Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 621
Healthy volunteers: no

Brief summary:
This is an efficacy and safety study of ertugliflozin in participants with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on metformin monotherapy. The primary study hypothesis is that at Week 26, the mean reduction from baseline in hemoglobin A1c (HbA1c) for ertugliflozin is greater than that for placebo.

Detailed description:
The trial includes a 13-15 week run-in period prior to randomization, and a 26-week, double-blind, placebo-controlled treatment period followed by a 78-week double-blind, extension period.

Arms:
arm 1: Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated. arm 2: Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received glimepiride/placebo. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated. arm 3: Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with open-label glimepiride, and if they met rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. After Week 26, non-rescued participants who had a fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride. If a participant met glycemic rescue criteria after 26 weeks, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.

Interventions: intervention 1: Ertugliflozin 5 mg intervention 2: Ertugliflozin 15 mg intervention 3: Placebo to Ertugliflozin intervention 4: Glimepiride intervention 5: Placebo to Glimepiride intervention 6: Basal Insulin intervention 7: Metformin
Intervention descriptions: intervention 1: Ertugliflozin 5 mg orally (1 ertugliflozin 5 mg tablet and 1 placebo ertugliflozin 10 mg tablet), once daily from Day 1 to Week 104. intervention 2: Ertugliflozin 15 mg orally (1 ertugliflozin 5 mg tablet and 1 ertugliflozin 10 mg tablet), once daily from Day 1 to Week 104. intervention 3: Placebo to ertuglioflozin (1 placebo ertugliflozin 5 mg tablet and/or 1 placebo ertugliflozin 10 mg tablet), orally once daily from Day 1 to Week 104. intervention 4: Open-label Glimepiride will be used for glycemic rescue therapy (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) in the 26-week initial period. Blinded Glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride will be used in the 78-week extension period in participants who were not rescued with open-label glimepiride during the 26-week initial period. intervention 5: Placebo to glimepiride will be used in the 78-week extension period in participants who were not rescued with open-label glimepiride during the 26-week initial period. Dosing and titration of placebo to glimepiride is at the discretion of the investigator. intervention 6: Basal insulin will be administered in the initial 26-week period for participants with glucose values exceeding protocol-specified values and for participants requiring rescue therapy in the 78-week extension period. Dosing and titration of basal insulin is at the discretion of the Investigator. intervention 7: Metformin \>=1500 mg/day, orally, once a day

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 26-
Week Multicenter Study With A 78-Week Extension To 
Evaluate The Efficacy And Safety Of Ertugliflozin In Subjects 
With Type 2 Diabetes Mellitus And Inadequate Glycemic 
Control On Metformin Monotherapy
NCT number: 
NCT02033889 
Document Date: 
20-Sep-2013


