driven by a reduction in CV death and not non-fatal 
myocardial infarction or non-fatal stroke may suggest that SGLT2 inhibition might provide 
cardiovascular benefit from mechanisms not directly linked to an effect on atherosclerosis 
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per se.  Therefore, while MACE is an ideal endpoint to assess cardiovascular safety, it might 
not be the most sensitive end point to assess the potential cardiovascular benefits of SGLT2 
inhibitors.  Cardiovascular death and hospitalization for heart failure are both very prevalent 
in the patient population enrolled in this study.  Furthermore, heart failure is associated with 
an increased risk of mortality and has been shown to be the main cause of mortality post 
myocardial infarction.14
Subjects with T2DM and established vascular disease comprise a large segment of the 
population which would be treated with an SGLT2 inhibitor.  Such subjects are often 
underrepresented in clinical trials which limits their ability to provide meaningful 
information on the benefit:risk profile of novel agents in an important population.  Therefore, 
this trial will enroll subjects with T2DM who are at elevated risk of cardiovascular events.  
The population enrolled in this trial is, therefore, representative of those subjects often
treated in clinical practice, with T2DM and elevated risk of cardiovascular disease.
Additionally, this trial includes a sub-study to generate safety and efficacy data in subjects 
using insulin with or without metformin, a sub-study to generate safety and efficacy data in 
subjects using SU monotherapy and another sub-study to generate safety and efficacy data in 
subjects using metformin with SU.
While the subjects in the placebo arm in this trial will not receive active treatment with 
ertugliflozin, they will be counseled on life style measures to attain improved glycemic 
control and for all subjects in the trial (either on placebo or ertugliflozin), following the 
initial 18 weeks of the trial, the investigator or subject´s treating physician is able to make 
any necessary adjustments in background diabetes medications to achieve appropriate, 
individualized treatment goals.  Furthermore, as described in Section 5.5.2 all subjects in the 
trial will continue to receive treatment to address cardiovascular risk factors (eg, blood 
pressure management, lipid management). 
1.4. Rationale for Dose Selection of Ertugliflozin
The ertugliflozin doses being evaluated in Phase 3 are 5 mg and 15 mg once daily. Since 
oral doses of ertugliflozin as high as 300 mg (single dose), 100 mg once daily (up to 14 days) 
and 25 mg once daily (up to 12 weeks) were safe and well-tolerated, dose selection was 
based on dose-response modeling of efficacy end-points (HbA1c and fasting plasma glucose 
[FPG]) from study B1521006 as well as 24-hour urinary glucose excretion (mechanism 
biomarker) in T2DM subjects from study B1521004.  For these endpoints, the 5 mg and 
15 mg doses consistently elicit a response that is >80% and >90% of the maximum response, 
respectively (Table 1). 
Table 1.
Estimated Percent Maximum Response for Various Endpoints
Ertugliflozin 
Dose
UGE – T2DM
(ED50=0.78 mg)
HbA1C
(ED50=1 mg)
5 mg
87%
83%
15 mg
95%
94%
UGE = urinary glucose excretion;  ED50 = dose producing half (50%) of the maximal response.
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In addition, the dose-response modeling of 24-hour UGE in healthy volunteers estimated the 
ED50 at 3 mg, which translates to 63% and 83% of maximum effect for 5-mg and 15-mg 
doses.  The selection of the 5 mg and 15 mg doses is also supported by the safety and 
tolerability profile for ertugliflozin in clinical studies up to 12 weeks in duration.  When 
accounting for species differences in protein binding, the highest Phase 3 dose of 15 mg once 
daily represents an exposure which is approximately 12-fold [for Cmax] and 11-fold [for area 
under the concentration-time curve from time 0 to 24 hours (1 day) after dose (AUC(0-24))]
lower than exposure at the no observed adverse effect level (NOAEL) in the 6-month 
toxicology study in the most sensitive species (rat).  Thus, both the 5 and 15 mg doses are 
expected to provide clinically meaningful efficacy and allow for a thorough assessment of 
the benefit/risk of ertugliflozin in the Phase 3 program.
1.5. Rationale for Future Biomedical Research
The sponsor will conduct Future Biomedical Research on whole blood DNA, plasma and 
serum specimens collected 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.  Specimens may be used for future assay 
development.  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 
pharmacogenetics (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, and/or to ensure that subjects 
receive the correct dose of the correct drug at the correct time.  The details of this Future 
Biomedical Research sub-trial are presented in Appendix 1:  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 Appendix 2.
2. STUDY OBJECTIVES, HYPOTHESES AND ENDPOINTS
2.1. Objectives and Hypotheses
2.1.1. Primary Objective and Hypothesis

Objective: To demonstrate the non-inferiority of ertugliflozin compared with 
placebo on the time to first occurrence of the composite endpoint of MACE.  
(MACE: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke)
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
Hypothesis: The time to first occurrence of the composite endpoint of MACE in 
subjects treated with ertugliflozin is non-inferior compared to that in subjects treated 
with placebo.
2.1.2. Secondary Objectives and Hypotheses

Objective: To demonstrate the superiority of ertugliflozin compared with placebo on 
the time to first occurrence of the composite endpoint of cardiovascular death or 
hospitalization for heart failure.

Hypothesis: The time to first occurrence of the composite endpoint of cardiovascular 
death or hospitalization for heart failure in subjects treated with ertugliflozin is 
superior compared to that in subjects treated with placebo.

Objective: To demonstrate the superiority of ertugliflozin compared with placebo on 
the time to cardiovascular death.

Hypothesis: The time to cardiovascular death in subjects treated with ertugliflozin is 
superior compared to that in subjects treated with placebo.

Objective:  To demonstrate the superiority of ertugliflozin compared with placebo on 
the time to first occurrence of the composite endpoint of renal death, renal 
dialysis/transplant, or 2x increase in baseline serum creatinine.

Hypothesis:  The time to first occurrence of the composite endpoint of renal death, 
renal dialysis/transplant, or 2x increase in baseline serum creatinine in subjects 
treated with ertugliflozin is superior compared to that in subjects treated with placebo.

Objective: To assess the effect of ertugliflozin as compared with placebo on the time 
to first occurrence of:

MACE plus;

Fatal or non-fatal myocardial infarction;

Fatal or non-fatal stroke;

Hospitalization for heart failure;

Individual components of MACE (cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke). 

Objective: To assess the effect of ertugliflozin as compared with placebo on the time 
to:

All-cause mortality;
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
All MACE events (not censored at time of first event);

All cardiovascular death or hospitalizations for heart failure (not censored at time 
of first event).
When added to usual background therapy in subjects with T2DM and established vascular 
disease:

Objective: To assess the overall safety and tolerability of ertugliflozin.

Objective: To assess the effect on HbA1c of 15 mg ertugliflozin as compared with 
placebo.

Objective: To assess the effect on HbA1c of 5 mg ertugliflozin as compared with 
placebo.

Objective: To assess the effect on FPG of 15 mg ertugliflozin as compared with 
placebo.

Objective: To assess the effect on FPG of 5 mg ertugliflozin as compared with 
placebo.

Objective: To assess the effect on time to first occurrence of a subject requiring 
glycemic rescue therapy during the first 18 weeks of 15 mg ertugliflozin as compared 
with placebo.

Objective: To assess the effect on time to first occurrence of a subject requiring 
glycemic rescue therapy during the first 18 weeks of 5 mg ertugliflozin as compared 
with placebo. 

Objective: To assess the effect on the time to initiation of insulin for subjects not on 
insulin at randomization of 15 mg ertugliflozin as compared with placebo. 

Objective: To assess the effect on the time to initiation of insulin for subjects not on 
insulin at randomization of 5 mg ertugliflozin as compared with placebo. 

Objective:  To assess the change in insulin dose over time for subjects receiving 
insulin at the time of randomization of 15 mg ertugliflozin as compared with placebo.

Objective:  To assess the change in insulin dose over time for subjects receiving
insulin at the time of randomization of 5 mg ertugliflozin as compared with placebo

Objective: To assess the effect on body weight of 15 mg ertugliflozin as compared 
with placebo.

Objective: To assess the effect on body weight of 5 mg ertugliflozin as compared 
with placebo.
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
Objective: To assess the effect on the incidence of HbA1c <7% (53 mmol/mol) of 
15 mg ertugliflozin as compared with placebo.

Objective: To assess the effect on the incidence of HbA1c <7% (53 mmol/mol) of 
5 mg ertugliflozin as compared with placebo.

Objective: To assess the effect on the incidence of HbA1c of <6.5% (48 mmol/mol) 
of 15 mg ertugliflozin as compared with placebo.

Objective: To assess the effect on the incidence of HbA1c <6.5% (48 mmol/mol) of 
5 mg ertugliflozin as compared with placebo.

Objective: To assess the effect on systolic blood pressure of 15 mg ertugliflozin as 
compared with placebo.

Objective: To assess the effect on systolic blood pressure of 5 mg ertugliflozin as 
compared with placebo.

Objective: To assess the effect on diastolic blood pressure of 15 mg ertugliflozin as 
compared with placebo.

Objective: To assess the effect on diastolic blood pressure of 5 mg ertugliflozin as 
compared with placebo.

Objective: To assess the effect on renal function of 15 mg ertugliflozin as compared 
with placebo.

Objective: To assess the effect on renal function of 5 mg ertugliflozin as compared 
with placebo.
2.2. Insulin with or without Metformin Add-on Glycemic Sub-Study Objectives and 
Hypotheses
In subjects with T2DM and established vascular disease with inadequate glycemic control 
receiving only insulin (with or without metformin):
2.2.1. Primary Objectives and Hypotheses

Objective: At Week 18, to assess the effect on HbA1c of 15 mg ertugliflozin as 
compared with placebo.

Hypothesis: At Week 18, the mean reduction from baseline in HbA1c for 15 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on HbA1c of 5 mg ertugliflozin as 
compared with placebo. 
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
Hypothesis: At Week 18, the mean reduction from baseline in HbA1c for 5 mg 
ertugliflozin is greater than that for placebo.

Objective: To assess the safety and tolerability of ertugliflozin.
2.2.2. Secondary Objectives and Hypotheses

Objective: At Week 18, to assess the effect on FPG of 15 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in FPG for 15 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on FPG of 5 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in FPG for 5 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on body weight of 15 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in body weight for 
15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on body weight of 5 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in body weight for 5 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on the incidence of HbA1c <7% 
(53 mmol/mol) of 15 mg ertugliflozin as compared with placebo.

Hypothesis: At Week 18, the proportion of subjects with HbA1c<7% (53 mmol/mol) 
for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on incidence of HbA1c <7% 
(53 mmol/mol) of 5 mg ertugliflozin as compared with placebo.

Hypothesis: At Week 18, the proportion of subjects with HbA1c<7% (53 mmol/mol) 
for 5 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on systolic blood pressure of 15 mg 
ertugliflozin as compared with placebo. 
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
Hypothesis: At Week 18, the mean reduction from baseline in systolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on systolic blood pressure of 5 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in systolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18 to assess the effect on diastolic blood pressure of 15 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in diastolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on diastolic blood pressure of 5 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in diastolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the change in insulin dose of 15 mg ertugliflozin 
as compared with placebo. 

Objective: At Week 18, to assess the change in insulin dose of 5 mg with 
ertugliflozin as compared with placebo. 
2.3. SU Monotherapy Add-on Glycemic Sub-Study Objectives and Hypotheses
In subjects with T2DM and established vascular disease with inadequate glycemic control on 
SU monotherapy:
2.3.1. Primary Objectives and Hypotheses

Objective: At Week 18, to assess the effect on HbA1c of 15 mg ertugliflozin as 
compared with placebo.

Hypothesis: At Week 18, the mean reduction from baseline in HbA1c for 15 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on HbA1c of 5 mg ertugliflozin as 
compared with placebo.

Hypothesis: At Week 18, the mean reduction from baseline in HbA1c for 5 mg 
ertugliflozin is greater than that for placebo

Objective:  To assess the safety and tolerability of ertugliflozin.
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2.3.2. Secondary Objectives and Hypotheses

Objective: At Week 18, to assess the effect on FPG of 15 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in FPG for 15 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on FPG of 5 mg ertugliflozin as 
compared with placebo.

Hypothesis: At Week 18, the mean reduction from baseline in FPG for 5 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on body weight of 15 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in body weight for 
15 mg ertugliflozin is greater than that for placebo

Objective: At Week 18, to assess the effect on body weight of 5 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in body weight for 5 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on the incidence of HbA1c <7% 
(53 mmol/mol) of 15 mg ertugliflozin as compared with placebo.

Hypothesis: At Week 18, the proportion of subjects with HbA1c<7% (53 mmol/mol)
for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on the incidence of HbA1c
<7% (53 mmol/mol) of 5 mg ertugliflozin as compared with placebo.

Hypothesis: At Week 18, the proportion of subjects with HbA1c<7% (53 mmol/mol) 
for 5 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on systolic blood pressure of 15 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in systolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on systolic blood pressure of 5 mg 
ertugliflozin as compared with placebo. 
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
Hypothesis: At Week 18, the mean reduction from baseline in systolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18 to assess the effect on diastolic blood pressure of 15 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in diastolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on diastolic blood pressure of 5 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in diastolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.
2.4. Metformin with SU Add-on Glycemic Sub-Study Objectives and Hypotheses
In subjects with T2DM and established vascular disease with inadequate glycemic control 
receiving only metformin with SU:  
2.4.1. Primary Objectives and Hypotheses

Objective: At Week 18, to assess the effect on HbA1c of 15 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in HbA1c for 15 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on HbA1c of 5 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in HbA1c for 5 mg 
ertugliflozin is greater than that for placebo.

Objective:  To assess the safety and tolerability of ertugliflozin.
2.4.2. Secondary Objectives and Hypotheses

Objective: At Week 18, to assess the effect on FPG of 15 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in FPG for 15 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on FPG of 5 mg ertugliflozin as 
compared with placebo. 
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
Hypothesis: At Week 18, the mean reduction from baseline in FPG for 5 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on body weight of 15 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in body weight for 
15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on body weight of 5 mg ertugliflozin as 
compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in body weight for 5 mg 
ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on the incidence of HbA1c <7% 
(53 mmol/mol) of 15 mg ertugliflozin as compared with placebo.

Hypothesis: At Week 18, the proportion of subjects with HbA1c<7% (53 mmol/mol) 
for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on incidence of HbA1c
<7% (53 mmol/mol) of 5 mg ertugliflozin as compared with placebo.

Hypothesis: At Week 18, the proportion of subjects with HbA1c<7% (53 mmol/mol) 
for 5 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on systolic blood pressure of 15 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in systolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on systolic blood pressure of 5 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in systolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18 to assess the effect on diastolic blood pressure of 15 mg 
ertugliflozin as compared with placebo. 

Hypothesis: At Week 18, the mean reduction from baseline in diastolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.

Objective: At Week 18, to assess the effect on diastolic blood pressure of 5 mg 
ertugliflozin as compared with placebo. 
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
Hypothesis: At Week 18, the mean reduction from baseline in diastolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.
2.5. Objective and Hypothesis Across the Ertugliflozin Phase 2 and Phase 3 
Development Program 

Objective: To demonstrate the non-inferiority of ertugliflozin as compared with a 
non-ertugliflozin comparator group on the time to first occurrence of the composite 
endpoint of MACE plus.

Hypothesis: The time to first occurrence of the composite endpoint of MACE plus in 
subjects treated with ertugliflozin is non-inferior compared to that in subjects not 
treated with ertugliflozin.
Further details regarding the meta-analysis across the Ertugliflozin Phase 2 and Phase 3 
Development Program are provided in the Statistical Analysis Plan (SAP) document.
2.6. Study Endpoints
All potential cardiovascular endpoints across the ertugliflozin Phase 2 and Phase 3 
development program are to be adjudicated by members of an independent Endpoint 
Adjudication Committee (EAC) who will be blinded to the treatment assignment.  Endpoint 
definitions will be included in the Endpoint Adjudication Manual used by the EAC.  Only 
adjudicated and confirmed endpoints will be used in the analysis of the cardiovascular event 
data.
2.6.1. Primary Endpoint

The primary cardiovascular endpoint is time to first occurrence of the composite 
endpoint of MACE. 
2.6.2. Secondary Endpoints

Time to first occurrence of: 

Cardiovascular death or hospitalization for heart failure;

Cardiovascular death;

MACE plus;

Fatal or non-fatal myocardial infarction;

Fatal or non-fatal stroke;

Hospitalization for heart failure;

Individual components of MACE (cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke). 
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
All-cause mortality.

All MACE events (ie, not censored at the time of the first event).

All cardiovascular death or hospitalizations for heart failure (ie, not censored at the 
time of the first event).

Time to first occurrence of the composite of renal death, renal dialysis/transplant, or 
2x increase in baseline serum creatinine.
When added to usual background therapy in subjects with T2DM and established vascular 
disease:

Change from Baseline in HbA1c at Week 18, Week 52 and annually thereafter.

Proportion of subjects with HbA1c <7% (53 mmol/mol) and <6.5% (48 mmol/mol) at 
12, 24 and 36 months and annually thereafter.

Time to the first occurrence of a subject receiving glycemic rescue therapy during the 
first 18 weeks of the study.

Time to initiation of insulin for subjects not on insulin at randomization.

Change in insulin dose from Baseline at Week 18, Week 52 and annually thereafter.

Change from Baseline in systolic and diastolic blood pressure at Week 18, Week 52 
and annually thereafter.

Change from Baseline in body weight at Week 18, Week 52 and annually thereafter.

Change from Baseline in eGFR and serum creatinine at Week 18, Week 52 and 
annually thereafter.

Change from Baseline in albuminuria as measured by the urinary albumin to 
creatinine ratio at Week 18, Week 52 and annually thereafter stratified by 
albuminuria category at baseline (normoalbuminuria, microalbuminuria and 
macroalbuminuria).

Progression of nephropathy as measured by the progression of normoalbuminuria to 
microalbuminuria and/or macroalbuminuria as well as measurement of regression of 
albuminuria (eg, macroalbuminuria microalbuminuria).
2.7. Insulin with or without Metformin Add-on Glycemic Sub-Study Endpoints
2.7.1. Primary Endpoint

Change in HbA1c from Baseline to Week 18.
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2.7.2. Secondary Endpoints

Change in FPG from Baseline to Week 18.

Change in body weight from Baseline to Week 18.

Proportion of subjects with an HbA1c of <7% (53 mmol/mol) at Week 18.

Change in systolic and diastolic blood pressure from Baseline to Week 18.