Ertugliflozin (MK-8835/PF-04971729)
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CLINICAL PROTOCOL 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
26-WEEK MULTICENTER STUDY WITH A 78-WEEK EXTENSION TO 
EVALUATE THE EFFICACY AND SAFETY OF ERTUGLIFLOZIN IN SUBJECTS 
WITH TYPE 2 DIABETES MELLITUS AND INADEQUATE GLYCEMIC 
CONTROL ON METFORMIN MONOTHERAPY
Compound:
MK-8835/PF-04971729
Compound Name:
Ertugliflozin
United States (US) Investigational New 
Drug ( IND) Number:
106,447
European Clinical Trial Database 
(EudraCT) Number:
2013-003290-95
Protocol Number:
MK-8835-007-00 (Merck Protocol Number)
B1521017 (Pfizer Protocol Number)
Phase:
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
Original protocol
20 September 2013
Not Applicable (N/A)
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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 (SGLT1) and several other glucose transporters 
(GLUT1-4).  Ertugliflozin inhibits renal glucose reabsorption resulting in urinary glucose 
excretion and thereby reducing plasma glucose and 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.  The purpose of this trial is to evaluate the 
efficacy and safety of the addition of ertugliflozin to the treatment regimen of subjects with 
T2DM who have inadequate glycemic control on metformin monotherapy.  This trial will 
also provide an assessment of bone safety of ertugliflozin by measurement of bone mineral 
density (BMD). 
Objectives and Hypotheses:
In subjects with T2DM and inadequate glycemic control on a stable dose of metformin
monotherapy;
The primary objectives and hypotheses of the trial are:
1. Objective:  At Week 26, to assess the effect on HbA1c of 15 mg ertugliflozin as 
compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in HbA1c for 15 mg 
ertugliflozin is greater than that for placebo.
2. Objective:  At Week 26, to assess the effect on HbA1c of 5 mg ertugliflozin as 
compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in HbA1c for 5 mg 
ertugliflozin is greater than that for placebo.
3. Objective:  To assess the safety and tolerability of ertugliflozin.
The secondary objectives and hypotheses of the trial are:
1. Objective:  At Week 26, to assess the effect on fasting plasma glucose (FPG) of 
15 mg ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in FPG for 15 mg 
ertugliflozin is greater than that for placebo.
2. Objective:  At Week 26, to assess the effect on FPG of 5 mg ertugliflozin as 
compared with placebo.
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Hypothesis:  At Week 26, the mean reduction from baseline in FPG for 5 mg 
ertugliflozin is greater than that for placebo.
3. Objective:  At Week 26, to assess the effect on body weight of 15 mg ertugliflozin 
as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in body weight for 
15 mg ertugliflozin is greater than that for placebo.
4. Objective:  At Week 26, to assess the effect on body weight of 5 mg ertugliflozin 
as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in body weight for 5 mg 
ertugliflozin is greater than that for placebo.
5. Objective:  At Week 26, to assess the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 15 mg ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 15 mg ertugliflozin is greater than that for placebo.
6. Objective:  At Week 26, to assess the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 5 mg ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 5 mg ertugliflozin is greater than that for placebo.
7. Objective:  At Week 26, to assess the effect on systolic blood pressure of 15 mg 
ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in systolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.
8. Objective:  At Week 26, to assess the effect on systolic blood pressure of 5 mg 
ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in systolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.
9. Objective:  At Week 26, to assess the effect on diastolic blood pressure of 15 mg 
ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in diastolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.
10. Objective:  At Week 26, to assess the effect on diastolic blood pressure of 5 mg 
ertugliflozin as compared with placebo.
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Hypothesis:  At Week 26, the mean reduction from baseline in diastolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.
11. Objective: At Week 26, to assess the proportion of subjects with an HbA1c 6.5%, 
incidence of subjects requiring glycemic rescue therapy, and time to initiation of 
glycemic rescue therapy for each ertugliflozin arm compared with placebo.
12. Objective: At Week 52, to assess the change from baseline in efficacy endpoints 
relating to HbA1c and FPG; proportion of subjects with an HbA1c <7%; the 
proportion of subjects with an HbA1c 6.5%; incidence of subjects requiring 
glycemic rescue therapy; and time to initiation of glycemic rescue therapy for each 
of the two ertugliflozin arms.
13. Objective: At Week 52, to assess the change from baseline in efficacy endpoints 
relating to body weight, and the change from baseline in systolic and diastolic 
blood pressure.
14. Objective: At Week 104, to assess the change from baseline in efficacy endpoints 
relating to HbA1c, and FPG; proportion of subjects with anHbA1c <7%; proportion 
of subjects with anHbA1c 6.5%, incidence of subjects requiring glycemic rescue
therapy; and time to initiation of glycemic rescue therapy for each of the two 
ertugliflozin arms.
15. Objective: At Week 104, to assess the change from baseline in efficacy endpoints 
relating to body weight, and the change from baseline in systolic and diastolic 
blood pressure.
16. Objective:  To descriptively summarize pharmacokinetics of ertugliflozin in this 
study and provide pharmacokinetic (PK) data for potential population PK analysis.
Secondary objectives related to bone safety are:
17. Objective: At Week 26, to assess the effect on BMD as measured by dual energy 
X-Ray Absorptiometry (DXA) at the lumbar spine (L1-L4), femoral neck, total hip,
and distal forearm for each of the two ertugliflozin arms ertugliflozin as compared 
with placebo.
18. Objective: At Week 26, to assess the effect on bone biomarkers of each of the two 
doses of ertugliflozin as compared with placebo.
19. Objective: At Week 52, to assess the change from baseline in BMD as measured 
by DXA at the lumbar spine (L1-L4), femoral neck, total hip and distal forearm for 
each of the two ertugliflozin arms.
20. Objective: At Week 52, to assess the change from baseline in bone biomarkers for 
each of the two ertugliflozin arms.
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21. Objective: At Week 104, to assess the change from baseline in BMD as measured 
by DXA at the lumbar spine (L1-L4), femoral neck, total hip and distal forearm for 
each of the two ertugliflozin arms.
22. Objective: At Week 104, to assess the change from baseline in bone biomarkers for 
each of the two ertugliflozin arms.
Study Population:
Men and women, 18 years of age with T2DM, diagnosed in accordance with American 
Diabetes Association (ADA) guidelines, and inadequate glycemic control [HbA1c 
7.0-10.5%, 53-91 mmol/mol, inclusive)] on metformin monotherapy at a dose 1500 mg/day.
Approximately 50% of the population enrolled in the trial will be women who have been 
post-menopausal for 3 years or more (at least 3 years since their last menstrual period [LMP]
or bilateral oophorectomy performed 3 years or more prior to screening), and the 
randomization will be stratified based on this post-menopausal status (as well as geographical 
region – primarily to facilitate drug supply logistics).  Details on the stratification factors for 
randomization are provided in Section 4.3.
Study Design:
This trial is a Phase 3 multi-center, randomized, parallel-group study with a 26-week, 
double-blind, placebo-controlled treatment period (Phase A) followed by a 78-week 
double-blind, extension period (Phase B) in subjects with T2DM and inadequate glycemic 
control on metformin monotherapy. Subjects could participate in the trial for approximately 
up to 119 weeks. The trial includes a 1-week screening period, a variable interval for 
metformin titration (if needed), and at least an 8-week metformin stable dose period when 
subjects will discontinue and remain off any previous allowable background diabetes therapy 
(except for metformin), and a 2-week single-blind placebo run-in period prior to 
randomization. 
The trial is designed to accommodate subjects taking a variety of baseline diabetes therapy 
regimens at the Screening visit by incorporating a period of metformin titration and dose 
stabilization, and washoff of another anti-hyperglycemic agent (AHA) if necessary, prior to 
placebo run-in.  Subjects will be eligible to screen for this trial if they are receiving one of 
the following diabetes therapy regimens at the time of Screening Visit 1 (S1): 