Change in insulin dose from Baseline to Week 18.
2.8. SU Monotherapy Add-on Glycemic Sub-Study Endpoints 
2.8.1. Primary Endpoint

Change in HbA1c from Baseline to Week 18.
2.8.2. Secondary Endpoints

Change in FPG from Baseline to Week 18.

Change in body weight from Baseline to Week 18.

Proportion of subjects with an HbA1c of <7% (53 mmol/mol) at Week 18.

Change in systolic and diastolic blood pressure from Baseline to Week 18.
2.9. Metformin with SU Add-on Glycemic Sub-Study Endpoints 
2.9.1. Primary Endpoint 

Change in HbA1c from Baseline to Week 18.
2.9.2. Secondary Endpoints 

Change in FPG from Baseline to Week 18.

Change in body weight from Baseline to Week 18.

Proportion of subjects with an HbA1c of <7% (53 mmol/mol) at Week 18.

Change in systolic and diastolic blood pressure from Baseline to Week 18.
2.10. Endpoint Across the Ertugliflozin Phase 2 and Phase 3 Development Program

Time to first occurrence of the composite endpoint of MACE plus.
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3. STUDY DESIGN
3.1. Overview of Study Design (Main Cardiovascular Study and add-on Glycemic 
Sub-Studies)
This trial is a multicenter, randomized, double-blind, placebo-controlled, event-driven trial 
that includes a main cardiovascular study and three add-on glycemic sub-studies in subjects 
receiving specific background anti-hyperglycemic treatments.  Periodic assessments of safety 
will be performed by an external Data Monitoring Committee (E-DMC).  Further details are 
provided in Section 9.9. 
To be enrolled in this trial subjects must be 40 years of age with a previous diagnosis of 
T2DM in accordance with ADA guidelines,5 HbA1c of 7.0-10.5%, inclusive
(53-91 mmol/mol) and a history of established vascular disease involving the coronary, 
cerebrovascular, or peripheral vascular system.  Subjects who are treated with oral 
anti-hyperglycemic agents (AHA), insulin or GLP-1 agonists, either alone or in combination, 
stable for at least 8 weeks prior to the Screening visit (V1) or subjects who are on only diet 
and exercise for T2DM are eligible to be enrolled.  Background AHA treatment must 
continue to remain stable throughout the length of the Screening period.  The only prohibited 
concomitant AHA therapy is the use of any other SGLT2 therapy (eg, dapagliflozin, 
canagliflozin, empagliflozin, etc.), rosiglitazone or chlorpropamide within 8 weeks of the 
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Screening visit (V1), between the screening period and randomization or during the trial.  
Other key exclusion criteria include subjects with an eGFR <30 mL/min/1.73 m2, see for 
further details.  Full inclusion and exclusion criteria are found in Section 4.2. Specific
criteria for inclusion in the glycemic sub-studies are detailed in Sections 3.4, 4.1.1, 4.1.2, 
4.2.1. Subjects will be screened for eligibility at the Screening visit (V1). At the Day 1 
visit (V2), subjects who meet all enrollment criteria will have all baseline laboratory tests and 
trial procedures performed and will be randomized in a 1:1:1 ratio to ertugliflozin 5 mg once 
daily, ertugliflozin 15 mg once daily or matching placebo added to their background therapy.
This trial will contribute to the program-wide meta-analysis of cardiovascular events 
occurring in the ertugliflozin Phase 2 and Phase 3 development program as follows.
For the initial global registration dossiers (including the NDA submission), the 
cardiovascular events from this trial will be combined with the cardiovascular events from 
the rest of the Phase 2 and Phase 3 development program to conduct a program-wide 
meta-analysis to support the cardiovascular safety of ertugliflozin.  The endpoint for this 
meta-analysis will be MACE plus.  The goal of this meta-analysis will be to rule out a hazard 
ratio of 1.8 (an 80% increase in the risk of MACE plus relative to a non-ertugliflozin 
comparator group) by showing that the upper bound of the two-sided alpha-adjusted
confidence interval for the hazard ratio is <1.8.
The primary cardiovascular endpoint for this study will be MACE.  The goal of this analysis 
is to rule out a hazard ratio of 1.3 (a 30% increase in the risk of MACE relative to placebo). 
If non-inferiority at the 1.3 margin is established for the primary MACE endpoint, then tests
of superiority on the secondary endpoints of cardiovascular death or hospitalization for heart 
failure (composite) and cardiovascular death (individual component) will also be performed. 
The trial will utilize a group sequential design that includes interim analyses. With two 
enrollment periods of 19 months each and assuming an event rate of 3.5% per annum for 
MACE, a total of approximately 8000 subjects randomized in a 1:1:1 ratio to ertugliflozin 
5 mg, ertugliflozin 15 mg or placebo will be sufficient to accrue approximately 714 MACE 
events within approximately 5.0 years and approximately 939 MACE events within 
approximately 6.1 years from the start of this trial.  These calculations assume that subjects
will withdraw from the study at a rate of 5% per annum.
All randomized subjects will be followed until the scheduled end of the trial regardless of 
adherence to or discontinuation of investigational product unless a subject withdraws consent
for follow-up.  This follow-up will be undertaken so that information on SAEs and clinical 
events continues to be collected.  Further details are provided in Section 6.6.
All subjects enrolled under the original protocol prior to Amendment 1 will be randomized 
into the overall study, and subjects meeting additional inclusion criteria will also be included 
in specific glycemic sub-studies. Subjects enrolled after the approval of Amendment 1 will 
only be randomized into the overall study.  For these subjects, the protocol sub-study details 
described below and in Sections 4.1.1, 4.1.2, and 4.2.1 are not applicable.  At the time of 
randomization, subjects in Cohort 1 will be stratified into the main cardiovascular study, the 
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insulin (with or with metformin) sub-study or the SU monotherapy sub-study, according to 
their background anti-hyperglycemic treatment as follows.  Subjects receiving background 
insulin (with or without metformin) at doses specified in the protocol are included into the 
insulin (with or without metformin) add-on glycemic sub-study, subjects receiving 
background SU monotherapy (at doses specified in the protocol) are included into the SU 
monotherapy add-on glycemic sub-study.  Subjects receiving background metformin with SU 
at doses specified in the protocol are included in the metformin plus SU sub-study.  Unlike 
the other two sub-studies, inclusion in the metformin with SU sub-study will not be stratified 
at randomization.  Instead, all subjects randomized into the main cardiovascular study who 
meet the additional eligibility requirements will be considered enrolled in this sub-study.  
Since all the subjects participating in the three sub-studies are enrolled in the main 
cardiovascular study, visit schedules and protocol-required tests and procedures are the same 
for all subjects irrespective of whether or not a subject also participates in a sub study.  The 
glycemic sub-studies will run during the initial 18 weeks of the study.  Following the 
collection of efficacy and safety end points at Week 18 (V5), subjects in the glycemic 
sub-studies will continue participating in the main cardiovascular study. 
3.2. Insulin with or without Metformin Add-on Glycemic Sub-Study
This trial includes an 18-week sub-study to generate safety and efficacy data in T2DM 
subjects using insulin therapy alone or insulin with metformin as the only background 
anti-hyperglycemic treatment.  The insulin with or without metformin sub-study has different 
requirements with respect to allowable background AHA than the main cardiovascular study.
Subjects are entered into the sub-study if they are using insulin 20 units/day (with or 
without metformin 1,500 mg/day) as the only background anti-hyperglycemic treatment. 
Subjects can be on basal insulin alone (eg, insulin glargine, insulin detemir, Neutral 
Protamine Hagedorn (NPH) insulin, degludec), split mixed insulin (eg, 70/30) or basal 
insulin + prandial insulin (eg, regular, aspart, lispro or glulisine).  Subjects receiving prandial 
insulin as their only insulin regimen, without basal insulin, are not eligible for enrollment
into the sub-study.  Insulin total daily dose variations of up to 10% during the 8 weeks prior 
to the Screening visit (V1) or during the period between the Screening visit (V1) and 
randomization are permitted and fulfill the criterion of stable insulin therapy. It is 
recommended that the daily dose variations are compared to the average weekly dose to 
account for day-to-day variability.  Further details on the inclusion criteria for the insulin 
with or without metformin sub-study can be found in Section 4.1.1.
Subjects eligible for the main cardiovascular study using insulin with any diabetes regimen 
other than insulin with or without metformin 1,500 mg/day or subjects not meeting the 
insulin type and dose requirements as specified in the inclusion criteria will be enrolled in the 
main study, but not in the sub-study. Further details on the exclusion criteria for the insulin 
with or without metformin sub-study can be found in Section 4.2.1. 
This insulin with or without metformin sub-study plans to enroll a minimum of 450 subjects 
who will be randomized in a 1:1:1 ratio to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo. 
The sub-study randomization will be stratified by background therapy and geographic region.  
The background therapy stratification factor will have two levels: insulin alone and insulin 
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with metformin.  The number of subjects using background insulin in the overall study 
population enrolled in this trial will not be allowed to exceed approximately 50%. The 
primary endpoint of HbA1c change from Baseline will be measured at Week 18.  Secondary 
endpoints include change from Baseline in FPG, body weight, the proportion of subjects with 
an HbA1c <7% (53 mmol/mol) at Week 18, change from Baseline in systolic and diastolic 
blood pressure at Week 18 and change from Baseline in insulin dose at Week 18.  Details on 
the treatment for glycemic control can be found in Section 5.5.1.  After Week 18 subjects 
enrolled in the insulin with or without metformin sub-study will continue to participate in the 
main cardiovascular study.
3.3. SU Monotherapy Add-on Glycemic Sub-Study
This trial includes an 18-week sub-study to generate safety and efficacy data in subjects 
using a SU as monotherapy at the pre-specified doses specified in Table 2 in Section 4.1.2. 
The SU monotherapy sub-study has different requirements with respect to allowable 
background AHA than the main cardiovascular study.  Further details on the inclusion 
criteria for the SU monotherapy sub-study can be found in Section 4.1.2.
Subjects receiving a SU eligible to participate in the main study at a dose less than that 
specified in Table 2 could still be enrolled in the main cardiovascular study but not in the 
sub-study.
Based on the percentage of subjects receiving treatment with SU monotherapy enrolled in a 
similar trial, the CANVAS study (approximately 3% of the total population)12 it is estimated 
that approximately 120 subjects will be enrolled in the SU monotherapy sub-study and they 
will be randomized in a 1:1:1 ratio to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo.  
There is no maximum number of subjects who can be enrolled in the sub-study on SU 
monotherapy.
The primary endpoint of HbA1c change from Baseline will be measured at Week 18.  
Secondary endpoints include change from Baseline in FPG, body weight, the proportion of 
subjects with an HbA1c <7% (53 mmol/mol) at Week 18 and change from Baseline in 
systolic and diastolic blood pressure at Week 18. Details on the treatment for glycemic 
control can be found in Section 5.5.1.  After Week 18 subjects enrolled in the SU 
monotherapy sub-study will continue to participate in the main cardiovascular study. 
3.4. Metformin with SU Add-on Glycemic Sub-Study
This trial includes an 18-week sub-study to generate safety and efficacy data in T2DM 
subjects using metformin with a SU as the only background anti-hyperglycemic treatment.  
The metformin with SU sub-study has different requirements with respect to allowable 
background AHA than the main cardiovascular study.
Subjects will be included in this sub-study if they are receiving at the Screening visit (V1) 
metformin 1500 mg/day with a SU at the doses specified in Table 2 in Section 4.1.2. The 
doses of the metformin and SU must have been stable for at least 8 weeks prior to the time of 
the Screening visit (V1) and during the period between the Screening visit (V1) and 
randomization.  Subjects will not be included in the metformin with SU sub-study if their 
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screening eGFR is <55 mL/min/1.73m2 or the screening serum creatinine is 1.3 mg/dL 
(115 mol/l) in males or 1.2 mg/dL (110 mol/l) in females.  These renal entry criteria were 
selected as they match the renal entry criteria used throughout the ertugliflozin program for 
studies where metformin is a required background treatment.
As there is no separate randomization stratum for the metformin with SU sub-study, this 
sub-study will consist of a sub-group of subjects from the “main cardiovascular study” 
stratum.  The determination of inclusion in the sub-study will be based on a programmatic 
assessment of the sub-study criteria.
The primary endpoint of HbA1c change from Baseline will be measured at Week 18.  
Secondary endpoints include change from Baseline in FPG, body weight, the proportion of 
subjects with an HbA1c <7% (53 mmol/mol) at Week 18 and change from Baseline in 
systolic and diastolic blood pressure at Week 18.  Details on the treatment for glycemic 
control can be found in Section 5.5.1.
4. SUBJECT SELECTION
This trial can fulfill its objectives only if appropriate subjects are enrolled and followed 
throughout the completion of the trial irrespective of whether they are maintained on 
investigational product.  All efforts should be made to follow randomized subjects for the 
entire duration of the study.  Importantly, discontinuation of investigational product does not 
imply or constitute withdrawal of the subject from the study.  Section 6.6 describes the 
follow-up procedures for subjects who withdraw from investigational product.  In general, 
investigators should try to obtain the most complete collection of data as possible from 
subjects who discontinue investigational product, weighing the subject’s willingness to 
participate with the scientific integrity of the protocol.  Those subjects who are a priori
unwilling to agree to the collection of the information in the event that they discontinue 
investigational product should not be enrolled. 
The following eligibility criteria are designed to select subjects for whom protocol-specified
treatment is considered appropriate.  All relevant medical and non-medical conditions should 
be taken into consideration when deciding whether this protocol is suitable for a particular 
subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s trial team before subjects are included in the trial. Subjects must meet 
all of the following inclusion criteria at the time of the Screening visit (V1) to be eligible for 
enrollment into the trial:
1. Subjects 40 years of age at the time of the initial Screening visit (V1) with a diagnosis 
of T2DM in accordance with American Diabetes Association (ADA) guidelines.5
2. HbA1c at the Screening visit (V1) of 7.0-10.5% (53-91 mmol/mol) on stable allowable 
AHA(s) or on no background AHA for at least 8 weeks prior to the Screening visit (V1).
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3. Body Mass Index (BMI) 18.0 kg/m2.
4. Subjects must have evidence or a history of atherosclerosis involving the coronary, 
cerebral or peripheral vascular systems as follows (must have at least one of the 
following a-d):
a.
Coronary artery disease as indicated by a history of presumed spontaneous 
myocardial infarction (hospitalized with final diagnosis of myocardial infarction, 
excluding peri-procedural or definite secondary myocardial infarction [eg, due to 
profound anemia or hypertensive emergency, troponin increase in sepsis] in which the 
most recent event occurred at least 3 months (90 days) prior to the Screening visit
(V1); OR
b. Coronary artery disease as indicated by a history of coronary revascularization 
through either a Percutaneous Coronary Intervention (PCI) at least 3 months
(90 days) prior to the Screening visit (V1) or Coronary Artery Bypass Graft (CABG)
at least 3 months (90 days) prior to the Screening visit (V1); OR
c.
Ischemic (presumed thrombotic) cerebrovascular disease as indicated by a history of 
ischemic stroke (hospitalized with a final diagnosis of non-hemorrhagic stroke 
[includes completion of a standard evaluation for stroke in an acute care facility or 
stroke clinic without hospital admission] with the most recent event occurring at least 
3 months (90 days) prior to the Screening visit (V1) or a history of carotid 
revascularization at least 3 months (90 days) prior to the Screening visit (V1); OR
d. Peripheral arterial disease as indicated by:
1. Angiographically-documented peripheral vascular disease; or
2. Resting ankle/brachial index (ABI) of <0.85 (measured by a certified vascular 
laboratory) plus symptoms of claudication; or
3. Amputation, peripheral bypass, or peripheral angioplasty of the extremities 
secondary to ischemia occurring at least 3 months (90 days) prior to the Screening
visit (V1).
5. There is adequate documentation of the objective evidence that the subject has 
established vascular disease such as investigational site's medical records, copies of such 
records from other institutions, or a letter from a referring physician that specifically 
states the diagnosis and date of the most recent occurrence of the qualifying event(s) or 
procedure(s).
6. Subject meets one of the following criteria (a, b or c):
a.
Is a male;
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b. Is a female not of reproductive potential defined as one who (See Section 4.4.4.1 and 
Section 4.4.4.2 for reference on childbearing potential):
1. Is postmenopausal: defined as at least 12 months with no menses in women 
45 years of age. or
2. Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal 
ligation or occlusion at least 6 weeks prior to the Screening visit (V1).
c.
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); or
2. Agrees to use (or have their partner use) acceptable contraception to prevent 
pregnancy while the subject is receiving investigational product and for 14 days 
after the last dose of investigational product. 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 an 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 intrauterine device (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).
7. Evidence of a personally signed and dated informed consent document (ICD) indicating 
that the subject (or a legal representative) 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.
8. In the investigator’s opinion subjects are willing and likely able to comply with 
scheduled visits, treatment plan, laboratory tests, and other study procedures whether or 
not they receive investigational product for the duration of the trial.
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4.1.1. Inclusion Criteria – Specific to Insulin with or without Metformin Add-on 
Glycemic Sub-Study
In addition to meeting the above mentioned inclusion criteria for enrollment in the main 
cardiovascular study, subjects will be eligible to be enrolled in this sub-study if they meet the 
following additional entry criteria at the time of the Screening visit (V1):
9. Insulin 20 units/day with or without metformin 1,500 mg/day, where doses of insulin 
with or without metformin have been stable for at least 8 weeks prior to the time of the 
Screening visit (V1) and during the period between the Screening visit (V1) and 
randomization. Variations in the total daily dose of insulin of up to 10% are permitted
and still meet the definition of stable insulin dose.
4.1.2. Inclusion Criteria – Specific to SU Monotherapy Add-on Glycemic Sub-Study
In addition to meeting the above mentioned inclusion criteria for enrollment in the main 
cardiovascular study, subjects will be eligible to be enrolled in this sub-study if they meet the 
following additional entry criteria at the time of the Screening visit (V1):
10. Monotherapy with a SU at the doses specified in Table 2. The dose of the SU
monotherapy must have been stable for at least 8 weeks prior to the time of the Screening
visit (V1) and during the period between the Screening visit (V1) and randomization.
Table 2.
Minimum Daily Doses of SU for Entry into Sub-Studies
Drug
Minimum Daily Doses of SU
Glyburide (Glibenclamide)
10 mg
Micronized Glyburide
6 mg
Glipizide
10 mg
Gliclazide (immediate-release)
160 mg
Gliclazide (modified-release)
60 mg
Glimepiride
4 mg
Acetohexamide
750 mg
Tolbutamide
1500 mg
Tolazamide
500 mg
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the trial:
1. Subjects who had been previously randomized into this trial.
2. Subjects experiencing a cardiovascular event (eg, myocardial infarction or stroke) or 
undergoing coronary angioplasty or peripheral intervention procedure between the 
Screening visit (V1) and randomization.
3. Subjects undergoing any cardiovascular surgery (eg, valvular surgery) within 3 months 
(90 days) of the Screening visit (V1).
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4. Subjects with any planned coronary revascularization or peripheral intervention 
procedure or other cardiovascular surgery.
5. Subjects with New York Heart Association (NYHA) Class IV heart failure at the 
Screening visit (V1).
6. Mean value for triplicate screening sitting systolic blood pressure >160 mm Hg and/or 
diastolic blood pressure >90 mm Hg after at least a 5-minute seated rest at the Screening
visit (V1), confirmed via 1 repeat triplicate set at the Screening visit (V1) if deemed 
necessary. For subjects with a mean triplicate value of sitting systolic blood pressure 
>160 mm Hg and/or diastolic blood pressure >90 mm Hg after at least a 5-minute seated 
rest at the Screening visit (V1) the investigator or the treating physician is allowed to 
adjust background blood pressure medication(s) to lower blood pressure values in order 
for the subject to be re-assessed for enrollment eligibility.
7. Subject has a clinically significant electrocardiogram (ECG) abnormality at Screening 
visit (V1) that requires further diagnostic evaluation or intervention (eg, new, clinically 
significant arrhythmia or a conduction disturbance). 
8. History of type 1 diabetes mellitus or a history of ketoacidosis.
9. History of other specific types of diabetes (eg, genetic syndromes, secondary pancreatic 
diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ 
transplant).
10. Subject has active, obstructive uropathy or indwelling urinary catheter.
11. Subject has a history of malignancy 5 years prior to signing informed consent, 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 informed 
consent should have no evidence of residual or recurrent disease. 
Note (2) A subject with any history of melanoma, leukemia, lymphoma, or renal cell 
carcinoma is excluded.
12. Subject 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.
13. Any clinically significant malabsorption condition.
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14. Subjects with a known hypersensitivity or intolerance to any SGLT2 inhibitor.
15. Screening fasting plasma or finger-stick glucose >270 mg/dL (15 mmol/L), confirmed by 
a single repeat following counseling on exercise and diet. 
16. History of one or more severe hypoglycemic episodes within 6 months of Screening (V1) 
or a severe hypoglycemic episode occurring during the interval between the Screening 
visit (V1) and randomization.
17. Fasting triglycerides >600 mg/dL (6.78 mmol/L) at Screening (V1), confirmed by a 
single repeat if deemed necessary.  For subjects with fasting triglycerides >600 mg/dL the 
investigator or treating physician is allowed to adjust background lipid altering 
medication(s) to lower fasting triglycerides in order for the subject to be re-assessed for 
enrollment eligibility.
18. Subjects currently taking blood pressure or lipid altering medications that have not been 
on a stable dose for at least 4 weeks prior to randomization. Subjects who require a 
change in blood pressure and/or lipid altering medications to meet the entry criteria 
related to blood pressure and/or triglycerides must be on a stable dose of such therapy for 
at least 4 weeks prior to randomization.
19. Subjects who meet any of the following categories:

Subject is on a weight-loss program and is not weight-stable.

Subject is on a weight-loss medication (eg, orlistat, phentermine/topiramate, 
lorcaserin) and is not weight-stable.

Subject is on other medications associated with weight changes (eg, anti-psychotic 
agents) and is not weight-stable.

Subject has undergone bariatric surgery >12 months prior to Visit 1/Screening and is 
not weight-stable.

Subject has undergone bariatric surgery within 12 months of Screening visit (Visit 1).
Note: Weight-stable is defined as <5% change in body weight in the last 6 months.
20. Subjects currently being treated for hyperthyroidism, subjects on thyroid replacement 
therapy that have not been on a stable dose for at least 6 weeks prior to the Screening 
visit (V1) and/or subjects who have a thyroid stimulating hormone (TSH) outside of the 
laboratory reference range at the Screening visit (V1). Subjects excluded due to TSH 
criterion may be re-tested after being on a stable thyroid replacement regimen for at least 
6 weeks.
21. eGFR <30 mL/min/1.73 m2 as determined by the 4-variable Modification of Diet in 
Renal Disease (MDRD) equation, confirmed via a single repeat if deemed necessary.
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22. Subjects with a hemoglobin <10 g/dL (100 g/L).  Confirmed via a single repeat if deemed 
necessary.
23. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 X the upper 
limit of normal (ULN) at the Screening visit (V1), or a total bilirubin >1.5 X the ULN 
unless the subject has a history of Gilbert’s.
24. Subject has a medical history of active liver disease (other than non-alcoholic hepatic 
steatosis), including chronic active hepatitis B or C (assessed by medical history), 
primary biliary cirrhosis, or symptomatic gallbladder disease.
25. Subject is on or likely to require treatment for 14 consecutive days or repeated courses 
of pharmacologic doses of corticosteroids. These medications are not to be used from the 
time of the start of the Day 1 Visit (Visit 2) to the completion of the trial.
Note: Inhaled, nasal, and topical corticosteroids and physiological replacement doses of 
adrenal steroids are permitted.
26. The following therapeutic agents are prohibited for the duration of the trial.  These 
medications are not to be used from 8 weeks before the Screening visit (V1) until the 
completion of the trial.

Treatment with another SGLT2 inhibitor;

Treatment with rosiglitazone;

Treatment with chlorpropamide.
27. Subjects who have donated blood or blood products within six weeks of Screening (V1)
or who plan to donate blood or blood products at any time during the trial.
28. Subjects who have undergone a surgical procedure within 4 weeks prior to signing 
informed consent or have planned major surgery during the trial.  Note: A subject who 
has undergone minor surgery within the 4 weeks prior to Screening Visit (V1) 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.  For exclusion 
regarding cardiovascular surgery, see exclusion criterion #3.
29. Subjects with:

Known history of Human Immunodeficiency Virus (HIV);

Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells.
30. At randomization, subject 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 or medication during the pre-randomization period which 
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meets any previously described trial exclusion criterion or which, in the opinion of the 
investigator, exposes the subject to risk by enrolling in the trial.
31. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality
at the Screening visit (V1) that may increase the risk associated with trial participation or 
investigational product administration or may interfere with the interpretation of trial
results and, in the judgment of the investigator, would make the subject inappropriate for 
entry into this trial.
32. Subjects who have previously been randomized in a trial with ertugliflozin.
33. Participation in other studies involving investigational drug (s) (Phases 1-4) within 
30 days before the Screening visit (V1) and/or during trial participation.
34. Subject is pregnant or breast-feeding, or is expecting to conceive during the trial, 
including 14 days following the last dose of blinded investigational product.
35. Subject is expecting to undergo hormonal therapy in preparation to donate eggs during 
the period of the trial, including 14 days following the last dose of blinded investigational 
product.
36. Subjects who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer/Merck employees directly involved in the conduct 
of the trial.
4.2.1. Exclusion Criteria – Specific to Insulin with or without Metformin Add-on 
Glycemic Sub-Study
In addition to above mentioned exclusion criteria for the main cardiovascular study, subjects 
will not be eligible to be enrolled in this sub-study if they meet any of the following 
additional exclusion criteria at the time of the Screening visit (V1):
37. Subjects using prandial insulin alone without basal insulin.
4.3. Randomization Criteria
Subjects will be assigned a unique identifier via IVRS at the Screening visit (V1), which will 
be retained throughout the duration of participation in the trial. Subjects will be randomized 
into the trial at Day 1 visit (V2), provided that they have satisfied all subject eligibility 
criteria.  Eligibility criteria are outlined in Section 4.1, Section 4.1.1 and Section 4.1.2, and 
should be verified at the Screening visit (V1) and at the Day 1 visit (V2).  A 
computer-generated randomization code using the method of random permuted blocks will 
be utilized to assign subjects to 1 of 3 treatment regimens (5 mg ertugliflozin once daily, 
15 mg ertugliflozin once daily or matching placebo) on Day 1 visit (V2).  For subjects 
enrolled under the original protocol, the randomization will be stratified by sub-study and by 
geographic region (within sub-study).  The stratification factor for sub-study will have four
levels: subjects entering the insulin with or without metformin sub-study on a background of 
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insulin alone, subjects entering the insulin with or without metformin sub-study on a 
background of insulin plus metformin, subjects entering the SU monotherapy sub-study and 
subjects entering the main cardiovascular study but not any of the aforementioned 
sub-studies. For subjects enrolled under Amendment 1, the randomization will be stratified 
by geographic region only.
4.4. Life Style Guidelines
4.4.1. Dietary Restrictions

Subjects must abstain from all food and drink (except water) at least 10 hours prior to 
any blood sample collection for clinical laboratory tests and fasting glucose testing.

Subjects who do not fast before a scheduled clinic visit will be required to return 
fasting for a clinic visit within 7 days.

On scheduled outpatient visits to the site, subjects must be instructed to arrive 
without having taken the dose of investigational product or any other AHA (if 
applicable).  Other medications may be administered prior to the clinic visit if they 
can be administered without food.  On clinic visit days, subjects may eat to break 
their fast after the collection of weight, completion of laboratory procedures and 
blood pressure and pulse rate per the Schedule of Activities.  Other AHA therapy 
should be administered after the subject has consumed a meal, if applicable.

Subjects will be counseled on appropriate dietary and lifestyle guidelines for T2DM 
at Day 1 visit (V2) and asked to follow the advice throughout participation in the trial.  
Counseling on dietary guidelines should be in accordance with local medical 
standards of care for subjects with T2DM, further details in Section 6.1.2.
4.4.2. Physical Activity
Subjects must not engage in physically strenuous exercise (for example: heavy lifting, weight 
training, calisthenics, or aerobics) within 48 hours before each blood sample collection for 
clinical laboratory tests for the duration of their participation in the trial.
4.4.3. Alcohol, Caffeine and Tobacco

Intake of alcohol should be limited (refer to Exclusion 12 for acceptable amount of 
alcohol consumption).

Ingestion of caffeine will be prohibited for at least 30 minutes prior to scheduled 
electrocardiogram and blood pressure determinations.

Ingestion of nicotine-containing products will be prohibited for at least 30 minutes 
prior to scheduled electrocardiogram and blood pressure determinations.
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4.4.4. Contraception
Only female subjects of non-childbearing potential as per Section 4.4.4.1, and females of 
childbearing potential who agree to use adequate methods of contraception, as outlined 
below in Section 4.4.4.2, will be allowed to enroll in this trial.
4.4.4.1. Females – Non-childbearing Potential
To be considered as non-childbearing potential, female subjects must meet at least one of the 
following criteria:
1. Postmenopausal: defined as at least 12 months with no menses in women ≥45 years of 
age; or
2. Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or 
occlusion at least 6 weeks prior to the Screening visit (V1).
4.4.4.2. Females of Childbearing Potential
Non-pregnant, non-breast-feeding women may be enrolled if they are considered highly 
unlikely to conceive.  Highly unlikely to conceive is defined as (1) surgically sterilized, 
(2) postmenopausal, (3) not heterosexually active for the duration of this trial (this form of 
birth control must be accepted by local regulatory agencies and review committees as the 
sole method of birth control), or (4) heterosexually active and agrees to use (or their partner 
use) two acceptable methods of contraception to prevent pregnancy within the projected 
duration of the trial and for 14 days after the last dose of investigational product.
Subjects need to affirm that they meet the criteria for correct use of at least 2 of the selected 
methods of contraception.  The investigator or his or her designee will discuss with the 
subject the need to use highly effective contraception consistently and correctly according to 
the schedule of activities and document such conversation in the subject’s chart.  In addition, 
the investigator or his or her designee will instruct the subject to call immediately if a 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
subject or the subject’s partner.  
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 contraceptive sponge and a condom.

Use of hormonal contraception (any registered and marketed contraceptive agent that 
contains an 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).
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
Vasectomy with one of the following: diaphragm with spermicide; cervical cap; 
contraceptive sponge; condom; IUD; or hormonal contraception (see above).
4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the trial contact list provided to each site.
To facilitate access to appropriately qualified medical personnel on trial related medical 
questions or problems, subjects are provided with a contact card after signing the ICD.  The 
contact card contains, at a minimum, protocol and investigational compound identifiers, 
subject study number, contact information for the investigational site and contact details for a 
contact center in the event that the investigational site staff cannot be reached to provide 
advice on a medical question or problem originating from another healthcare professional not 
involved in the subjects participation in the trial.  The contact number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however it 
should only be used in the event that the established communication pathways between the 
investigational site and the trial team are not available.  It is therefore intended to augment, 
but not replace the established communication pathways between the investigational site and 
study team for advice on medical questions or problems that may arise during the trial.  The 
contact number is not intended for use by the subject directly and if a subject calls that 
number they will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
Approximately 8000 subjects will be randomized in a 1:1:1 ratio to receive 5 mg ertugliflozin 
once daily, ertugliflozin 15 mg once daily or matching placebo.
Allocation of subjects to treatment groups will proceed through the use of a randomization 
system (IVRS or equivalent) that is accessible 24 hours per day, 365 days per year.  The 
dispenser will be required to enter or select the information specified by the IVRS user 
manual. Subject information will be entered into the system starting at the Screening visit
(V1) when the subject will be assigned to a unique identifier which will be retained 
throughout the duration of participation in the trial. On the Day 1 visit (V2), once the 
inclusion, exclusion and randomization criteria have been verified, each subject will be 
provided with a subject randomization number.  Once subject numbers and randomization 
numbers have been assigned, they cannot be reassigned.
The investigator must maintain a log linking the subject screening number and randomization 
number (if applicable) to the subject’s name.  The investigator must follow all applicable 
privacy laws in order to protect a subject’s privacy and confidentiality.  Information that 
could identify a subject will be masked on material received by the sponsor.
5.2. Breaking the Blind
The trial will be subject-, investigator- and sponsor- blinded. 
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At the initiation of the trial, the sites will be instructed on the method for breaking the blind.  
The method will be an electronic process via IVRS.  Blinding codes should only be broken in 
emergency situations for reasons of subject safety.  Whenever possible, the investigator or 
sub-investigator should consult with a member of the sponsor trial team prior to breaking the 
blind.  When the blinding code is broken, the reason must be fully documented and entered in 
the source documents.
5.3. Drug Supplies
5.3.1. Formulation and Packaging
Ertugliflozin 5 mg, ertugliflozin 10 mg and matching placebos will be supplied as immediate 
release tablets for oral administration.  Tablets will be packaged into bottles. 
Pfizer will provide investigator sites with sufficient amounts of blinded investigational 
product to accommodate expected recruitment.  Investigational product will be assigned to 
subjects via IVRS or equivalent.
All investigational product containers dispensed to subjects should be returned to the 
investigator site at the next clinic visit for assessment of subject compliance and drug 
accountability.
5.3.2. Administration
On Day 1, each subject will be randomly assigned to ertugliflozin 5 mg, ertugliflozin 15 mg, 
or placebo. 
The trial utilizes a double-dummy approach to maintain double-blinding, with a placebo 
tablet matching the ertugliflozin 5 mg tablet and another placebo tablet matching the 
ertugliflozin 10 mg tablet.  Subjects randomized to ertugliflozin 5 mg will be instructed to 
take 1 ertugliflozin 5 mg tablet and 1 placebo tablet matching the ertugliflozin 10 mg tablet 
per day.  Subjects randomized to ertugliflozin 15 mg will be instructed to take 1 ertugliflozin 
5 mg tablet and 1 ertugliflozin 10 mg tablet per day.  Subjects randomized to placebo will 
take 1 placebo tablet matching the ertugliflozin 5 mg tablet and 1 placebo tablet matching the 
ertugliflozin 10 mg tablet per day.  Thus, all subjects will take two tablets each day of 
ertugliflozin/placebo.
The investigational product should be taken orally in the morning at approximately the same 
time of day from Day 1 visit (V2) through to the end of the trial or early termination.  In 
addition, subjects will be instructed to delay the self-administration of investigational product 
and other AHA(s), if applicable, on the days of their visits, when the visit assessments should 
be completed prior to administration.
If a subject misses a dose of investigational product 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 a double dose at the same time or 
on the same day.
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5.3.3. Compliance
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 investigational product.
Compliance for subjects must be assessed for the investigational product by taking the 
subject’s report.
The investigator or designee will counsel subjects who report taking <80% of the prescribed 
investigational product following randomization.  The investigator or designee determine 
factors that resulted in <80% compliance with the investigational product and will take steps 
to improve compliance.  Subjects will continue investigational product but will also be 
counseled on the importance of taking their medication as prescribed. Subject counseling 
will be documented in source documents.
5.4. Drug Storage and Drug Accountability
The blinded investigational product dispensing and accountability will be managed by IVRS 
and monitored by clinical research associates (CRAs) in addition to the investigational 
product inventory monitoring at each site.  The investigator, or an approved representative, 
eg, pharmacist, will ensure that all medication is stored in a secured area, under 
recommended storage conditions, and in accordance with applicable regulatory requirements. 
Storage conditions stated in the SRSD [Investigator Brochure’s (IB)] will be superseded by 
the conditions stated on the investigational product label.
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product(s).  Pfizer or its designee may supply drug 
accountability forms that must be used or may approve use of standard institution forms. 
At the end of the trial, Pfizer or its designee will provide instructions as to disposition of any 
unused investigational product.  If Pfizer or its designee authorizes destruction at the study 
site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer or its designee.  Destruction must be adequately documented. 
5.5. Concomitant Medication(s)
All AHA(s) received by the subject at any time prior to the Screening visit (V1) and 
non-AHA(s) taken within 8 weeks before the Screening visit (V1), during the interval 
between the Screening period and randomization and those taken throughout the trial will be 
recorded on the appropriate electronic case report form (eCRF). The site may rely on subject 
report for this information.  All subjects must be questioned about concomitant medication at 
each visit.
Medications that are indicated as prohibited in the Exclusion Criteria must not be used within 
8 weeks before the Screening visit (V1) during the interval between the Screening period and 
randomization or during the trial as specified in Section 4.2.
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5.5.1. Treatment for Glycemic Control for Type 2 Diabetes
To enable an assessment of the glycemic effects of ertugliflozin (or dietary and exercise 
counseling alone for subjects randomized to placebo), doses of background AHA 
medications will be required to be held constant in all subjects enrolled in this trial for the 
initial 18 weeks of the trial with two exceptions:  
First, subjects will be prescribed glycemic rescue therapy if they meet specific, progressively 
more stringent, glycemic thresholds (see Table 3) based on a repeated, confirmed FPG 
measured by the central lab according to the directions below.  Subjects who require a 
repeat FPG to determine if they meet the criterion for glycemic rescue therapy should have 
the repeat FPG measurement performed as early as possible (within approximately 7 days 
following the receipt of initial test results).
Second, a subject experiencing clinically significant hypoglycemia according to the 
investigator at any time during the trial is permitted to have the dose of appropriate 
background AHA (eg, insulin, SU, glinide) reduced or discontinued as per the judgment of 
the investigator or the treating physician.
Choice and dosing of glycemic rescue will be at the discretion of the investigator or the 
treating physician and they will be responsible for managing the initiation and titration of the 
glycemic rescue therapy consistent with standards of care for management of patients with 
T2DM within the country of the investigational site. If glycemic rescue therapy is initiated 
by the investigator it can be initiated at a scheduled or unscheduled visit but not during a 
telephone call.  For details on the Glycemic Rescue Visit see Section 6.5. 
Following the Week 18 visit (V5), the investigator/treating physician is able to make any 
changes in the subject’s AHA treatment regimen to achieve an appropriate HbA1c level for 
the subject (with exception of prohibited concomitant medications listed in Section 4.2).
Details on the specific glycemic rescue criteria for the initial 18 weeks of the trial are 
provided in Table 3 below.
Table 3.
Glycemic Rescue Criteria for All Subjects for the First 18 Weeks
Randomization through Week 6
FPG >270 mg/dL (15.0 mmol/L)
After Week 6 through Week 12
FPG >240 mg/dL (13.3 mmol/L)
After Week 12 through Week 18
FPG >200 mg/dL (11.1 mmol/L)
Subjects who receive glycemic rescue therapy will continue taking investigational product 
for the duration of the trial unless they meet withdrawal criteria as per Section 6.7.4.
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5.5.2. Treatment for Secondary Prevention of Cardiovascular Disease
Subjects may be administered other medications necessary for the treatment of concomitant 
medical disorders, particularly other disorders that are cardiovascular risk factors, including 
but not limited to hypertension and dyslipidemia.  Attention should be placed on appropriate 
use of medications recommended in local country or national guidelines including
anti-platelet therapy, statins and angiotensin-converting enzyme (ACE) inhibitors.  Smokers 
should be counseled to quit and receive treatment if needed.
Subjects enrolled in this trial should continue to be treated by their treating physician who 
normally manages their cardiovascular disease and prescribes medication for the subject´s
cardiovascular disease.  The investigator or the treating physician is able to make any 
changes in the subject’s background cardiovascular treatment regimen to achieve appropriate 
targets for secondary disease prevention at any time during the trial. 
All concomitant medication administration will be recorded on the eCRF.
6. STUDY PROCEDURES
The same visit schedule will be followed by all subjects, those in the main 
cardiovascular study and those in the sub-studies.
Centers should attempt to schedule each subject’s visits at approximately the same time 
of day for that subject.
Recommended visit windows are detailed for each visit in the corresponding sections.
For the procedures described below, where multiple procedures are scheduled at the same 
visit, the following chronology of events should be adhered to, where possible:

12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing.

Vital Signs (blood pressure and pulse rate): obtain after 12-lead ECG collection but 
prior to obtaining blood samples and prior to dosing.

Fasting blood and urine samples: prior to dosing but after assessment of 12-lead 
ECG, and vital signs.

Other procedures: all other procedures may be obtained before or after blood 
specimen collection.
6.1. Instructions to Subjects
At the Day 1 visit (V2), subjects will be given the following instructions/guidance to be 
complied with for the duration of their participation in the trial and provided the following or 
similar items to aid in the management of their T2DM (provided to the sites by the sponsor):
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
Home glucose monitoring supplies including a sponsor-provided glucose meter and 
accompanying supplies;

Hypoglycemia Assessment Log and Self –Monitoring Blood Glucose log to be 
completed at home and brought to each outpatient visit to the site along with the 
glucose meter;

Instructions for home glucose monitoring:

Recommended frequency for routine home glucose monitoring will be determined 
for each subject by the investigator.

Home glucose monitoring should also be undertaken in the event that subjects
experience symptoms of hyperglycemia or hypoglycemia. 
6.1.1. Dispense Hypoglycemia Assessment Log and Instruct on Hypoglycemia 
Symptoms and Management
At Day 1 visit (V2), the site will review the symptoms and management of hypoglycemia 
with the subject.  The site will counsel the subject to perform a fingerstick glucose 
measurement if any symptoms occur that may be related to hypoglycemia (eg, 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 for any 
symptomatic episode he or she believes may represent hypoglycemia.  If a fingerstick 
glucose has been obtained before or shortly (ie, within a few minutes) after treatment, 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 
clinical symptoms.
Subjects should be instructed to contact the investigational site to report:

Any episode of hypoglycemia for which assistance was required (ie, severe 
hypoglycemia);

Any episode of fingerstick glucose 70 mg/dL (3.9 mmol/L) with or without 
symptoms.
Note: As indicated, subjects will record symptoms and/or fingerstick glucose measurements 
that they believe are related to hypoglycemia in the log.  Each episode should be evaluated 
by the investigator and recorded on the Hypoglycemia Assessment (HA) eCRF.  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 
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 
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hypoglycemia considered by the investigator to be an adverse event should also be reported 
on the adverse event eCRF.
6.1.2. Diet and Exercise Counseling
Subjects will be seen by a dietician or qualified healthcare professional for dietary and 
exercise counseling at Day 1 visit (V2) only; monitoring at other visits may be done by other 
appropriate site personnel evaluating the subject.
At Day 1 visit (V2), the subject will receive counseling on diet consistent with local 
guidelines.  At each subsequent visit, the subject will be asked about their diet and exercise.  
Detailed dietary information will not be captured.
Subjects will be counseled to maintain a medically appropriate, routine exercise program; 
consistency in physical activity levels will be encouraged throughout the trial.
6.2. Screening
6.2.1. Screening (Visit 1)
As subjects must be fasting for the Screening visit (V1), it is permissible that the ICD is 
signed by the subject prior to the Screening visit (V1).  Because some of the laboratory data 
at the Screening visit (V1) can be repeated (see Exclusion Criteria Section 4.2), the Screening 
visit (V1) may actually occur over several days.
Subjects will be instructed to arrive at the site after a minimum 10-hour fast (except water) 
in order to have the blood tests done at the Screening visit (V1).  At this visit, the following 
procedures will be completed to confirm that they meet the eligibility criteria for this trial:

Obtain informed consent if not obtained previously (Section 12.3).  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. 

Contact IVRS.

Collect demography, medical history including cardiac ejection fraction (if available) 
for all subjects, smoking status, as well as concomitant medications used.

Measure body weight and height in duplicate (Section 7.4).

Obtain 12-lead ECG (Section 7.5).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Perform an optional fingerstick HbA1c assessment while at the site.  The fingerstick 
HbA1c cannot substitute for a central laboratory measurement to determine subject 
eligibility.

Obtain blood and urine specimens for:
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
Chemistry (Section 7.9);

Hematology (Section 7.9);

Urinalysis (Section 7.9);

Fasting triglycerides and TSH (Section 7.9);

HbA1c and FPG (Section 7.9);

Urine pregnancy test for women of child-bearing potential (Section 7.1.6).

Assess eligibility: Adequate documentation of objective evidence that the subject has
established vascular disease must be available prior to Day 1 visit (V2) through the 
investigational site’s medical records, copies of such records from other institutions, 
or a letter from a referring physician that specifically states the diagnosis and date of 
the most recent occurrence of the qualifying event(s) or procedure(s).
6.3. Double-Blind Treatment Period
6.3.1. Visits During Year 1
6.3.1.1. Day 1 (Visit 2) – Randomization Visit
Subjects who meet the trial eligibility based on assessments performed at the Screening visit 
(V1) will return to the clinic at Day 1 visit (V2) for randomization into the trial.  The 
randomization visit, Day 1 visit (V2) is to take place approximately 1 to 4 weeks following 
the Screening visit (V1).  Background AHA treatment must continue to remain stable 
throughout the length of the Screening period. 
Subjects will return to the site after a minimum 10-hour fast (except water) for the Day 1 
visit (V2).  At this visit, the following procedures will be completed:

Review and confirm eligibility criteria.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Complete physical examination (Section 7.3).

Obtain duplicate orthostatic blood pressure and pulse rate measurement 
(supine standing) (Section 7.8).

Obtain triplicate sitting blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:
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
Chemistry (Section 7.9);

Hematology (Section 7.9);

Urinalysis (Section 7.9);

HbA1c and FPG (Section 7.9);

Urinary albumin/creatinine ratio (Section 7.9.2);

Lipid panel (Section 7.9.1);

Urine pregnancy test for women of child-bearing potential (Section 7.1.6);

Whole blood (DNA), plasma and serum for Future Biomedical Research (FBR)
(Appendix 1).  The FBR sample for DNA analysis should be obtained pre dose, at 
the Day 1 visit (V2) as the last sample drawn, on subjects who qualify for 
randomization, but may be obtained at a later date during the trial after the FBR 
informed consent is obtained.

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1).

Subjects will be instructed on exercise and dietary guidelines for management of 
T2DM consistent with local standards of care by a dietician or qualified healthcare 
professional Section 6.1.2.

Subjects will be given a sponsor-provided glucose meter, a self-monitoring blood 
glucose log and needed supplies to enable them to perform fingerstick blood glucose 
self- monitoring at home. Subjects should be instructed on how to complete the log 
(Section 6.1). 

As a means of confirming subject´s understanding of the instructions, subject will 
perform a fasting fingerstick blood glucose assessment while at the site.

Subjects will be educated on the symptoms of hyperglycemia (ie, polyuria, 
polydipsia) and instructed to call the site should these symptoms occur and/or worsen 
before next visit. 

Subjects will be given a hypoglycemia assessment log that they must use to track 
episodes of hypoglycemia. Subjects should be educated on the symptoms and 
management of hypoglycemia (Section 6.1.1). 

Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event.
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
Register/randomize the subjects into trial using IVRS (Section 4.3 and Section 5.1).

Provide subjects with study contact card (Section 4.5).

Subjects will be administered the first witnessed dose of investigational product
before leaving the site.

Subjects will be provided with investigational product to last until the next visit.
6.3.1.2. Week 6 (Visit 3)
At Week 6 7 days relative to Day 1 visit (V2), subjects will return to the site after a 
minimum 10-hour fast (except water).  At this visit, the following procedures will be 
completed:

Contact IVRS.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Obtain duplicate orthostatic blood pressure and pulse rate measurement 
(supine standing) (Section 7.8).

Obtain triplicate sitting blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:

Chemistry (Section 7.9);

Hematology(Section 7.9);

HbA1c and FPG (Section 7.9);

Urine pregnancy test for women of child-bearing potential (Section 7.1.6);

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1);

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6);
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
Diet and exercise monitoring (Section 6.1.2);

Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event.
Following completion of the above procedures:

Provide subjects with glucose meter supplies and additional self-monitoring blood 
glucose and hypoglycemia assessments logs as needed;

Subjects will be provided investigational product to last until the next visit.
6.3.1.3. Week 12 (Visit 4)
At Week 12 7 days relative to Day 1 visit (V2), subjects will return to the site after a 
minimum 10-hour fast (except water).  At this visit, the following procedures will be 
completed:

Contact IVRS.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:

Chemistry (Section 7.9);

HbA1c and FPG (Section 7.9);

Urine pregnancy test for women of child-bearing potential (Section 7.1.6).

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1).

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6).

Diet and exercise monitoring (Section 6.1.2).
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
Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event.
Following completion of the above procedures:

Provide subjects with glucose meter supplies and additional self-monitoring blood 
glucose and hypoglycemia assessments logs as needed.

Subjects will be provided with investigational product to last until the next visit.
6.3.1.4. Week 18 (Visit 5)
At Week 18 7 days relative to Day 1 visit (V2), subjects will return to the site after a 
minimum 10-hour fast (except water).  At this visit, the following procedures will be 
completed:

Contact IVRS.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Obtain 12-lead ECG (Section 7.5).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:

Chemistry (Section 7.9);

Hematology(Section 7.9);

Urinalysis(Section 7.9);

HbA1c and FPG (Section 7.9);

Urinary albumin/creatinine ratio (Section 7.9.2);

Lipid panel (Section 7.9.1);

Urine pregnancy test for women of child-bearing potential (Section 7.1.6);

Plasma and serum for Future Biomedical Research.
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
Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1).

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6).

Diet and exercise monitoring (Section 6.1.2).

Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event.
Following completion of the above procedures:

Provide subjects with glucose meter supplies and additional self-monitoring blood 
glucose and hypoglycemia assessments logs as needed.

Subjects will be provided with investigational product to last until the next visit.
6.3.1.5. Week 26 (Visit 6)
At Week 26 7 days relative to Day 1 visit (V2), subjects will return to the site after a 
minimum 10-hour fast (except water).  At this visit, the following procedures will be 
completed:

Contact IVRS.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Obtain duplicate orthostatic blood pressure and pulse rate measurement 
(supine standing) (Section 7.8).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:

Chemistry (Section 7.9);

Hematology (Section 7.9);

Urinalysis (Section 7.9);
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
HbA1c and FPG (Section 7.9);

Urine pregnancy test for women of child-bearing potential (Section 7.1.6).

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1).

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6).

Diet and exercise monitoring (Section 6.1.2).

Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event.
Following completion of the above procedures:

Provide subjects with glucose meter supplies and additional self-monitoring blood 
glucose and hypoglycemia assessments logs as needed.

Subjects will be provided with investigational product to last until the next visit.
6.3.1.6. Week 39 (Visit 7)
At Week 39 14 days relative to Day 1 visit (V2), subjects will return to the site after a 
minimum 10-hour fast (except water).  At this visit, the following procedures will be 
completed:

Contact IVRS.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:

Chemistry (Section 7.9),

HbA1c and FPG (Section 7.9),
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
Urine pregnancy test for women of child-bearing potential (Section 7.1.6).

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1).

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6).

Diet and exercise monitoring (Section 6.1.2).

Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event.
Following completion of the above procedures:

Provide subjects with glucose meter supplies and additional self-monitoring blood 
glucose and hypoglycemia assessments logs as needed.

Subjects will be provided with investigational product to last until the next visit.
6.3.1.7. Week 52 (Visit 8)
At Week 52 14 days relative to Day 1 visit (V2), subjects will return to the site after a 
minimum 10-hour fast (except water). At this visit, the following procedures will be 
completed:

Contact IVRS.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Brief physical examination (Section 7.3).

Obtain 12-lead ECG (Section 7.5).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:

Chemistry (Section 7.9);
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
Hematology (Section 7.9);

Urinalysis (Section 7.9);

HbA1c and FPG (Section 7.9);

Urinary albumin/creatinine ratio (Section 7.9.2);

Lipid panel (Section 7.9.1);

Urine pregnancy test for women of child-bearing potential (Section 7.1.6);

Plasma and serum for Future Biomedical Research.

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1).

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6).

Diet and exercise monitoring (Section 6.1.2).

Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event.
Following completion of the above procedures:

Provide subjects with glucose meter supplies and additional self-monitoring blood 
glucose and hypoglycemia assessments logs as needed.

Subjects will be provided with investigational product to last until the next visit.
6.3.2. Visits Following Year 1
Following the first year of double-blind treatment, subjects will return for clinic visits after a 
minimum 10-hour fast (except water) on an every 4 month 1 month period (ie, Months 16, 
20, 24, 28, 32, 36, 40, 44, 48, 52, 56 and 60) until completion of the trial; where completion 
is the occurrence of the required number of adjudicated primary cardiovascular endpoints.
The procedures to be completed at these visits are as follows:

Contact IVRS – All visits.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed. – All visits.
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Update concomitant medications since last visit – All visits.

Measure body weight in duplicate (Section 7.4) – All visits.

Brief physical examination (Section 7.3) – Months 24, 36, 48, 60.

12-Lead ECG (Section 7.5) – Months 24, 36, 48, 60.

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7) –
All visits.

Obtain blood and urine specimens for:

HbA1c and FPG (Section 7.9) – All visits.

Chemistry (Section 7.9) – All Visits.

Hematology (Section 7.9) – Months 24, 36, 48, 60.

Urinalysis (Section 7.9) – Months 24, 36, 48, 60.

Urinary albumin/creatinine ratio (Section 7.9.2) – Months 24, 36, 48, 60.

Lipid panel (Section 7.9.1) – Months 24, 36, 48, 60.

Urine pregnancy test for women of child-bearing potential (Section 7.1.6) – All 
visits.

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?” – All visits.

Assessment of potential cardiovascular event(s) (Section 7.1) – All visits.

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6) – All visits.

Diet and exercise monitoring (Section 6.1.2). – All visits.

Subjects will be instructed to contact the site if they are admitted to hospital for any 
reason or if they experience a cardiovascular event – All visits.

Provide subjects with glucose meter supplies and additional self-monitoring blood 
glucose and hypoglycemia assessments logs as needed. – All visits, (except End of 
Study or Early Termination visits).

Subjects will be provided with investigational product to last until the next visit – All 
visits (except End of Study or Early Termination visits).
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If the trial is not complete by Visit 20 (Month 60), visits will continue on an every 
4 month 1 month schedule and the list of procedures to be performed are the same as for
the visits for Months 52, 56 and 60 respectively.  For example, assessments at Month 64 are 
identical to Month 52, assessments at Month 68 are identical to Month 56 and assessments at 
Month 72 are identical to Month 60.
6.3.3. End of Study Visit/Early Termination Visit
The trial sponsor will provide the best estimate of when the pre-specified required number of 
adjudicated primary cardiovascular endpoints has occurred in the trial.  After the sponsor
recommendation to close the trial, all investigators will receive communication with a 
recommendation to contact trial subjects for completion of an End of Study Visit.  Subjects 
who complete the trial on investigational product or those who discontinue investigational 
product prematurely, should complete the procedures listed below even if they are not taking 
investigational product when the trial is terminated. 
The following procedures will occur at this visit after a minimum 10-hour fast (except 
water):

Contact IVRS.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Brief physical examination (Section 7.3).

12-Lead ECG (Section 7.5).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Obtain blood and urine specimens for:

Chemistry (Section 7.9);

Hematology (Section 7.9);

Urinalysis (Section 7.9);

HbA1c and FPG (Section 7.9);

Urinary albumin/creatinine ratio (Section 7.9.2);

Lipid panel (Section 7.9.1);
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
Urine pregnancy test (women of childbearing potential) (Section 7.1.6);

Plasma and serum for Future Biomedical Research.