Metformin monotherapy;

Combination therapy with metformin and one of the following oral AHAs: 
sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, meglitinide, or alpha-
glucosidase inhibitor. 
Subjects receiving metformin in combination with another allowable AHA must discontinue 
the other AHA beginning at the Screening Visit 2 (S2) and remain off the other AHA for the 
duration of this trial.
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The following table provides information on the allowable HbA1c levels at S1 based upon 
the background diabetes therapy.  In addition, the table includes the subsequent actions to be 
taken based on the background diabetes regimen.
Table 1.
Background Diabetes Therapy at Screening Visit 1 (S1), HbA1c Initial 
Inclusion and Appropriate Changes in Background Diabetes Therapy
Diabetes Therapy at Screening 
Visit (S1)
HbA1c 
Inclusion Criterion at S1
Change in Background Diabetes Therapy 
Prior to Placebo Run-in (S3)
Metformin monotherapy, 
1500 mg/day for 8 weeks
7.0%–10.5% (53-91
mmol/mol), inclusive
None.  Subjects proceed directly to a 
combined S2/S3 Visit.
Metformin monotherapy,
1500 mg/day for <8 weeks
7.0%–10.5% (53-91
mmol/mol), inclusive
Maintain metformin dose 1500 mg/day so 
subject has 8 weeks on stable dose.
Metformin monotherapy, 
<1500 mg/day
7.5% - 11.0% (58-97
mmol/mol), inclusive 
Titrate metformin dose to 1500 mg/day.  
The dose stable period must be 8 weeks.
Metformin + another single 
allowable AHA*
6.5%–9.5% 
(48-80 mmol/mol), 
inclusive
Discontinue the other AHA.  Titrate 
metformin dose to 1500 mg/day (if 
needed).  The dose stable period for 
metformin monotherapy must be 8 weeks.
HbA1c = Glycosylated hemoglobin; AHA = Anti-hyperglycemic agent; S1 = Initial screening visit; 
S2/S3 = Combined Screening Visits 2 and 3. 
*allowable AHA agents are sulfonylurea, DPP-4 inhibitor, meglitinide, or alpha-glucosidase inhibitor.
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The trial scheme is illustrated below:
Met= Metformin
The trial is designed with three phases:
1. Screening phase including discontinuation of background diabetes therapy other 
than metformin (if applicable) and a placebo run-in period (Visits S1 up to V4) - the 
length of this standardization period will vary depending on the diabetes therapy of 
subjects at S1 (metformin monotherapy 1500 mg/day for 8 weeks or for <8 weeks, 
metformin monotherapy <1500 mg/day or metformin + another single allowable AHA) 
as shown in Table 1.
2. Phase A: Randomized, double-blind, placebo-controlled treatment period (Visits V4 
through V8) - a 26-week treatment period for assessment of primary and secondary 
safety and efficacy endpoints.  At entry into Phase A, subjects will be randomized to 
ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo, while maintaining metformin at a 
dose 1500 mg/day.  Glycemic rescue therapy with open-label glimepiride and basal
insulin should be initiated in subjects with glucose values exceeding protocol-specified 
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values as mentioned in Section 5.6. Dosing and titration of open-label glimepiride rescue 
therapy is at the discretion of the Investigator.
3. Phase B: Double-Blind, extension period (Visits V8 through V15) – a 78-week, 
double-blind extension period where subjects randomized to ertugliflozin will remain on 
their randomized treatment–: subjects randomized to placebo will have the addition of 
treatment with glimepiride (if they were not rescued during Phase A), maintaining the 
double-blinding; this is accomplished by the use of blinded glimepiride or matching 
placebo, as described below:   

Subjects randomized to ertugliflozin (5 or 15 mg) are continued on their randomized 
dose of ertugliflozin, and

If not rescued in Phase A: will be started on the addition of placebo matching 
glimepiride (and with mock uptitration using glimepiride placebo tablets 
matching 1 or 2 mg tablets, as determined appropriate by the investigator).

If rescued in Phase A: will not be started on placebo matching glimepiride, and 
open-label glimepiride will be continued into Phase B.

Subjects randomized to the placebo treatment group will continue on the placebo 
tablets matching ertugliflozin and

If not rescued in Phase A: will be started on the addition of glimepiride (1 mg), 
with titration with 1 or 2 mg tablets (to maximum allowed dose [6 or 8 mg] based 
upon the local label]) as determined appropriate by the investigator.

If rescued in Phase A: will not be started on glimepiride, and open label rescue 
glimepiride will be continued into Phase B. 
Note: subjects whose Week 26 visit fasting fingerstick glucose is <110 mg/dL 
(6.1 mmol/L) will not have the glimepiride or matching placebo initiated at the 
Week 26 visit. At each subsequent scheduled study visit, if the fasting fingerstick 
glucose (FFSG) is 110 mg/dL, glimepiride or matching placebo tablets may be 
initiated (unless not considered appropriate by the investigator based upon the risk of 
hypoglycemia). 
During Phase B, glycemic rescue therapy with basal insulin should be initiated in subjects 
with glucose values or HbA1c values exceed protocol-specified values (See Section 5.6)
The trial is designed to evaluate the efficacy, safety and tolerability of the 5 mg and 15 mg 
oral doses of ertugliflozin on glycemic control, body weight, and blood pressure following a 
26-week dosing period in adult subjects with T2DM and inadequate glycemic control on 
metformin monotherapy. It is also designed to evaluate the longer-term efficacy, safety and 
tolerability of ertugliflozin during the entire 104-week treatment period, which includes a 
78-week double-blind extension period.  A key purpose of this 78-week extension period is 
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to collect additional safety data of ertugliflozin on BMD.  The effect of ertugliflozin on BMD
will be assessed by DXA. All DXA data throughout the trial will be forwarded to a central 
evaluation facility to ensure standardization. 
Approximately 600 subjects will be randomized to ensure a minimum of 480 subjects 
(160 per arm) will provide HbA1c data at the Week 26 primary timepoint.  Given the plans 
not to replace those subjects who are withdrawn early, the 600 subjects randomized will also 
account for an approximate 20% premature withdrawal rate for HbA1c data to allow for 
withdrawn subjects who will still be included in the analysis, but will not necessarily have 
Week 26 data available. 
Glycemic Rescue Therapy:
Subjects will be prescribed rescue therapy in the form of open-label glimepiride and basal 
insulin, and dosed according to Investigator judgment, if they meet specific glycemic criteria 
which become progressively more stringent throughout the trial. Provision of rescue with 
basal insulin is to occur only once subjects have first been titrated to a maximum tolerated or 
maximum approved dose of glimepiride (based on local country label) and continue to 
exceed the protocol-specified glycemic values.
Endpoints:
Primary Endpoint: 

The primary endpoint is the change in HbA1c from Baseline at Week 26.
Secondary Endpoints:

Change in FPG from Baseline to Week 26.

Change in body weight from Baseline to Week 26.

Incidence of HbA1c of <7% (53 mmol/mol) at Week 26.

Change in systolic and diastolic blood pressure from Baseline to Week 26.

Change in HbA1c, FPG, and body weight from Baseline to Weeks 52 and 104.

Incidence of HbA1c <7% (53 mmol/mol) at Weeks 52 and 104.

Incidence of HbA1c 6.5% (48 mmol/mol) at Weeks 26, 52 and 104.

Change in systolic and diastolic blood pressure from Baseline to Weeks 52 and 104.

Incidence of subjects requiring glycemic rescue therapy up to Weeks 26, 52 and 104.

Time to glycemic rescue therapy up to Weeks 26, 52 and 104.
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
Endpoints related to pharmacokinetics of ertugliflozin.
Secondary endpoints related to bone safety are:

Change in BMD as measured by DXA at the lumbar spine (L1-L4), femoral neck, total 
hip and distal forearm from Baseline to Week 26.

Change in BMD as measured by DXA at the lumbar spine (L1-L4), femoral neck, total 
hip and distal forearm from Baseline to Weeks 52 and 104.