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1).

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6).

Diet and exercise monitoring (Section 6.1.2). 
6.4. Follow-up Phone Call
Each randomized subject should have a follow-up phone call 14 days after the last dose of 
investigational product to assess for AEs, SAEs and collect information on clinical events
(Section 7.1), if applicable.  The phone call should be completed within a ± 3 day window. 
6.5. Glycemic Rescue Visit (if Applicable)
Subjects who require glycemic rescue therapy during the first 18 weeks of the trial as per 
Section 5.5.1 will have glycemic rescue therapy initiated at either a scheduled or unscheduled 
visit. Glycemic rescue therapy can also be initiated by a non-study physician.  If glycemic 
rescue therapy is initiated by a non-study physician, subjects should be instructed to inform 
the site. In that case, subjects should be requested to attend the site at an unscheduled visit 
for the relevant laboratory tests/assessments as indicated below. The following procedures 
are to be completed at a Glycemic Rescue Visit:

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Update concomitant medications since last visit.

Measure body weight in duplicate (Section 7.4).

Obtain duplicate orthostatic blood pressure and pulse rate measurement 
(supine standing) (Section 7.8).

Obtain sitting triplicate blood pressure and pulse rate measurements (Section 7.7).

Brief physical examination (Section 7.3).

Obtain blood and urine specimens for:

Chemistry (Section 7.9),
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
Hematology (Section 7.9),

Urinalysis (Section 7.9),

HbA1c (only if visit is at least 6 weeks after randomization) and FPG
(Section 7.9),

Lipid panel (Section 7.9.1),

Urine pregnancy test (women of childbearing potential) (Section 7.1.6),

Plasma and serum for Future Biomedical Research.

Conduct inquiry about any spontaneously reported AEs by asking the subject to 
respond to a non-leading question such as “how do you feel?”

Assessment of potential cardiovascular event(s) (Section 7.1.1).

Review hypoglycemia assessment and self-monitoring blood glucose logs completed 
by the subjects (Section 7.6).

Diet and exercise monitoring (Section 6.1).
6.6. Discontinuation of Investigational Product
All efforts should be made to follow randomized subjects for the entire duration of the 
study.  Discontinuation of investigational product does not imply or constitute 
withdrawal of the subject from the study.
Subjects who temporarily or permanently discontinue treatment with investigational product, 
should remain in the study and continue to be followed for collection of information on 
cardiovascular events, other events eligible for adjudication, and SAEs.  Investigators should 
try to obtain the most complete collection of data as possible, weighing the subject’s 
willingness to participate with the scientific integrity of the protocol.  The protocol offers 
subjects the option of continuing in the study off investigational product by: (1) attending the 
normally scheduled clinic visits; (2) attending the annual clinic visits only; (3) receiving
phone contacts to collect information on cardiovascular events/SAEs, without attending 
clinical visits.  The site phone contacts could occur either at the time of the normally 
scheduled visits or they could occur just annually and/or at the completion of the trial.  The 
sole exception to this requirement is when a subject fully withdraws consent for both 
continued treatment with investigational product and study procedures (see Section 6.7). 
Subjects who have not withdrawn consent, but who have discontinued from investigational 
product may initiate any other therapy as needed (previously prohibited medications may be 
used).  Permanent discontinuation of investigational product must be registered in IVRS.
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As noted above, if a subject has not fully withdrawn consent for further contact with the 
study site, the subject should be encouraged to remain in contact with the investigator, either 
by attending study visits or via phone contacts, throughout the remainder of the study.  The 
study sponsor team will provide to the study site, information regarding a “clinicians’
hotline”, to be used by investigators to contact a member of the study team after a subject 
discontinues investigational product.  The objective of this call is to ensure that investigators 
(and by extension subjects) are aware of the importance of continued follow-up in the study 
after investigational product discontinuation and of the multiple options available for 
continued study participation.  Every effort must be made to retain subjects in the study, even 
if they are no longer taking investigational product as it is important to the scientific integrity 
of the protocol.
6.7. Subject Withdrawal
6.7.1. Withdrawal of Consent
Subjects who request to discontinue investigational product will remain in the study and must 
continue to be followed as outlined in Section 6.6.  The only exceptions to this are when a 
subject specifically withdraws consent for any further contact with him/her or persons 
previously authorized by the subject to provide this information, or when a subject dies.  
Subjects should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal represents the 
discontinuation from further treatment with investigational product only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page.  
As vital status (whether the subject is alive or dead) is being measured in this study, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site.  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 are reasons for 
withdrawal of consent.  In such circumstances, subjects should be encouraged to remain in 
contact with the investigator, either by attending study visits or via phone contacts
throughout the remainder of the study as described in Section 6.6 in order to provide safety 
information as it occurs.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  When a subject has missed a scheduled visit, every attempt should be made to 
contact him/her, to reschedule the visit, by phone, e mail, text message, and if necessary, by 
letter and/or certified mail, in instances where the subject is not responsive to contact 
attempts.  The study team must be contacted, ideally through the “clinicians’ hotline”, to 
discuss strategies available for assistance with locating subjects who are potentially lost to 
follow-up.  All efforts to retain a subject should continue throughout the course of the study 
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and should be documented in the subject’s medical source record.  No subject should be 
considered lost to follow-up, until the study has been completed.  In any circumstance, every 
effort should be made to document subject outcome, if possible.  The investigator should 
inquire about the reason for study drug discontinuation, request that the subject return all 
unused investigational product, request that the subject to return for a final visit, if 
applicable, and follow up with the subject regarding any unresolved AEs.
Every effort should be made to ensure that all subjects complete study participation.  
Subjects who discontinue study treatment will be asked and encouraged to continue 
participation in the study as described above. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
6.7.2. Avoiding Lost to Follow-Up
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  When a subject has missed a scheduled visit, every attempt should be made to 
contact him/her, to reschedule the visit, by phone, e mail, text message, and if necessary, by 
letter and/or certified mail, in instances where the subject is not responsive to contact 
attempts.  The study team must be contacted, ideally through the “clinicians’ hotline”, to 
discuss strategies available for assistance with locating subjects who are potentially lost to 
follow up.  All efforts to retain a subject should continue throughout the course of the study 
and should be documented in the subject’s medical source record.  No subject should be 
considered lost to follow up, until the study has been completed.  In any circumstance, every 
effort should be made to document subject outcome, if possible.  The investigator should 
inquire about the reason for study drug discontinuation, request that the subject return all 
unused investigational product, request that the subject to return for a final visit, if 
applicable, and follow up with the subject regarding any unresolved AEs.
Lost to follow-up is defined by the inability to reach the subject by the end of the study only.  
All reasonable efforts must be made to locate subjects who miss scheduled study visits to 
determine and report their ongoing status.  Sites should make at least three attempts for a 
telephone contact.  If the three attempts of telephone contact are unsuccessful, sites should 
make at least two attempts to reach the subject via certified letter.  Procedures will be put in 
place and described in the Informed Consent Document to ensure that if a subject loses 
contact with the trial site, alternative measures will be utilized for the follow-up portion of 
the study including the collection of information on cardiovascular events.  This may include 
contacting family members and health care providers and, when applicable, using subject 
location services.  Continued attempts to contact the subject must be performed, until the 
study is completed.  This includes follow-up with persons authorized by the subject as noted 
above.  All attempts at contacting the subject must be documented in the subject’s medical 
records. 
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If it is determined that the subject has died, the site will use permissible local methods to 
obtain the date and cause of death.  If after all attempts, the subject remains lost to follow-up, 
then the last known alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
6.7.3. 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 
(clinical.specimen.management@merck.com), 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 (eg, if the 
investigator is no longer required by regulatory agencies 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. 
6.7.4. Reasons for Discontinuation from Investigational Product or from the Trial
The investigator or sub-investigator is able to interrupt or discontinue investigational product
if he/she feels that interruption or discontinuation is necessary for safety or behavioral
reasons.  The investigational product can also be restarted based on the judgment of the 
investigator.  Notably, occurrence of a non-fatal cardiovascular event or a SAE should not 
automatically result in interruption or discontinuation of investigational product and the 
subject should continue to receive investigational product unless interruption or 
discontinuation is deemed to be clinically necessary.
Reasons for protocol-specified discontinuation from the investigational product or from the 
trial are listed, but not limited to, below.  All subjects will be followed until resolution (ie,
return to baseline values or diagnosis determined or new stable state established, based upon 
investigator and sponsor or its designated representative assessment) for any laboratory 
safety test abnormality resulting in discontinuation from investigational product.
Withdrawal from the Trial
1.
Subject requests withdrawal from the trial.
2. Death.
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Discontinuation of Investigational Product
3. Elevation in ALT and/or AST that meet the definition of a potential Case of 
Drug-Induced Liver Injury per Section 8.7.
4. Parameters of Renal Function: Investigational product is to be discontinued if the eGFR 
falls to <15 mL/min/1.73m2 and where the value is confirmed by a second measurement.  
Additionally, any subject who requires renal replacement therapy will also have 
investigational product discontinued.
A confirmed value is defined as a repeat measurement performed within 7 days of 
notification from the central laboratory of the initial results.
5. Requirement for one of the prohibited medications listed in Section 4.2.
6. Pregnancy.
Note: A positive urine pregnancy test requires immediate interruption of investigational 
product until serum human chorionic gonadotropin beta-subunit test (-hCG) can be 
performed and found to be negative.  Subject must be permanently discontinued and 
pregnancy should be reported and followed per Section 8.3 if pregnancy is confirmed by 
a positive serum pregnancy test.
7. The investigator or subject becomes aware of the subject’s treatment assignment.
If a subject discontinues investigational product, he/she should complete all Early 
Termination Visit procedures as described in Section 6.3.3 and listed in Schedule of 
Activities.  Unless the consent to follow the subject is specifically withdrawn, the subject will 
continue in the trial off investigational product until the end of the trial as outlined in
Section 6.6.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.
The trial team will be informed of these incidents in a timely fashion.
All biological samples will be assayed by a sponsor-identified laboratory, using an analytical 
method in compliance with standard and validated methodologies, with adherence to written 
standard operating procedures. 
Details regarding the sample processing, handling, storage, and shipment will be offered 
separately in the study-specific central laboratory manual prior to the initiation of the trial.
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7.1. Clinical Event Adjudication
7.1.1. Cardiovascular Events, Venous Thromboembolic Events, and All Deaths
Cardiovascular disease is a major cause of mortality for subjects with T2DM.  In order to 
evaluate the cardiovascular safety of ertugliflozin and to meet regulatory requirements for the 
assessment of cardiovascular safety of any new diabetic therapy, serious cardiovascular 
events and all deaths will be adjudicated in this trial (including events from subjects who 
continue to be followed after discontinuation of investigational product), and across the 
Phase 2 and 3 ertugliflozin program.  The EAC will be comprised of an external panel of 
independent physicians experienced in assessing cardiovascular endpoints.  The panel will be 
blinded to treatment assignments.  The members of the EAC will not be an investigator in 
any trial for ertugliflozin.  The events to be adjudicated by the committee include:
1. All deaths;
2. Non-fatal myocardial infarction; hospitalization for chest pain or to rule out myocardial 
infarction, or other hospitalization due to suspected myocardial ischemia where 
myocardial infarction needs to be ruled out;
3. Non-fatal stroke (and all events that may be a stroke including all transient ischemic 
attack (TIA) events, reversible ischemic neurologic deficit (RIND) or other acute 
ischemic cerebrovascular event where stroke needs to be ruled out);
4. Hospitalization for unstable angina;
5. Hospitalization for heart failure;
6. Venous thromboembolism/pulmonary embolus.
The criteria to define clinical cardiovascular events will be detailed in the Endpoint 
Adjudication Committee charter.  All potential clinical cardiovascular events will be 
collected from the first day of double-blind treatment through the end of study (including 
14 day post-dose reporting period) for all randomized subjects who have received at least one 
dose of investigational product.  The collection period will continue through study 
completion/end-of-study whether or not the subject continues to receive investigational 
product unless the subject is unwilling to be contacted by the personnel at the investigational 
site. 
Clinical cardiovascular events occurring between the Screening visit (the time of informed 
consent) and double-blind treatment randomization will not be adjudicated as that subject 
will be excluded from the trial as per Section 4.2.
The identification of a potential clinical cardiovascular event will be made by the trial site or 
by Pfizer or designee.  The site will communicate the event to Pfizer or designee within 
24 hours of awareness of the potential clinical cardiovascular event using the appropriate 
CRF module.  Pfizer or designee will in turn provide a listing of specific documents needed 
to support adjudication by the EAC.  Obtaining documentation will be the responsibility of 
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the trial site.  Documentation will include, but is not limited to any of the following:  hospital 
discharge summaries, operative reports, clinic notes, ECGs, diagnostic cardiac enzymes, 
results of other diagnostic tests, autopsy reports and death certificate information.  The 
adjudication charter will contain additional information on source documents to be collected 
for event adjudication.
7.1.2. Fractures
Spontaneously reported fractures will be adjudicated by an independent and blinded external 
fracture adjudication committee. In the event that a subject experiences a clinical fracture 
during the trial, the radiographs and/or local radiologist report and other relevant 
documentation will be sent to an independent external committee comprised of radiologists.
The radiologists will review the radiograph(s) (if available) and, where applicable the local 
radiologist report and other source documents and confirm the presence of the fracture, 
location of fracture, number of fractures, and type of fracture (ie, high-trauma, low-trauma, 
pathological fracture, stress fracture, and other fracture). The radiologists will not be 
investigators or sub-investigators in any trial in the Phase 3 program and they will be blinded 
to the subject’s assigned treatment group. A Fracture Adjudication Committee charter will 
describe the precise mandates and procedures to be used for the adjudication of clinical 
fractures.
7.1.3. Pancreatitis
Type 2 diabetes is a risk factor for pancreatitis.  As part of the overall assessment of the 
safety profile of ertugliflozin, events of pancreatitis reported in this trial and throughout the 
Phase 3 program will be adjudicated by an independent external panel of physicians 
experienced in assessing pancreatic disease.  The panel will blinded to treatment assignment.  
A Pancreatitis Adjudication Charter will describe the precise mandates and procedures to be 
used for the adjudication of pancreatitis. 
7.1.4. Liver Injury
As hepatic safety is a significant issue in drug development, all events that meet pre-specified 
criteria for potentially important hepatotoxicity will be adjudicated by an external 
independent panel of physicians experienced in assessing liver injury. The panel will be 
blinded to treatment assignment and will assess causality. A Liver Injury Adjudication 
Charter will describe the precise mandates and procedures to be used for assessing liver 
injury and assigning causality. 
7.1.5. Acute Renal Failure
Ertugliflozin increases urinary glucose excretion leading to an osmotic diuresis, and has the 
potential to reduce estimated GFR. As part of the overall assessment of renal safety, events 
reported in this trial and throughout the phase 3 program that meet pre-specified criteria for 
potentially important renal failure events will be adjudicated by an external independent 
panel of physicians experienced in adjudication of renal events. The panel will be blinded to 
treatment assignment and will assess causality. A Renal Failure Adjudication Charter will 
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describe the precise mandates and procedures to be used for assessing renal failure and 
assigning causality.
7.1.6. Ketoacidosis
Cases of ketoacidosis (KA) have been reported with marketed SGLT2 inhibitors.  Events 
reported in this trial and throughout the program that meet pre-specified criteria for a 
potential ketoacidosis event will be adjudicated by an Internal Case Review Committee 
experienced in diabetes.  The committee will be blinded to treatment assignment.  A 
Ketoacidosis Internal Case Review Committee Charter will describe the precise mandates 
and procedures to be used for the identification and adjudication of events. 
7.2. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL will be performed at the Screening visit (V1), before investigational 
product administration at Day 1 visit (V2) and a positive result may be confirmed with a 
serum pregnancy test.  A negative pregnancy result is required before the subject may receive 
the investigational product.  Pregnancy tests will also be done whenever one menstrual cycle 
is missed during the active treatment period (or when a potential pregnancy is otherwise 
suspected), repeated at visits listed in the Schedule of Activities, and at the end of the trial to 
confirm the subject has not become pregnant during the trial.  In the case of a positive serum 
hCG test, the subject will be discontinued from investigational product but should continue to 
be contacted according to the same schedule as if he/she were still taking investigational 
product, see Section 6.6 for instructions on follow up of subject withdrawal.  Pregnancy tests 
may also be repeated as per request of institutional review boards/ethics committees 
(IRB/IECs) or if required by local regulations.
7.3. Physical Examinations
A complete physical examination will be performed at the Day 1 visit (V2).  A brief physical 
examination including assessment of the heart, lungs, abdomen, extremities, and skin will be 
performed at the times listed in the Schedule of Activities. Abnormalities considered 
clinically significant should be reported as AEs.  Other body systems may be evaluated as per 
judgment of the investigator or as needed to evaluate adverse events.
7.4. 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 “Schedule of Activities” as follows:

Weight will be taken in duplicate throughout the trial at approximately the same time 
of day, after voiding (ie, forced void) and while wearing only a gown and underwear 
(no street clothes, 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 
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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 (eg, 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.
7.5. 12-Lead Electrocardiogram
Single, supine 12-lead ECG will be obtained at the pre-defined nominal time points outlined 
in “Schedule of Activities”.  ECG equipment with an instruction manual will be provided by 
the sponsor.

Subjects will refrain from nicotine-containing products and/or ingesting caffeine for 
at least 30 minutes preceding the ECG collection.