Change from baseline in bone biomarkers at Weeks 26, 52 and 104.
Statistical Methods:
Sample Size: With respect to the primary endpoint of reduction in HbA1c from Baseline to 
Week 26 and assuming a standard deviation (SD) of 1.0%, the sample size of approximately 
600 subjects (200 per arm) provides at least 99% power to detect a difference of 0.5% 
between each ertugliflozin dose and placebo (and 98% power for detecting this difference for 
both doses vs placebo) using a two-sided 0.05 alpha level test, allowing for a dropout rate of 
up to 20%. To control the overall Type I error rate at 0.05 a sequential testing approach will 
be used across the primary and secondary efficacy endpoints for which hypotheses will be 
tested, and for the two doses of ertugliflozin.
The sample size for this trial also provides adequate precision for the comparison of 
ertugliflozin versus placebo with respect to the changes in BMD from Baseline to Week 26.  
In a recent study of another SGLT2 inhibitor (dapagliflozin) in subjects with inadequately 
controlled T2DM on metformin, the largest variability for the change from baseline in BMD 
was at the total hip site, with an SD of approximately 3.3% after 50 weeks.13  Assuming that 
the SD of the change in BMD increases over time, 3.3% was taken as a conservative estimate 
of the variability at 26 weeks for precision calculations, and also to ensure adequate precision 
for all BMD sites.
Assuming an SD of 3.3% and allowing for a dropout rate of up to 15% at Week 26, the
half-width of the 95% confidence interval for the between-treatment difference is expected to 
be 0.7% from the point estimate for the overall study population, and also of approximately 
1.0% for the 3 years post-menopausal sub-group which will be analyzed separately 
(approximately 50% of the overall study population). 
These CI half-widths would be precise enough to rule out clinically relevant changes in 
BMD, both for the overall study population and the 3 years post-menopausal subgroup. 
This is based on changes in BMD that are approximately 50% of the average changes from 
baseline to Week 80 observed for thiazolidinediones, which are known to be associated with 
significant bone loss and an increased risk of fracture.19
BMD data will not be censored at the point of a subject taking glycemic rescue therapy so the 
dropout rate assumed for this precision calculation (15%) is lower than that assumed for the 
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HbA1c power calculation (20%).  However BMD data will be censored at the point of a 
subject taking BMD rescue therapy.
Primary analysis population: The primary analysis population for all efficacy analyses will 
be the Full Analysis Set defined separately for each analysis endpoint as all randomized 
subjects who have received at least one dose of investigational product and have at least one 
measurement of the respective endpoint at any time during Phase A of the trial, including 
Baseline and post-Baseline time points.  The post glycemic rescue therapy data from subjects 
who require rescue therapy prior to Week 26 will be censored from primary and secondary 
endpoint efficacy analyses.
Efficacy analyses:
Analysis of Primary Endpoint: 
The primary endpoint of HbA1c will be analyzed by fitting a constrained longitudinal data 
analysis model with terms for treatment, visit, treatment by-visit interaction and menopausal 
status randomization stratum.  Least-squares means and 95% confidence intervals will be 
used to estimate the treatment effect (difference between ertugliflozin and placebo) at the 
primary time point of Week 26.  The two-sided p-value will also be provided for testing the 
significance of the difference between treatment groups. 
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.
Analysis of Secondary Endpoints: 
The proportion of subjects with an HbA1c <7% (53 mmol/mol) at Week 26 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, 95% 
confidence interval for the odds ratio, and p-value for the comparison of treatment groups. 
The secondary endpoints of FPG, body weight, systolic blood pressure and diastolic blood 
pressure will be analyzed separately by fitting constrained longitudinal data analysis models 
similar to that used for the primary endpoint.
The secondary efficacy endpoints of FPG, proportion of subjects achieving an HbA1c <7%, 
body weight, systolic blood pressure and diastolic blood pressure will be tested for each 
ertugliflozin dose versus placebo using a multiple testing procedure that strongly controls the 
overall Type I error rate at 0.05. 
Analysis of BMD
The changes in BMD from Baseline to Week 26 at the lumbar spine, femoral neck, total hip, 
and distal forearm will be safety endpoints.  A BMD analysis set will be defined to include 
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all randomized subjects who have received at least one dose of investigational product and 
have at least one observation of BMD at any time during Phase A of the trial, including 
Baseline and post-Baseline time points.  For analyses of changes in BMD, measurements 
obtained post glycemic rescue therapy will be utilized if available; however BMD 
measurements will be censored at the point of a subject taking BMD rescue therapy. 
Changes from Baseline to Week 26 in BMD will be analyzed by fitting a constrained 
longitudinal data analysis model with terms for treatment, visit, treatment by-visit interaction 
and menopausal status randomization stratum.  Least-squares means and 95% confidence 
intervals will be used to estimate the treatment effect (difference between ertugliflozin and 
placebo) at Week 26.
The BMD analyses will also be conducted separately for the male and female subgroups, and 
also for subjects who completed 20 weeks of study treatment.  Another sub-group analysis 
will be conducted separately for women post-menopausal for 3 years or more after last LMP 
(approximately 50% of the overall study population).  Descriptive statistics will also be 
provided for each of the four randomization strata.
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c.
All Day 1 procedures to be completed prior to dosing.
d.
ET = Early termination, subjects who discontinue taking investigational product prematurely should complete procedures for the ET visit and have a 2-week 
follow-up phone call from their last dose of investigational product.  In addition, if subjects agree, they will also be contacted via telephone by the 
Investigator/qualified designee according to the same schedule as if the subjects were still taking investigational product to assess for SAEs and to collect 
information on clinical events per Section 7.8, if applicable.  See Section 6.7 for additional details.
e.
Each randomized subject should have a follow-up phone call 14 3 days after the last dose of investigational product to assess for SAEs and to collect 
information on clinical events per Section 7.8, if applicable.
f.
Subjects who require glycemic rescue therapy per Section 5.6 must have rescue therapy initiated at either a scheduled or unscheduled visit, and not by a 
telephone call. 
g.
Brief physical examination includes assessment of heart, lungs, abdomen, extremities and skin. 
h.
Sitting triplicate blood pressure and pulse rate should be collected, as instructed in Section 7.4.2.
i.
Duplicate measurements of supine and standing blood pressure and pulse rate should be taken per Section 7.4.3. Postural changes should only be collected 
at the Rescue Visit if the Rescue Visit occurs in Phase A.
j.
S2 ECG is read locally at investigative site.  ECG for all other time points should be submitted to be read centrally.
k.
Screening DXA scans should be performed at Visit S3 or at least ten days before Day 1 visit. In case of discontinuation of investigational product during 
Phase A, a DXA scan will be performed if the discontinuation occurs between Week 12 and Week 26.  In case of discontinuation of investigational product 
during Phase B, a DXA scan will be performed if the discontinuation occurs at least 12 weeks from the previous scan.  See Section 7.6 for additional details.
l.
Routinely collected urinalysis samples will be sent to the central laboratory for dipstick analysis (not including glucose assessment) and microscopy if 