12-lead ECGs should be performed after the subjects have 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.
The Screening visit (V1) ECG should be transmitted to the central vendor for reading and 
interpretation. This screening ECG will serve as the “baseline” ECG for comparison.  All 
ECGs collected during the trial (planned and unplanned) should be reviewed at the 
investigative site for subject safety monitoring, as well as electronically transmitted to a 
central vendor for reading and interpretation centrally.  The investigator is responsible for 
retaining all copies of the ECG reports.
If a subject experiences a non-fatal myocardial infarction after randomization, a new baseline 
ECG should be performed between 6 and 12 weeks following the myocardial infarction at an 
unplanned visit if necessary.
Subject demographic information will be made available to the central reading facility and 
the central reading facility will provide results on heart rate (BPM), overall interpretation, 
rhythm type, and heart rate intervals PR, QRS, QT, QTcB, and QTcF (msec), along with any 
comments.
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7.6. Review of Self-Monitoring Glucose Logs
The site must review and assess the glucose values recorded on the self-monitoring glucose 
logs completed by the subjects at each site visit subsequent to the Day 1 visit (V2). For 
details on the treatment of glycemic control see Section 5.5.1.
7.6.1. Review of Hypoglycemia Assessment Logs
The site must review the hypoglycemia logs completed by the subjects at each site visit 
subsequent to the Day 1 visit (V2). Based on this information, an assessment of any 
symptomatic occurrence of hypoglycemia must be undertaken and appropriate decisions 
should be made by the investigator or the treating physician. For details on the treatment of 
glycemic control see Section 5.5.1.
7.6.2. Management of Hypoglycemia
Subjects will be instructed to check fingerstick glucose when they have symptoms consistent 
with hypoglycemia such as hunger, headache, dizziness, light headedness, sweating, 
palpitations, tachycardia, tremulousness, irritability, blurred vision, and disorientation.  
Subjects should be instructed to call the site should these symptoms occur and/or worsen 
before next visit, see Section 6.1.1.
Any episode of hypoglycemia must be captured on the HA eCRF.  For definition of 
hypoglycemic episode and severity categorization, refer to Section 7.6.3 below.
7.6.3. Definition and Severity Categorization of Hypoglycemic Events
Based on review of the subject completed hypoglycemia logs at each outpatient visit to the 
site, the investigator must assess the glucose values as well as any symptoms documented.  
Each hypoglycemic event must be characterized with respect to severity and type.
Severe Hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure or coma. Fingerstick or plasma 
glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence 
that the event was induced by a low plasma glucose concentration.
Documented Symptomatic Hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by a measured fingerstick or plasma glucose concentration 
70 mg/dL (3.9 mmol/L).
Asymptomatic Hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured fingerstick or plasma glucose concentration 70 mg/dL 
(3.9 mmol/L).
Probable Symptomatic Hypoglycemia: An event during which symptoms of 
hypoglycemia are not accompanied by a fingerstick or plasma glucose determination, but 
was presumably caused by a plasma glucose concentration 70 mg/dL (3.9 mmol/L).  Since 
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many people with diabetes choose to treat symptoms with oral carbohydrate without a test of 
plasma glucose, it is important to recognize these events as probable hypoglycemia. 
7.6.4. Guidance on Adverse Events Related to 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 fingerstick or plasma 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 8.1). 
7.7. Sitting Blood Pressure and Pulse Rate
Triplicate measurement of sitting blood pressure and pulse rate should be performed using an 
automated oscillometric device at all time points noted in the Schedule of Activities.  Site 
personnel should use the same blood pressure measuring device throughout the study for 
each subject.
The following method should be used to record sitting blood pressure and pulse rate in 
triplicate for subjects:

Subjects will 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.

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 should begin after at least 5 minutes of rest.

The three measurements of both the blood pressure and pulse rate must be taken 
approximately 2 minutes apart with the triplicate 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.
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Other procedures should not be performed during the time of the blood pressure and pulse 
rate measurements.
7.8. Postural (Orthostatic) Blood Pressure and Pulse Rate
On the Day 1 visit (V2), Week 6 visit (V3) and Week 26 visit (V6), duplicate measurements 
of supine and standing blood pressure and pulse rate will be taken in order to evaluate 
postural changes in blood pressure and pulse rate.  These measurements will be in addition to 
the sitting blood pressure and pulse rate measurements taken on these clinic visits and 
described above.  Measurement of postural blood pressure and pulse rate will also occur at 
the Glycemic Rescue Visit.
Postural blood pressure changes will be measured according to the following procedure:
First supine measurements:

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).
Second standing measurements:

After the duplicate supine measurements have been performed, 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 performed 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.
7.9. Laboratory Studies
The tests outlined in Table 4 will be performed at the pre-specified time points outlined in the 
SOA following an overnight fast of at least 10 hours (except water).  The FPG and HbA1c 
results from the central laboratory will be masked after randomization through the initial 
18 weeks of the trial for both the sponsor and investigative site unless the results meet 
pre-specified glycemic rescue alert criteria as provided in Section 5.5.1. A confirmatory
plasma glucose value from the central lab on a new plasma sample will be required to make a 
final determination as to whether a subject meets the criteria for glycemic rescue therapy.  
For all alerts that meet rescue criteria, the central laboratory will do a confirmatory test.  If it 
is confirmed that a subject meets glycemic rescue criteria, FPG and HbA1c will be unmasked 
for the remainder of the trial. Following Week 18, HbA1c and FPG results will be reported 
to the investigative sites.  Additionally, during the first 18 weeks of the study, the central 
laboratory will also unmask any FPG 70 mg/dl (3.9 mmol/L) only at that visit.
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Table 4.
Clinical/Safety-Related Laboratory Tests
Hematology
Chemistry 
Urinalysis [b]
Others
Hemoglobin
Hematocrit
RBC Count
Platelet Count
WBC Count
Total Neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Serum Creatinine
eGFR (using MDRD equation)
Ca++ (total)
Na+
K+
Cl-
Total CO2 (Bicarbonate)
Mg++
Phosphate
Uric Acid
AST (SGOT)
ALT (SGPT)
Alkaline Phosphatase
Total bilirubin
Direct (conjugated) bilirubin [a]
Indirect (unconjugated) bilirubin [a]
Albumin
Total Protein
pH
Protein (qual)
Blood (qual)
Ketones
Leukocyte esterase
Nitrites
Microscopy [c]
At Screening visit (V1) only:
- Fasting triglycerides/TSH
At selected visits only 
(refer to): Schedule of 
Activities):
-HbA1c
-FPG
- Urinary albumin/creatinine 
ratio [d]
- Pregnancy tests (where 
applicable)
- Lipid panel (ie, total 
cholesterol, HDL-C, LDL,-C
triglycerides, non-HDL-C) [e]
[a] Both direct and indirect bilirubin measured only when total bilirubin is greater than upper limit of normal.
[b] Routinely collected urinalysis samples will be sent to the central laboratory for dipstick analysis and microscopy if 
needed, see [c].  Urinalysis should not be collected for a female subject who is menstruating.
[c] Microscopy performed by the central laboratory if dipstick is positive for blood, nitrites, leukocytes and/or protein.  
Subjects found to have microscopic hematuria (defined as the presence of three or more red blood cells per high 
powered field on microscopic examination) from a properly collected, non-contaminated urinalysis with no evidence 
of infection should be referred to a urologist for appropriate work-up.
[d] Sample should not be obtained if the subject is menstruating, has vigorously exercised within 24 hours or had fever or 
an active infection within 2 days of the visit.
[e] If LDL-C is measured directly on a Day 1 sample, the central laboratory will perform direct LDL-C 
measurements on subsequent samples for that subject.
7.9.1. Lipid Panel
A fasting lipid panel will be collected at the times listed in the Schedule of Activities.  The 
lipid panel will consist of the following measurements:

Total cholesterol, LDL-C, HDL-C, non-HDL-C and triglycerides.
LDL-C will be calculated, using the Friedewald equation.  If the triglycerides are over 
400 mg/dL, the laboratory will measure LDL-C directly.  Non-HDL-C will be calculated as 
(total cholesterol - HDL-C).  If LDL-C is measured directly on a Day 1 sample, the central 
laboratory will perform direct LDL-C measurements on subsequent samples for that subject.
7.9.2. Urinary Albumin:Creatinine Ratio
A urine sample will be collected on site at the times listed in the for measurement of the 
urinary albumin:creatinine ratio (mg/g).  These samples will be used to assess the change in 
the urinary albumin:creatinine ratio throughout the trial.  Samples should not be obtained if 
the subject is menstruating, has vigorously exercised within 24 hours or had fever or an 
active infection within 2 days of the visit.
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7.10. Assessment of Infections
7.10.1. Urinary Tract Infections
Any subject presenting with symptoms considered to be a urinary tract infection should be 
recorded as having an adverse event of "urinary tract infection." The site should collect urine 
for microscopic analysis and culture performed by their local laboratory, but urine dipstick or 
routine urinalysis should not be performed by the site or local laboratory.  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 either empirically as per local practice or following results 
from the urine culture and sensitivity analysis.  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 will be captured as an adverse event. The site should attempt to obtain information 
from the treating physician regarding diagnostic tests performed and treatment provided, and 
this information should be recorded.
7.10.2. 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 the central laboratory.  The choice and duration of antifungal agent used is left to 
the investigator or treating physician’s discretion. 
7.11. Follow-up for Subjects Who Discontinue Due to Decreased Renal Function
Subjects who discontinue study drug for eGFR discontinuation criteria (see Section 6.7.4) or 
renal-related adverse events should have a repeat performed 1 week after the End of Study or 
Early Termination visit.  The out of range test(s) should continue to be repeated at intervals, 
as considered appropriate (eg, weekly or every other week) until the value returns to baseline 
(pre-randomization value) or a new baseline is established.  The investigator should 
implement an appropriate evaluation for events of clinically significant change in eGFR 
(eg, >30% reductions in eGFR 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 (eg, non-steroidal anti-inflammatory agents, fenofibrate, ACE inhibitors, 
diuretic agents, etc.), and clinical assessment of volume status (eg, measurement of 
orthostatic heart rate and blood pressure, and physical examination focused on assessment of 
volume status); additional evaluations, including renal ultrasound, dipstick and microscopic 
urinalysis (with culture and sensitivity if infection is considered possible), urine creatinine 
and electrolytes, should be performed, as clinically appropriate.
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8. ADVERSE EVENT REPORTING
8.1. Assessing and Recording Adverse Events
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 (ie, 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 in clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
For randomized subjects only, all adverse events that occur after the consent form is signed 
but before randomization must be reported by the investigator if they 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 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 Serious Adverse Events.  The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome.
8.2. Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than 100 mg/day of ertugliflozin or matching 
placebo or any dose higher than 25 mg/day of ertugliflozin or matching placebo for more 
than 14 days.
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.
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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 within 24 hours 
to the sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
8.3. Reporting of Pregnancy and Lactation to the Sponsor
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 or within 14 days of completing 
the trial.  All subjects who become pregnant 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.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
8.4. Immediate Reporting of Adverse Events to the Sponsor
8.4.1. 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 a cancer;

Is associated with an overdose;

Is another important medical event.
Refer to Table 5 for additional details regarding each of the above criteria.
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For the time period beginning when the consent form is signed until 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.
For the time period beginning at 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.  Sponsor Contact information 
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.
8.5. Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 5. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 5 for instructions in evaluating adverse events.
Table 5.
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 [including hospitalization for an elective procedure] for a 
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preexisting condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis); or
Is a cancer; or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with 
an overdose is considered a serious adverse event.  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
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.)
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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 U.S. CLINICAL 
MONITOR 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 there is another 
obvious cause of the AE.  (Also entered for a subject with overdose without an 
associated AE.)
Sponsor Responsibility for Reporting Adverse Events
All adverse events will be reported to regulatory authorities, IRBs/IECs and investigators in 
accordance with applicable local laws and regulations. 
8.6. Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the sponsor either by electronic media or paper.  Sponsor Contact 
information 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 8.2 - 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. 
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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).
8.7. Management of Subjects with Elevated Liver Enzymes (ALT or AST 3X ULN)
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) are defined as clinically 
significant for this study.  The central laboratory report will alert the investigator if a subject 
meets this threshold.  When a randomized subject who is receiving investigational study drug 
has an ALT or AST elevation beyond the clinical significant margin above, the investigator 
should monitor the subject according to the instructions below and discontinue the subject 
from investigational study drug if a pre-specified criterion is met. 
The investigator should select the appropriate set of instructions (either a, b, or c below) for 
managing a subject with elevated liver enzymes based upon the following factors: (1) the 
magnitude of a subject’s ALT or AST elevation, (2) the presence or absence of symptoms, 
(3) whether there is a corresponding increase in total bilirubin (TBL) 2X ULN. 
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 (ALP) 
<2X ULN
The subject should interrupt investigational study drug.
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. 
If an etiology for the elevated ALT or AST and TBL levels is established and the 
abnormalities resolve, investigational study drug may be restarted with approval by the
Sponsor.  Otherwise, the subject should discontinue treatment with investigational 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 
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unwilling to undergo the prescribed testing should be discontinued from treatment with 
investigational study drug. 
B)
Subject has: 
ALT or AST 8X ULN OR
ALT or AST 3X ULN and signs or symptoms of a drug reaction consistent with liver 
injury (eg, fever, eosinophilia, right upper quadrant pain, dark urine, fatigue, etc.)
The subject should interrupt investigational study drug. 
Perform repeat ALT and AST within 3 days of receipt of the laboratory report. 
Initiate evaluation for potential causes.  See Section II below. 
Repeat ALT and AST tests at appropriate intervals, initially approximately 2-times per 
week, until resolution or return to baseline. 
If an etiology for the elevated liver enzymes is established (eg, active hepatitis, 
cholecystitis, biliary obstruction), investigational study drug may be restarted with 
approval by Pfizer or designee.  Otherwise, the subject should discontinue treatment with 
investigational study drug.
Note: Local laboratory assessments can be used to support compliance with the repeat 
testing procedure described above if required.  Subjects unwilling to undergo repeat ALT 
and AST testing at the frequency recommended above should be discontinued from 
treatment with investigational study drug.    
C)
Subject has:
ALT or AST 3X and <8X ULN
For subjects with:
ALT or AST 3X and <5X ULN: 
Perform repeat ALT and AST within 3-5 days of receipt of the laboratory report. 
           OR
ALT or AST 5X ULN and <8X ULN:
Perform repeat ALT and AST within 3 days of receipt of the laboratory report.  Subjects 
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unable to undergo repeat measurements within 3 days must interrupt study drug. 
Initiate evaluation for potential causes.  See Section II below. 
Actions based upon initial repeat testing:
If ALT or AST 3X ULN with TBL 2X ULN, then interrupt investigational study drug 
and see “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.
If ALT or AST 8X ULN or ALT or AST 3X ULN with symptoms present (eg, fever, 
eosinophilia, right upper quadrant pain, dark urine, fatigue, etc.), then interrupt
investigational study drug and monitor as described in Section B Instructions above. 
If ALT or AST 3X ULN and <8X ULN (without above criteria met), continue to 
measure ALT and AST 1- to 2-times per week (2-times per week if ALT or AST 5X 
ULN or if an increase >20% occurred since the first elevated value[s]). 
If ALT and AST > ULN and <3X ULN, perform repeat determination in 5-7 days, and 
then at appropriate intervals (eg, every other week) until the subject’s ALT and AST levels 
are within normal limits or are similar to baseline. 
Actions based upon follow-up repeat testing:
If ALT or AST 5X ULN after 2 weeks, discontinue investigational study drug.
If ALT or AST remain elevated (3X and <5X ULN) but stable, the frequency of 
retesting can decrease (eg, every other week) with approval from the Sponsor.
If ALT and AST > ULN and <3X ULN, perform repeat determination in 5-7 days, and 
then at appropriate intervals (eg, every other week) until the subject’s ALT and AST levels 
are within normal limits or are similar to baseline. 
Note: Local laboratory assessments can be used to support compliance with the repeat 
testing procedures described above if required.  Subjects unwilling to undergo repeat ALT 
and AST testing at the frequency defined above should be discontinued from treatment 
with investigational study drug.  
In summary, subjects should be discontinued from investigational study drug for any of the 
following reasons:

ALT or AST 3X ULN with TBL 2X ULN and ALP <2X ULN and without an 
established etiology;
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
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 or longer.
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 (eg, 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 (eg, 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 (eg, autoimmune disorder, cancer, 
Gilbert’s syndrome, obesity, Wilson’s disease, Nonalcoholic steatohepatitis (NASH), 
alcoholic or infectious hepatitis, biliary tract disease, hypoxic/ischemic hepatopathy, 
etc.)?
4. Has the subject recently been treated with a concomitant medication(s) with 
demonstrated or suspected effects on the liver (eg, 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)?
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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. 
8.8. Serious Adverse Events Exempt from Expedited Reporting
Potential pre-specified cardiovascular SAEs will be submitted for adjudication to an 
independent EAC (see Section 7.1 for details). 
The following potential cardiovascular SAEs will not be subject to expedited reporting (ie, if 
reported as related to study drug by the investigator), unless and until the event is reviewed 
by the EAC and found not to meet the specified criteria in the EAC charter for that event 
type: 
1. Cardiovascular deaths;
2. Non-fatal myocardial infarction; hospitalization for chest pain or to rule out myocardial 
infarction, or other hospitalization due to suspected myocardial ischemia where 
myocardial infarction needs to be ruled out;
3. Non-fatal stroke; TIA, reversible ischemic neurologic deficit (RIND) or other acute 
ischemic cerebrovascular event where stroke needs to be ruled out;
4. Hospitalization for unstable angina.
As noted above, SAEs that are confirmed by the EAC as one of the pre-specified 
cardiovascular endpoints (ie, cardiovascular death, non-fatal myocardial infarction, non-fatal 
stroke, and hospitalization for unstable angina) in the meta-analysis of cardiovascular safety 
will not be subject to expedited reporting by the sponsor to investigators, Ethics 
Committees/IRBs and regulatory agencies, regardless of causality.  Note that all SAEs, 
including confirmed adjudicated cardiovascular events, will be reviewed and monitored by 
an E-DMC unblinded to treatment as part of the overall assessment of safety for ertugliflozin.  
Based upon their regular review of unblinded safety results, the E-DMC is empowered by the 
E-DMC charter to make recommendations with regard to trial conduct to assure the 
continuing appropriate safety of the subjects participating in the study. 
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If an event submitted for adjudication is determined by the EAC not to meet the endpoint 
criteria (for the pre-specified events of cardiovascular death, non-fatal myocardial infarction, 
non-fatal stroke, or hospitalization for unstable angina) in the EAC charter, the event will 
then be subject to expedited reporting (as appropriate, based upon investigator assessment of 
drug relationship).  The SAE awareness date in this instance is identified as the date that 
Pfizer or designee receives notification from the EAC that the event does not meet the 
endpoint criteria.
9. DATA ANALYSIS/STATISTICAL METHODS
Methodology for summary and statistical analyses of the data collected in this study are 
outlined here and further detailed in a statistical analysis plan, which will be dated and 
maintained by the sponsor.  The statistical analysis plan may modify what is outlined in the 
protocol where appropriate; however, any major modifications of the endpoint definitions or 
their analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The cardiovascular safety of ertugliflozin will be assessed in two stages.  Stage 1 will consist 
of a meta-analysis of MACE plus events across the Phase 2 and Phase 3 development 
program with the majority of events expected to come from this trial.  Stage 2 will consist of 
an analysis of MACE and secondary endpoints [eg, CV death or hospitalization for heart 
failure (composite), CV death (individual component), and the renal composite] in this trial.  
The two doses of ertugliflozin (5 and 15 mg) will be pooled for the purpose of all these 
analyses. 
The primary objective for the Stage 1 across-program meta-analysis will be addressed by 
testing the hypotheses H0:HR1.8 versus H1:HR<1.8 for the MACE plus endpoint; the 
primary Stage 2 analysis (assessed within this study) will be addressed by testing the 
hypotheses H0:HR1.3 versus H1:HR<1.3 for the MACE endpoint. For these analyses, the
HR represents the risk of ertugliflozin relative to a non-ertugliflozin comparator group at 
Stage 1 and relative to placebo at Stage 2 as measured by the hazard ratio. 
Stage 1 of the trial uses a group sequential design with up to two analyses: an interim 
analysis and a final analysis.  The Stage 1 interim analysis will take place at the later of 1) the 
time at which at least 130 adjudicated MACE plus events have accrued throughout the 
Phase 2 and Phase 3 development program or 2) the approximate time at which all necessary 
data are available to support the filing of ertugliflozin.  This analysis will assess the hazard 
ratio for the MACE plus endpoint with respect to the 1.8 non inferiority margin.  If the first 
analysis is conducted with less than 173 MACE plus events, then a second analysis (the final 
analysis for Stage 1) will take place, if necessary (ie, if the non-inferiority margin of 1.8 is 
not met in the first analysis), at the time at which at least 173 MACE plus events have 
accrued, and the appropriate alpha spending will be determined from an O’Brien-Fleming 
type spending function.  If the first analysis is conducted with 173 or more MACE plus 
events, then that will constitute the only analysis for Stage 1, and the full alpha of 0.025 
(1-sided) will be utilized.
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For these Stage 1 analyses, using an O’Brien-Fleming type alpha spending function, and 
analyses at 130 and 173 adjudicated MACE plus events, the meta-analysis will have 
approximately 95% power to demonstrate non-inferiority of ertugliflozin to a 
non-ertugliflozin comparator group when there is truly no difference between treatments 
(HR=1.0) using the non-inferiority margin of 1.8 and testing at the overall one-sided alpha 
level of 0.025.
Stage 2 of the trial uses a group sequential design with up to two analyses: an interim 
analysis and a final analysis.  The Stage 2 interim analysis and the final analysis are planned 
to occur when approximately 714 and 939 adjudicated MACE events have accrued in this 
study.  These analyses will assess the hazard ratio for the MACE endpoint with respect to the 
1.3 non-inferiority margin.  If non-inferiority is established for the primary MACE endpoint, 
then tests of superiority on the secondary endpoints of CV death or hospitalization for heart 
failure (composite), CV death (individual component), and the renal composite will also be 
performed in a sequential manner.  If any of the first three tests in this four-step testing 
sequence are unsuccessful at the interim analysis, the study may be continued to the final 
analysis (depending on the result of futility assessment).
For the primary Stage 2 analyses, using an O’Brien-Fleming type alpha spending function 
and analyses at approximately 714 and 939 adjudicated MACE events, the study will have 
approximately 96% power to demonstrate non-inferiority of ertugliflozin to placebo when 
there is truly no difference between treatments (HR=1.0) using the non-inferiority margin of 
1.3 and testing at the overall one-sided alpha level of 0.025.
The accrual of 714 MACE events (ie, an information fraction of about 76%) was selected as 
the time point for interim assessment as the power to demonstrate non-inferiority at the 
interim with this number of events is >80% and the estimated corresponding number of 
CV deaths and heart failure hospitalizations (ie, 442 events) provides approximately 
70% power to detect a 25% risk reduction in this secondary endpoint at the interim.
With two enrollment periods of 19 months each and assuming an event rate of 3.5% per 
annum for MACE, a total of approximately 8000 subjects (about 4000 per enrollment cohort) 
randomized in a 1:1:1 ratio to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo will be 
sufficient to accrue approximately 714 MACE events within approximately 5.0 years and 
approximately 939 MACE events within approximately 6.1 years from the start of this study.  
These calculations assume that subjects will withdraw from the study at a rate of 5% per 
annum.
Power for Secondary Hypotheses
For the Stage 2 analyses of secondary endpoints, using an O’Brien-Fleming alpha-spending 
approach and assuming accrual of at least 442 and 582 composite events of cardiovascular
death or hospitalization for heart failure at the interim and final analysis respectively, the 
study will have approximately 90% power to demonstrate superiority of ertugliflozin to 
placebo on the composite of cardiovascular death or hospitalization for heart failure when the 
true HR=0.75.  Moreover, assuming accrual of at least 287 and 377 cardiovascular death 
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events at the interim and final analysis respectively, the study will have approximately 
83% power to demonstrate superiority of ertugliflozin to placebo on cardiovascular death
when the true HR=0.725.  With accrual of at least 144 and 190 renal composite events at the 
interim and final analysis respectively, the study will have approximately 79% power to 
demonstrate superiority of ertugliflozin to placebo on the renal composite endpoint when the 
true HR=0.65.
9.1.1. Sample Size for Insulin with or without Metformin Add-on Glycemic Sub-Study: 
The sub-study is powered to demonstrate superiority of ertugliflozin compared with placebo 
in reducing HbA1c from Baseline to Week 18.  It is estimated that a minimum of 
450 subjects will be enrolled into the sub-study.  The sub-study enrollment will not be 
allowed to exceed 50% of the overall trial sample size.  The final determination of inclusion 
in the sub-study will be based on a programmatic assessment of the sub-study criteria. 
In two recent studies of another SGLT2 inhibitor (dapagliflozin) in subjects with type 2 
diabetes receiving high doses of insulin, estimates of the standard deviation of the change 
from baseline in HbA1c after 24 weeks ranged up to a maximum of 0.98%.15,16. Therefore, a 
standard deviation of 1.0% was taken as a conservative estimate for sample size calculations. 
Assuming a standard deviation of 1.0% and a lost to follow up rate of 10%, a sample size of 
450 subjects (150 per arm) will provide approximately 98% power to detect a difference of 
0.5% in the reduction of HbA1c from Baseline to Week 18 between ertugliflozin and placebo 
using a 2-sided 0.05 alpha level test.
9.1.2. Sample Size for SU Monotherapy Add-on Glycemic Sub-Study:  
The primary endpoint for the sub-study is the HbA1c change from Baseline to Week 18.  It is 
estimated that approximately 170 subjects will be enrolled into the sub-study.  The final 
determination of inclusion in the sub-study will be based on a programmatic assessment of 
the sub-study criteria. 
Assuming a standard deviation of 1.0%, a lost to follow up rate of 10%, and a sample size of 
170 subjects (~56 per arm), the power to detect a between treatment difference of 0.6% will 
be approximately 85% using a 2-sided alpha level of 0.05. 
9.1.3. Sample Size for Metformin with SU Add-on Glycemic Sub-Study
The primary endpoint for this sub-study is the HbA1c change from Baseline to Week 18.  It 
is estimated that at least 260 subjects will satisfy the criteria for inclusion in this sub-study.  
Assuming a standard deviation of 1.0% and a lost to follow up rate of 10%, a sample size of 
260 subjects (~86 per arm) will provide approximately 96% power to detect a difference of 
0.6% in the reduction of HbA1c from Baseline to Week 18 between ertugliflozin and placebo 
using a 2-sided 0.05 alpha level test. 
As there is no separate randomization stratum for the metformin with SU sub-study, this 
sub-study will consist of a sub-group of subjects from the “main cardiovascular study” 
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stratum.  The determination of inclusion in the sub-study will be based on a programmatic 
assessment of the sub-study criteria; see Section 3.4. 
9.2. Primary Cardiovascular Endpoints Analysis 
The two doses of ertugliflozin will be pooled for the analysis of cardiovascular endpoints.  
The analyses described below will be performed at the interim analysis and at the end of the 
trial.
The Stage 1 meta-analysis population will include all randomized subjects who have taken at 
least one dose of investigational product across the Phase 2 and 3 development program.  The 
Stage 2 non-inferiority analysis population will include all randomized subjects who have 
taken at least one dose of investigational product in this study.  For both stages, subjects will 
be analyzed in the group to which they were assigned by IVRS, regardless of the actual 
treatment received and only events confirmed by the Endpoint Adjudication Committee will 
be included in the analysis. For Stage 1, all confirmed MACE plus events will be included in 
the primary analysis. For Stage 2, confirmed MACE events occurring between 
randomization and 365 days after the last dose of study treatment will be included in the 
primary non-inferiority analysis.
The MACE plus and MACE endpoints will be analyzed using a stratified Cox proportional 
hazards model including treatment group as a covariate.  For the Stage 1 meta-analyses, the 
Cox model will include “Study” as a stratification factor with the following three levels: 
cardiovascular study, placebo-controlled non-cardiovascular studies, and active-controlled 
non-cardiovascular studies.  For the Stage 2 analyses, the Cox model will include “Cohort” 
as the stratification factor with the following levels: Cohort 1 (subjects randomized between 
December 2013 and July 2015) and Cohort 2 (subjects randomized in 2016 and beyond).  A 
test of non-inferiority at the one-sided 0.025 significance level will be performed based on 
the Cox model.  The upper bound of the alpha-adjusted two-sided confidence interval (CI) 
for the hazard ratio (HR) (ertugliflozin to a non ertugliflozin comparator group or placebo) 
will be calculated using an O’Brien-Fleming alpha spending function and compared with the 
appropriate non-inferiority margin (1.8 or 1.3). 
Kaplan-Meier curves for the distribution of time to MACE and MACE plus will also be 
provided for each of the three treatment groups. 
Subjects without cardiovascular events will be censored at the earliest of the study cut-off 
date, last contact date, or end of the applicable analysis ascertainment window (eg, 365 days 
after the last dose for primary Stage 2 non-inferiority analyses).
9.3. Secondary Endpoints Analysis 
Secondary time-to-event endpoints (eg, fatal and non-fatal myocardial infarction, fatal and 
non-fatal stroke, hospitalization for heart failure, cardiovascular death, the composite of 
cardiovascular death or hospitalization for heart failure, the renal composite, and all-cause 
mortality) will be analyzed using Cox proportional hazards models with the same model 
terms as those included for the primary endpoint.  A point estimate and two-sided nominal 
95% confidence interval for the hazard ratio will be calculated based on the Cox model for 
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each endpoint.  Kaplan-Meier methodology will be used to estimate event rates over time for 
each treatment group.
If non-inferiority at the 1.3 margin is established for the primary MACE endpoint based 
solely on this study, then tests of superiority on the secondary endpoints of cardiovascular
death or hospitalization for heart failure (composite), cardiovascular death (individual 
component), and the renal composite will also be performed.  The population for superiority 
testing will include all randomized subjects and include all confirmed events, including those 
occurring more than 365 days following discontinuation of investigational product.  
Superiority tests will be implemented by comparing the upper bound of the appropriate 
alpha-adjusted two-sided CI to 1.0.
In order to control the Type I error rate across multiple hypotheses in Stage 2, a four-step 
hierarchical testing sequence for the pooled ertugliflozin group versus the placebo group will 
be utilized as follows:
1. Non-inferiority for MACE;
2. Superiority for cardiovascular death or hospitalization for heart failure (composite);
3. Superiority for cardiovascular death (individual component);
4. Superiority for composite of renal death, renal dialysis/transplant, or 2x increase in 
baseline serum creatinine.
If the result of the test at any step of the sequence is not statistically significant, then testing 
will stop so that tests further down in the sequence will not be conducted, and the 
corresponding null hypotheses will not be rejected.  The alpha spending to be utilized for the 
interim and final analyses of the primary and secondary endpoints is described in Section 9.7.
Recurrent MACE and recurrent cardiovascular death or hospitalization for heart failure will 
also be analyzed using Anderson-Gill models.  A point estimate and two-sided 95% 
confidence interval for the risk ratio (ertugliflozin compared to placebo) will be calculated 
based on the model for each endpoint.  These analyses of recurrent events will be considered 
exploratory and only performed at the end of the study.
9.4. Other Secondary Endpoints Analysis 
Continuous endpoints (HbA1c, FPG, body weight, systolic blood pressure and diastolic 
blood pressure) will be analyzed using a constrained longitudinal data analysis (cLDA)
model including fixed effects for treatment (categorical), visit (categorical), and treatment by 
visit interaction.  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. No explicit imputation of missing assessments will be 
performed.  The treatment difference in terms of mean change from baseline to the relevant 
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time points of interest will be estimated and tested from this model using least-squares means 
and 95% confidence intervals. An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. The Kenward-Roger adjustment will be used 
with restricted (or residual) maximum likelihood (REML) to make proper statistical 
inference.  Descriptive and graphical summaries by treatment group and time point will also 
be presented.  Other continuous endpoints will be summarized with descriptive statistics by 
treatment and time.
Dichotomous endpoints such as the proportion of subjects having an HbA1c <7% 
(53 mmol/mol) at specified time points, will be analyzed using a logistic regression model 
with terms for treatment (categorical) and baseline HbA1c (continuous).  Summary measures 
from the analysis will include the odds ratio and 95% confidence interval for the odds ratio.  
Other dichotomous endpoints will be summarized descriptively with numbers and 
percentages by treatment and time.
9.5. Analysis of Laboratory and Biomarker Endpoints
9.5.1. Albuminuria
Change from Baseline in the urinary albumin:creatinine ratio stratified by albuminuria 
category at baseline (normoalbuminuria, microalbuminuria and macroalbuminuria), will be 
compared between ertugliflozin and placebo-treated subjects.  In addition, albuminuria 
progression, defined as a change from normoalbuminuria to either microalbuminuria or 
macroalbuminuria or from microalbuminuria to macroalbuminuria, will be assessed 
comparing the baseline data to the data collected according to the following definitions:

Normoalbuminuria: <30 mg/g (albumin:creatinine ratio).

Microalbuminuria: 30mg/g to 300 mg/g (albumin:creatinine ratio).