dipstick is positive for blood, nitrites, leukocytes and/or protein.
m. Urine sample(s) for urinalysis and albumin:creatinine ratio 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.  Under these circumstances, the subject should provide a urine sample for evaluation at an
unscheduled visit.  
n.
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.
o.
C-peptide test is only for subjects assessed by the Investigator as possibly having type 1 diabetes.
p.
Includes total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides at all time points noted above.  ApoB 
and ApoA-1 are included at Day 1 and Week 26 visits as well as the glycemic rescue visit and early termination visit.
q.
Urine pregnancy tests will be performed for women of childbearing potential at all time points noted above, and if positive must be confirmed with a serum 
pregnancy test.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
r.
Subjects taking metformin monotherapy for less than 8 weeks at S1 or who require a change to their diabetes regimen at the S2 visit to remain eligible to 
participate (including subjects discontinuing AHA therapy at S2) must have an HbA1c of 7.0-10.5% (53-91 mmol/mol) at S3 in order to be randomized.  
s.
HbA1c should not be obtained if ET or rescue visit occurs within 6 weeks of randomization.
t.
PK samples are to be collected at approximately 24 hour following the prior day’s dose and before administration of the current day’s dose.  In addition, PK 
samples will also be collected 1 hr post dose at Weeks 12 and 18 (with an allowable time window up to 3 hours post dose).
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u.
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 Day 1/Visit 4, 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 26, Week 104 or Early 
Termination Visit, and 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.
v.
The sample(s) for measurement of bone biomarkers and PTH should not be collected if the investigational product has been discontinued for >7 days prior to 
the collection of the sample(s).
w.
Subjects will be seen by a dietician or qualified healthcare professional for dietary and exercise counseling at S2 Visit only; at other visits subjects should be 
asked about their diet and exercise which may be done by other appropriate site personnel evaluating the subject.
x.
Subjects should be educated on the symptoms of hyperglycemia (eg, polyuria, polydipsia) at S2.
y.
Assess AEs, SAEs, hypoglycemia assessment log as well as potential clinical events for adjudication (See Sections 7.4.6, 7.8, 8 for additional detail).
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................24
LIST OF FIGURES .................................................................................................................24
APPENDICES .........................................................................................................................25
1. INTRODUCTION ...............................................................................................................30
1.1. Indication.................................................................................................................30
1.2. Background .............................................................................................................30
1.3. Efficacy of Ertugliflozin..........................................................................................31
1.4. Safety Information for Ertugliflozin and Other SGLT2 Inhibitors.........................31
1.5. Rationale for Study and Design ..............................................................................33
1.5.1. Rationale for Dose Selection of Ertugliflozin ............................................34
1.5.2. Rationale for Future Biomedical Research.................................................35
2. STUDY OBJECTIVES, HYPOTHESES AND ENDPOINTS ...........................................35
2.1. Objectives and Hypotheses .....................................................................................35
2.2. Endpoints.................................................................................................................38
2.2.1. Primary Endpoint........................................................................................38
2.2.2. Secondary Endpoints ..................................................................................38
3. STUDY DESIGN.................................................................................................................39
4. SUBJECT SELECTION......................................................................................................43
4.1. Inclusion Criteria.....................................................................................................43
4.2. Exclusion Criteria....................................................................................................45
4.3. Randomization Criteria ...........................................................................................50
4.4. Life Style Guidelines...............................................................................................51
4.4.1. Dietary Restrictions ....................................................................................51
4.4.2. Physical Activities ......................................................................................51
4.4.3. Alcohol, Caffeine and Tobacco ..................................................................51
4.4.4. Female Contraception.................................................................................52
4.4.4.1. Females– Non-childbearing Potential .......................................52
4.4.4.2. Females of Childbearing Potential ............................................52
4.5. Sponsor Qualified Medical Personnel.....................................................................52
5. STUDY TREATMENT.......................................................................................................53
5.1. Allocation to Treatment ..........................................................................................53
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5.2. Breaking the Blind ..................................................................................................53
5.3. Drug Supplies..........................................................................................................54
5.3.1. Formulation and Packaging........................................................................54
5.3.2. Placebo Run-in............................................................................................54
5.3.3. Concomitant Metformin .............................................................................54
5.3.4. Administration (Ertugliflozin/Placebo) ......................................................55
5.3.5. Drug Supplies for Phase B..........................................................................55
5.3.5.1. Administration of Glimepiride/Matching Placebo....................56
5.3.6. Compliance.................................................................................................57
5.4. Drug Storage and Drug Accountability...................................................................57
5.5. Concomitant Medication(s).....................................................................................58
5.6. Glycemic Rescue Therapy ......................................................................................59
5.6.1. Drug Supplies for Glycemic Rescue Therapy ............................................60
6. STUDY PROCEDURES .....................................................................................................60
6.1. Instructions to Subjects ...........................................................................................61
6.1.1. Dispense Hypoglycemia Assessment Log and Instruct on 
Hypoglycemia Symptoms and Management ...................................................61
6.1.2. Diet and Exercise Counseling.....................................................................62
6.2. Screening.................................................................................................................62
6.2.1. Screening Visit 1 (S1).................................................................................62