Macroalbuminuria: >300 mg/g (albumin:creatinine ratio).
Regression of albuminuria will be defined as subjects noted to have an improvement in 
albuminuria defined as moving from macroalbuminuria to microalbuminuria (or 
normoalbuminuria) or from microalbuminuria to normoalbuminuria.
9.6. Safety Analysis
The safety analysis population will consist of all randomized and treated subjects, ie, all 
randomized subjects who received at least one dose of investigational product in this trial.
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify all AEs 
with respect to system organ class and preferred term.  Summaries of AEs will include 
treatment-emergent AEs according to treatment group.
Two approaches will be used for handling safety data occurring after the initiation of 
glycemic rescue therapy.  The first approach will exclude all data following the initiation of 
rescue, in order to avoid the confounding influence of the rescue therapy.  The second 
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approach will include data following the initiation of rescue therapy.  For the overall study 
analyses, the “including rescue” approach will be considered primary for all safety endpoints 
as, after Week 18, subjects are treated to standard of care, and there is no longer glycemic 
rescue.  For glycemic sub-study analyses, the “including rescue” approach will be considered 
primary for analyses of SAEs and discontinuations of study drug due to AEs, and the 
“excluding rescue” approach will be considered primary for all other endpoints.  Descriptive 
statistics will be used to summarize results and changes from Baseline in clinical laboratory
tests, vital signs, and ECGs. 
Furthermore, a 3-tier approach will be used to summarize AEs.  Tier-1 consists of AEs of 
special clinical interest and will include AEs or collections of AEs related to urinary tract 
infection, genital mycotic infection, symptomatic hypoglycemia and hypovolemia.  Where 
available, standard MedDRA queries may be used to pool different AE terms that are related 
to the Tier-1 AEs. The precise AE terms that will contribute to the Tier-1 endpoints will be 
determined prior to unblinding. For these events, the percentage of subjects with incident 
AE, the risk difference, its 95% confidence interval, and p-value will be provided.  The 
confidence intervals and p-values are not adjusted for multiplicity and therefore must be 
considered accordingly.  Tier-2 AEs are those that are not Tier-1, but that occur in a 
pre-specified minimum number of subjects in any treatment arm.  For the overall study, this 
requirement will be at least 0.5% of subjects in any treatment arm, and for each sub-study, 
the requirement will be at least 4 subjects in any treatment arm.  The cut-off 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 so adds little to the interpretation of potentially meaningful 
differences. For these events, the percentage of subjects with incident AE, the risk difference 
and its 95% confidence interval will be provided.  Tier-3 AEs are all other AEs (neither 
Tier-1 nor Tier-2).  For Tier-3 AEs, only within-group incidence proportions will be 
tabulated. 
9.7. Cardiovascular Endpoints Interim Analyses
Each stage of the study uses a group sequential design with planned interim analyses as 
described below.
Stage 1
The first interim analysis will be conducted at the later of 1) the time at which a minimum of 
130 adjudicated MACE plus events have accrued throughout the Phase 2 and Phase 3 
development program or 2) the approximate time at which all necessary data are available to 
support the filing of ertugliflozin.  The purpose of this interim analysis is to provide data for 
a meta-analysis of cardiovascular events that will support the initial regulatory submissions
and rule out a hazard ratio of 1.8 (an 80% increase in cardiovascular risk relative to the 
non-ertugliflozin comparator group).  If necessary (ie, if the first interim analysis is 
conducted with less than 173 MACE plus events and fails to rule out an HR>1.8), a 
subsequent final Stage 1 analysis will be conducted after at least 173 adjudicated MACE plus 
events have accrued.  For each of these analyses, the two-sided adjusted CI for the HR will 
be calculated using an O’Brien-Fleming spending function to preserve the overall Type I 
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error rate of 2.5% with respect to the non-inferiority margin of 1.8.  The analysis at 
approximately 130 MACE plus events corresponds to an information fraction of 
approximately 75% with respect to the Stage 1 MACE plus analyses and the amount of alpha
to be spent for this analysis is about 1.0% (one-sided).  If at either of these looks, the upper 
bound of the two-sided adjusted CI is <1.8, this result will be communicated to the E-DMC 
by an independent statistician(s) and may subsequently be submitted to regulatory 
authorities.  If, on the other hand, the upper bound of the adjusted CI is >1.8 at both of these 
analyses, then the study may be stopped for futility.
Stage 2
Once the 1.8 threshold has been met, the study will continue to Stage 2. An interim analysis 
will take place when approximately 714 MACE events have accrued in this study.  The 
purpose of this analysis will be to rule out an HR of 1.3 for MACE and to sequentially test 
for superiority on the secondary endpoints of cardiovascular death or hospitalization for heart 
failure (composite), cardiovascular death (individual component), and the renal composite.  If 
necessary (ie, if the interim analysis fails to rule out an HR >1.3 or to achieve superiority on 
both of the secondary CV endpoints), the final analysis will take place after accrual of
approximately 939 MACE events.  For the primary non-inferiority analysis of MACE, the 
two-sided adjusted CI for the HR will be calculated using an O’Brien-Fleming spending 
function to preserve the overall Type I error rate of 2.5% with respect to the non-inferiority 
margin of 1.3.  The analysis at approximately 714 MACE events corresponds to an 
information fraction of approximately 76%, and the amount of alpha to be spent for this 
analysis is about 1.0% (one-sided).  The subsequent secondary hypothesis tests will utilize a 
similar O’Brien-Fleming alpha spending approach with a 2.0% two-sided alpha spend for 
each hypothesis at the interim.  If at the end of the study, the upper bound of the two-sided 
adjusted CI is <1.3 for MACE, the study will be considered to have met its primary objective 
of demonstrating the non-inferiority of ertugliflozin as compared to placebo with respect to 
cardiovascular safety.  Details regarding alpha spending and power for the primary analyses 
at each potential analysis time are described in Table 6 below.
Table 6.
Alpha Adjusted Confidence Interval and Power for Primary Analyses
Stage
Analysis (within 
Stage)
Events (confirmed 
by adjudication)
Alpha for 
adjusted 
confidence 
interval
(one-sided)
Power to 
Demonstrate 
Non-Inferiority*
1
Phase 2 and 3 Meta-
analysis
1 Interim
130 MACE plus 
1.0%
79.5%
If the upper bound at interim analysis is 1.8 for MACE plus
2 Final
173 MACE plus
2.2%
95.1% 
(cumulative)
Once the 1.8 threshold has been met, the study will continue to Stage 2
2
Study 
P004/B1521021
1 Interim
714 MACE 
1.0%
83.8%
If the upper bound at interim analysis is 1.3 for MACE 
2 Final
939 MACE 
2.2%
96.4% 
(cumulative)
* Power under HR=1.0
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Interim Futility Analysis for Secondary Endpoints
Furthermore, if non-inferiority on MACE (1.3 margin) is achieved at the Stage 2 interim 
analysis, but superiority on cardiovascular death or heart failure hospitalization is not 
achieved at that same analysis, the conditional power for achieving superiority at the 
subsequently planned analysis will be computed by an appropriately firewalled 
cardiovascular analysis team and provided to the E-DMC for assessment as described in the 
Data Access Plan. Depending on the results of this conditional power evaluation, the study 
may be continued in order to use the remaining alpha to conduct further superiority testing of 
the secondary endpoints.  Under such a scenario, the study could be continued up to the 
pre-specified maximum number of events (ie, approximately 582 composite events of 
cardiovascular death or heart failure hospitalization and approximately 377 events of 
cardiovascular death).  On the other hand, if the conditional power for superiority is not high 
enough, the study may be terminated having achieved the primary objective of demonstrating 
non-inferiority for MACE in Stage 2. The relevant decision criteria for assessing the 
conditional power for superiority will be included in the Statistical Analysis Plan.  The
assessment of conditional power for superiority will be considered as a non-binding futility 
assessment for the secondary endpoints.
Stage 2 Type I Error Rate Control
The overall Type I error rate in Stage 2 will be strongly controlled using a combination of 
fixed sequential testing across endpoints and alpha spending approaches across analysis time 
points.17,18  The following chart summarizes the alpha levels that will be utilized for each 
endpoint at each analysis time point in Stage 2. The fixed sequential testing sequence of the 
endpoints is described in Section 9.3.  Note that alpha allocated to the secondary superiority 
tests at the interim will be considered to be consumed even if the test is not conducted due to 
the hierarchical testing sequence.  Also note that if the primary non-inferiority test is 
successful at the interim, but the study continues to the final analysis for the secondary 
superiority tests, a supportive analysis of the primary non-inferiority hypothesis will be 
conducted at the final analysis time point using the full alpha level of 0.025.  Similarly, if the 
secondary superiority test for the composite of CV death and hospitalization for heart failure 
is successful at the interim but the study continues to the final analysis (ie, the secondary 
superiority test for CV death is not successful at the interim), a supportive analysis of the 
secondary superiority hypothesis for CV death and hospitalization for heart failure will be 
conducted at the final analysis time point using the full alpha level of 0.05.
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Sequence 
Number*
Endpoint
(test)
Alpha for adjusted confidence interval
Interim Analysis
Final Analysis
1
MACE
(non-inferiority)
1% (one-sided)
2.2% (one-sided); if test not 
successful at interim
2.5% (one-sided); if test 
successful at interim
2
Cardiovascular 
death/hospitalization for 
heart failure
(superiority)
2% (two-sided)
4.4% (two-sided); if test not 
successful at interim
5% (two-sided); if test 
successful at interim
3
CV death
(superiority)
2% (two-sided)
4.4% (two-sided)
4
Renal composite
(superiority)
2% (two-sided)
4.4% (two-sided)
*Note: If the result of the test at any step of the sequence is not statistically significant, then testing will stop 
so that tests further down in the sequence will not be conducted (and therefore not considered successful).
The various possible actions to be taken based on the Stage 2 interim analysis results are 
summarized in the following table:
Scenario at Interim
Action
Primary test unsuccessful
Study continues to final analysis
Primary test successful and CV death/hospitalization 
for heart failure composite endpoint unsuccessful but 
not futile
Study continues to final analysis
Primary test successful and CV death/ hospitalization 
for heart failure composite endpoint futile
Study may be stopped for success on the primary 
objective and futility on the secondary superiority 
objectives
Primary test and CV death/ hospitalization for heart 
failure composite both successful; CV death 
unsuccessful
Study continues to final analysis
Primary test, CV death/ hospitalization for heart 
failure composite, and CV death all successful
Study may be stopped for success (regardless of the 
outcome for the renal composite)
The interim analyses will be performed by an independent team of statistician(s) and 
programmer(s) and will be reviewed by the E-DMC to determine whether excess risk with 
ertugliflozin relative to the non-ertugliflozin comparator group or to placebo (HR>1.8 or 1.3) 
may be ruled out.  The results of the meta-analysis (Stage 1) will be submitted to regulatory 
authorities. Only upon request from or with agreement of regulatory authorities may the 
three glycemic sub-studies be analyzed and submitted while the main study is on-going.  
9.8. Insulin with or without Metformin, SU Monotherapy Add-on and Metformin with 
SU Glycemic Sub-Study Analyses
Primary Efficacy Analyses: The primary analysis population for each sub-study will be the 
sub-study Full Analysis Set defined as all subjects randomized receiving those specific 
background treatments at baseline, who meet all sub-study inclusion criteria (eg, minimal 
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dose(s) and dose stable period),who have received at least one dose of investigational product 
and have at least one observation of HbA1c during the time of the sub-study, including 
baseline and post-baseline time points up to Week 18 inclusive.  If subjects receive glycemic 
rescue therapy, the observations post rescue therapy will be excluded from efficacy analyses 
of the primary and secondary endpoints.
The primary endpoint of HbA1c will be analyzed using a constrained longitudinal data 
analysis (cLDA) model with the following fixed effects:

Treatment (categorical);

Visit (categorical);

Treatment by visit interaction;

Baseline eGFR;

Metformin use (yes/no; applicable for insulin (with or without metformin) sub-study 
only).
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.  No explicit imputation of missing assessments will be performed.  The 
treatment difference in terms of mean change from baseline to the primary time point of 
Week 18 will be estimated and tested from this model using least-squares means and 
95% confidence intervals.  The two-sided p-value will also be provided for testing the 
significance of the difference between treatment groups.  An unstructured covariance matrix 
will be used to model the correlation among repeated measurements.  The Kenward-Roger 
adjustment will be used with restricted (or residual) maximum likelihood (REML) to make 
proper statistical inference.  Sensitivity analyses will be planned to assess the robustness of 
the primary model.  Descriptive and graphical summaries by treatment group and time point 
will also be presented.
The two primary hypotheses, comparisons of each ertugliflozin dose to placebo, will be 
tested sequentially to control the overall Type I error rate at 0.05.  The 15 mg dose will be 
tested first, and the 5 mg dose will be tested if and only if a statistically significant result is 
achieved for 15 mg. 
Secondary Efficacy Analyses:  The proportion of subjects achieving an HbA1c <7% 
(53 mmol/mol) at Week 18 will be analyzed using a logistic regression model with terms for 
treatment (categorical), metformin use (yes/no; applicable for insulin with or without 
metformin sub-study only), Baseline eGFR, and Baseline HbA1c (continuous).  Summary 
measures from the analysis will include the odds ratio, 95% confidence interval for the odds 
ratio, and p-value for the comparison of treatment groups.
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The secondary endpoints of fasting plasma glucose, body weight, and blood pressure will be 
analyzed separately by fitting constrained longitudinal data analysis models similar to that 
used for the primary endpoint.  For the insulin with or without metformin sub-study, the 
change in insulin dose from Baseline to Week 18 will also be summarized.
Hypothesis testing in the insulin with or without metformin sub-study, the SU monotherapy 
sub-study and in the metformin with SU sub-study will be performed with a 2-sided alpha of 
0.05.  The Type I error rate will be controlled by following a fixed testing sequence.  If the 
result of the test at any step of the sequence is not statistically significant, then testing will 
stop so that tests further down in the sequence will not be conducted, and the corresponding 
null hypotheses will not be rejected.  All tests will be conducted at the 0.05 alpha level.
For each endpoint, there are two hypotheses: comparisons of each ertugliflozin dose to 
placebo.  The 15 mg dose will be tested first, and the 5 mg dose will be tested if and only if a 
statistically significant result is achieved for 15 mg.  Testing will advance to the next 
endpoint in the sequence if and only if a statistically significant result is obtained for both 
doses.
The endpoints will be tested in the following sequence:
1. Reduction of HbA1c from Baseline at Week 18.
2. Reduction of FPG from Baseline at Week 18.
3. Reduction of body weight from Baseline at Week 18.
4. Proportion of subjects achieving an HbA1c <7% (53 mmol/mol) at Week 18.
5. Reduction of systolic blood pressure from Baseline at Week 18.
6. Reduction of diastolic blood pressure from Baseline at Week 18.
9.9. Data Monitoring Committee
This study will use an E-DMC.
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the trial 
and a separate E-DMC Charter will describe the precise mandates of the E-DMC.  The 
recommendations made by the E-DMC to alter the conduct of the trial will be forwarded to 
the sponsor for final decision.  The DMC charter will specify the role and responsibilities of 
the E-DMC and also the contact individuals within the sponsor organization and the E-DMC 
responsible for communication between these organizations.  The sponsor will forward such 
decisions, which may include summaries of aggregate analyses of safety data, to regulatory 
authorities, as appropriate.
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10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer/Merck or their agents will conduct periodic monitoring visits to 
ensure that the protocol and Good Clinical Practices (GCPs) are being followed.  The 
monitors may review source documents to confirm that the data recorded on eCRFs is 
accurate.  The investigator and institution will allow Pfizer/Merck monitors or its agents and 
appropriate regulatory authorities direct access to source documents to perform this 
verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer/Merck and should not be made available in any 
form to third parties, except for authorized representatives of Pfizer/Merck or appropriate 
regulatory authorities, without written permission from Pfizer/Merck.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital’s or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at the sponsor and 
clearly identify those data that will be recorded in the CRF, and for which the CRF will stand 
as the source document.
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11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer/Merck, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
ICD, copies of all CRFs, safety reporting forms, source documents, and detailed records of 
treatment disposition, and adequate documentation of relevant correspondence (eg, letters, 
meeting minutes, telephone calls reports).  The records should be retained by the investigator 
according to International Conference on Harmonisation (ICH), local regulations, or as 
specified in the Clinical Study Agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, ICD, and other relevant documents, eg, recruitment advertisements, if 
applicable, from the IRB/IEC.  All correspondence with the IRB/IEC should be retained in 
the investigator File.  Copies of IRB/IEC approvals should be forwarded to Pfizer or its 
designee.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
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12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where
required by laws.
Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
subject.  In case of data transfer, Pfizer/Merck will maintain high standards of confidentiality 
and protection of subject personal data.
The ICD must be in compliance with ICH GCP, local regulatory requirements, and legal 
requirements.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.
The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legal representative before any study-specific 
activity is performed. The investigator will retain the original of each subject's signed 
consent document.
12.4. Informed Consent 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.
12.5. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.6. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the
investigational product, Pfizer or its designee should be informed immediately.
In addition, the investigator will inform Pfizer or its designee immediately of any urgent 
safety measures taken by the investigator to protect the study subjects against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCP that the investigator 
becomes aware of.
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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all other Participating Countries
End of Trial in all other participating countries is defined as Database Lock.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer/Merck.  
In addition, the Pfizer/Merck retains the right to discontinue development of PF-04971729 at 
any time.
If a study is prematurely terminated or discontinued, Pfizer or its designee will promptly 
notify the investigator.  After notification, the investigator must contact all participating 
subjects and the hospital pharmacy (if applicable) within 28 days.  As directed by Pfizer or 
its designee, all study materials must be collected and all CRFs completed to the greatest 
extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by the Sponsor
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
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Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts European (EU) Basic Results on EudraCT for all Pfizer-sponsored interventional 
studies that are in scope of EU requirements.  EU Basic Results are submitted for posting 
within 1 year of the primary completion date for studies in adult populations or within 6 
months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov. 
15.2. Publications by Investigators
The sponsor has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected inventions, investigator will provide the sponsor an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to the 
sponsor at least 30 days before they are submitted for publication or otherwise disclosed. If 
any patent action is required to protect intellectual property rights, investigator agrees to 
delay the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, investigator is free to publish separately, subject to the other requirements 
of this section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
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Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
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16. REFERENCES
1.
Stratton IM, Adler AI, Neil HA, et al.  Association of glycemia with macrovascular and 
microvascular complications of type 2 diabetes (UKPDS35): prospective observational 
study.  BMJ 2000;321:405-12.
2.
Roger VL, Go AS, Lloyd-Jones DM, et al.  Heart disease and stroke statistics – 2011 
update: a report from the American Heart Association. Circulation 2011;123:e18-e209.
3.
Food and Drug Administration.  Guidance for Industry. Diabetes mellitus – evaluating 
cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes.  US 
Department of Health and Human Services. 2008.
4.
European Medicines Agency.  Guideline on clinical investigation of medicinal products 
in the treatment or prevention of diabetes mellitus.  Committee for Medicinal Products 
for Human Use (CHMP). 2012.
5.
American Diabetes Association. Executive summary: Standards of medical care in 
diabetes - 2012.  Diabetes Care 2012;35(Suppl. 1):S4–S10.
6.
International Diabetes Federation.  Diabetes Atlas.  Fifth Edition.  Brussels, Belgium. 
2011.
7.
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.
8.
Mokdad AH, Ford ES, Bowman BA, et al.  Prevalence of Obesity, Diabetes, and 
Obesity-Related Health Risk Factors, 2001.  JAMA 2003:289:76-79.
9.
Centers for Disease Control and Prevention. Prevalence of Overweight and Obesity 
Among Adults with Diagnosed Diabetes - United States, 1988-1994 and 1999-2002. 
MMWR 2004:53:1066-1068.
10.
Isaji M.  Sodium-glucose cotransporter inhibitors for diabetes.  Current Opinion in 
Investigational Drugs 2007;8(4):285-92.
11.
Kim Y, Babu AR.  Clinical potential of sodium-glucose cotransporter 2 inhibitors in the 
management of type 2 diabetes.  Diabetes Metab Syndr Obes 2012;5:313-27.
12.
Canagliflozin FDA Advisory Committee Information 2013.
13.
Zinman B, Wanner O, Lachin JM et al.  Empagliflozin, Cardiovascular Outcomes, and 
mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.
14.
Bell SH.  Heart Failure.  The frequent, forgotten and often fatal complication of 
Diabetes. Diabetes Care 2003;26:2433-41.
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15.
Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic 
patients with inadequate glycaemic control by diet and exercise: a randomized, 
double-blind, placebo-controlled, phase III trial. Diabetes Care 2010;33:2217–24.
16.
Wilding JP. A study of dapagliflozin in patients with type 2 diabetes receiving high 
doses of insulin plus insulin sensitizers.  Diabetes Care. 2009; 32 (9); 1656-62.
17.
Hung HMJ, Wang SJ, O’Neill R. Statistical considerations for testing multiple 
endpoints in group sequential or adaptive clinical trials. Journal of Biopharmaceutical 
Statistics 2007;17:1201-1210.
18.
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Statistics in Biopharmaceutical Research 2013;5:311-320.
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Appendix 1. Collection and Management of Specimens for Future Biomedical Research
Scope of Future Biomedical Research
The DNA, plasma and serum specimens collected in the current trial will be used to study 
various causes for how subjects may respond to a drug.  The DNA, plasma and serum 
specimens will be stored to provide a resource for future studies conducted by the sponsor 
focused on the study of biomarkers responsible for how a drug enters and is removed by the 
body, how a drug works, other pathways a drug may interact with, or other aspects of 
disease. 
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, 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 the sponsor or designees and research will be monitored 
and reviewed by a committee of our scientists and clinicians.
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 response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
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.
                                                
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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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all subjects or legal guardians, at a study visit by 
the investigator or his or her designate.  Informed consent for Future Biomedical 
Research should be presented to the subjects at the first visit.  If delayed, present consent 
at next possible subject visit.  Informed consent must be obtained prior to collection of all 
Future Biomedical Research specimens.
Subjects are not required to participate in Future Biomedical Research in order to 
participate in the main trial.
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.  Subjects who decline to sign the Future Biomedical 
Research informed consent will not have the specimen collected nor will they be 
withdrawn from the main study. 
A template of each study 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-study'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 study 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 (eg, DNA or RNA extraction, etc) following the Merck approved 
policies and procedures for specimen handling and preparation.
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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 study 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. 
At the clinical 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 study 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 study 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 
(ie, 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 health authorities (eg, EMA, 
FDA), whereby this information would be directly transferred to the health authority.
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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.
Analyses utilizing the Future Biomedical Research specimens may be performed by Merck, 
or an additional third party (eg, 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-study.  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.
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 
writing to the principal investigator for the main study.  If medical records for the main study 
are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) 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 study data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory agencies to retain the main study 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. 
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 agency has active questions that are being answered.  In this 
special circumstance, specimens will be stored until these questions have been adequately 
addressed.
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Specimens from the 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.
Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-study 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 study 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 
(eg, 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-study will not be used for any 
other purpose.
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 
study 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 practices 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 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 
(eg, 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.
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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 studies 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.
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 study. 
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 (ie, ethnicity, diagnosis, drug therapy and dosage, age, 
toxicities, etc) to be reassociated 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.
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.
Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
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