6.2.2. Screening Visit 2 (S2).................................................................................63
6.2.3. Placebo Run-in (Visit S3 or Combined S2/S3) ..........................................64
6.3. Phase A: Double-Blind, Placebo-Controlled Treatment Period (Visits 4 
through 8) ..................................................................................................................65
6.3.1. Day 1 (Visit 4) ............................................................................................65
6.3.2. Week 6 (Visit 5)..........................................................................................66
6.3.3. Week 12 (Visit 6)........................................................................................68
6.3.4. Week 18 (Visit 7)........................................................................................69
6.3.5. Week 26 (Visit 8)........................................................................................70
6.4. Phase B: Double-Blind Extension Period (Visits 8 through 15).............................71
6.4.1. Week 30 (Visit 9)........................................................................................71
6.4.2. Week 39 (Visit 10) through Week 91 (Visit 14) ........................................72
6.4.3. Week 52 (Visit 11)......................................................................................73
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6.4.4. Week 104 (Visit 15) – Final Study Visit/Early Termination Visit.............74
6.5. Follow-up Phone Call..............................................................................................75
6.6. Rescue Visit, if applicable.......................................................................................75
6.7. Subject Withdrawal.................................................................................................76
6.7.1. Withdrawal from Future Biomedical Research..........................................77
6.7.2. Reasons for Discontinuation from Investigational Product or from 
the Trial............................................................................................................77
6.7.2.1. Follow-up for Subjects who Discontinue Due to 
Decreased Renal Function.................................................................79
7. ASSESSMENTS..................................................................................................................80
7.1. Pregnancy Testing...................................................................................................80
7.2. Body Weight ...........................................................................................................80
7.3. Physical Examinations ............................................................................................81
7.4. Safety.......................................................................................................................81
7.4.1. Clinical Laboratory Tests ...........................................................................81
7.4.1.1. Lipid Panel and Apolipoproteins...............................................82
7.4.1.2. Urinary Albumin:Creatinine Ratio............................................82
7.4.2. Vital Signs (Sitting Blood Pressure and Pulse Rate)..................................83
7.4.3. Postural (Orthostatic) Blood Pressure and Pulse Rate................................83
7.4.4. Electrocardiogram, (12-lead ECG).............................................................84
7.4.5. Review of Self-Monitoring Glucose Logs..................................................84
7.4.6. Review of Hypoglycemia Assessment Logs ..............................................85
7.4.6.1. Management of Hypoglycemia .................................................85
7.4.7. Assessment of Infections............................................................................86
7.4.7.1. Urinary Tract Infections............................................................86
7.4.7.2. Genital Fungal Infections..........................................................86
7.5. Pharmacokinetics of Ertugliflozin...........................................................................87
7.5.1. Plasma for PK Analysis..............................................................................87
7.6. Dual-Energy X-Ray Absorptiometry (DXA)..........................................................87
7.6.1. Bone Mineral Densitometry .......................................................................87
7.6.1.1. Rescue Criteria Related to Loss of BMD..................................88
7.7. Bone Biomarkers, PTH ...........................................................................................88
7.8. Clinical Event Adjudication....................................................................................89
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7.8.1. Clinical Cardiovascular Events, Venous Thromboembolic Events 
and All Deaths..................................................................................................89
7.8.2. Fractures .....................................................................................................90
7.8.3. Pancreatitis..................................................................................................90
7.8.4. Liver Injury.................................................................................................90
7.8.5. Acute Renal Failure....................................................................................91
8. ADVERSE EVENT REPORTING......................................................................................91
8.1. Assessing and Recording Adverse Events ..............................................................91
8.2. Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor................................................................................................................92
8.3. Reporting of Pregnancy and Lactation to the Sponsor............................................92
8.4. Immediate Reporting of Adverse Events to the Sponsor ........................................92
8.4.1. Serious Adverse Events ..............................................................................92
8.5. Evaluating of Adverse Events.................................................................................93
8.6. Events of Clinical Interest.......................................................................................97
8.7. Management of Subjects with Elevated Liver Enzymes (ALT or AST 3X 
ULN)..........................................................................................................................97
8.8. Serious Adverse Events Exempt from Expedited Reporting by the Sponsor .......101
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................102
9.1. Sample Size Determination...................................................................................102
9.2. Efficacy Analysis ..................................................................................................103
9.2.1. Analysis of Primary Endpoint ..................................................................103
9.2.2. Analysis of Secondary Endpoints.............................................................104
9.2.3. Analysis of Other Secondary Endpoints...................................................105
9.2.3.1. Analysis of BMD ....................................................................105
9.2.4. Endpoints Related to Pharmacokinetics of Ertugliflozin..........................106
9.3. Safety Analysis......................................................................................................106
9.4. Planned Analyses ..................................................................................................107
9.5. Data Monitoring Committee .................................................................................107
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................107
11. DATA HANDLING AND RECORD KEEPING ...........................................................108
11.1. Case Report Forms/Electronic Data Record .......................................................108
11.2. Record Retention.................................................................................................108
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12. ETHICS............................................................................................................................109
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........109
12.2. Ethical Conduct of the Study ..............................................................................109
12.3. Subject Information and Consent........................................................................109
12.3.1. Informed Consent for Future Biomedical Research ...............................110
12.4. Subject Recruitment ............................................................................................110
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................110
13. DEFINITION OF END OF TRIAL.................................................................................110
13.1. End of Trial in a Member State...........................................................................110
13.2. End of Trial in all Other Participating Countries ................................................111
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................111
15. PUBLICATION OF STUDY RESULTS........................................................................111
15.1. Communication of Results by the Sponsor.........................................................111
15.2. Publications by Investigators ..............................................................................112
16. REFERENCES ................................................................................................................113
LIST OF TABLES
Table 1.
Background Diabetes Therapy at Screening Visit 1 (S1), HbA1c Initial 
Inclusion and Appropriate Changes in Background Diabetes Therapy..................7
Table 2.
Estimated Percent Maximum Response for Various Endpoints...........................34
Table 3.
Background Diabetes Therapy at Screening Visit 1 (S1), HbA1c Initial 
Inclusion and Appropriate Changes in Background Diabetes Therapy................40
Table 4.
Glycemic Thresholds............................................................................................59
Table 5.
Clinical/Safety Central Laboratory Tests .............................................................82
Table 6.
Evaluating Adverse Events...................................................................................94
LIST OF FIGURES
Figure 1.
Trial Scheme.........................................................................................................41
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APPENDICES
Appendix 1. Collection and Management of Specimens for Future Biomedical 
Research..............................................................................................................115
Appendix 2. Biomarker Brochure..........................................................................................121
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LIST OF ABBREVIATIONS
Abbreviation
Term
-hCG
beta human chorionic gonadotropin
ACE
angiotensin-converting enzyme
ADR
adverse drug reaction
AE
adverse event
AHA
anti-hyperglycemic agent
ALT
alanine transaminase
ANCOVA
analysis of covariance
Apo A1
apolipoprotein A1
ApoB
apolipoprotein B
AST
aspartate transaminase
AUC
area under the concentration-time curve
BMD
bone mineral density
BMI
body mass index
BP
blood pressure
BPM
beats per minute
BUN
blood urea nitrogen
CHF
Congestive heart failure
Cmax
maximum observed measurable concentration
CRA
clinical research associate
CRF
case report form
CSA
clinical study agreement
CTX
carboxy-terminal cross-linking telopeptides of Type I collagen
CV
cardiovascular
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl peptidase-4
DXA
dual energy X-Ray Absorptiometry
ECG
electrocardiogram
ECI
event of clinical interest
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ED50
dose achieving 50% of maximum response
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency 
ER
Extended Release
ET
early termination of the study
FAC
Fracture Adjudication Committee
FDA
Food and Drug Administration
FBR
Future Biomedical Research
FFSG
fasting fingerstick glucose
FPG
fasting plasma glucose 
GCP
Good Clinical Practice
HA
hypoglycemia assessment
HbA1C
glycated/glycosylated hemoglobin
HDL-C
high density lipoprotein cholesterol
HR
heart rate
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IND
investigational new drug application
iPTH
intact parathyroid hormone
IR
Immediate Release
IRB
institutional review board
IUD
Intra-uterine device
IVRS
interactive voice response system
LDL-C
low density lipoprotein cholesterol
LMP
last menstruation period
MACE
major adverse cardiovascular events
MDRD
Modification of Diet in Renal Disease
N/A
Not applicable
NASH
Non-alcoholic steatohepatitis
NOAEL
no observed adverse effect level
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NPH
Neutral protamine Hagedorn
NYHA
New York Heart Association
P1NP
procollagen type I N-terminal propeptide
PK
pharmacokinetic(s)
PR interval
time from the beginning of the P wave to the end of the QRS 
complex on electrocardiogram
PTH
parathyroid hormone
QD
once daily
QRS
the deflections in an electrocardiographic tracing and represent 
ventricular activity of the heart 
QT
time from the beginning of the QRS complex to the end of the 
T wave on electrocardiogram
QTcB
corrected QT interval Bazett’s formula
QTcF
corrected QT interval Fridericia’s formula
RNA
ribonucleic acid
S1
Screening Visit 1
S2
Screening Visit 2
S3
Screening Visit 3
S2/S3
combined Screening Visits 2 and 3
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SERM
Selective Estrogen Receptor Modulators
SGLT1
Sodium Glucose co-Transporter 1
SGLT2
Sodium Glucose co-Transporter 2
SLC5A
Sodium Glucose co-Transporter gene family
SOA
schedule of activity
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reactions
T2DM 
type 2 diabetes mellitus
TIA
Transient ischemic attack
TSH
thyroid-stimulating hormone
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UGE
urinary glucose excretion
US
United States
UTI
urinary tract infections
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1. INTRODUCTION
1.1. Indication
Use in patients with type 2 diabetes mellitus (T2DM) to improve glycemic control with once 
daily dosing with the Sodium Glucose co Transporter 2 (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 the prevalence of 
diabetes is projected to reach more than 550 million by the year 2030.1 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 2012.2  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.3  T2DM accounts for approximately 90-95% of all cases of 
diabetes.  Approximately 85% of patients with T2DM are obese or overweight, a key factor 
underlying the development and maintenance of insulin resistance.4,5  Individuals with 
T2DM have an increased risk of developing both microvascular and macrovascular 
disease-associated complications, including nephropathy, neuropathy, retinopathy, and 
cardiovascular disease, and are 2 to 4 times more likely to die from cardiovascular disease 
than adults who do not have diabetes.6 Orally administered pharmacological agents that 
lower glucose while also reducing other risk factors, eg, by lowering body weight and 
reducing blood pressure, represent a major advantage in the treatment of diabetes.
The sodium glucose co-transporter family (SLC5A) consists of 12 known members, 
including 6 gene products named SGLTs.7  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.8,9,10
Ertugliflozin (MK-8835/PF-04971729) is a potent inhibitor of the Sodium-Glucose 
co-transporter type 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 HbA1c in subjects with T2DM.  
Ertugliflozin is being developed as an adjunct to diet and exercise to improve glycemic 
control in patients with T2DM. 
The purpose of this trial is to evaluate the efficacy and safety of the addition of ertugliflozin 
to the treatment of subjects with T2DM and inadequate glycemic control on metformin 
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monotherapy.  Metformin is the standard and preferred first line pharmacological agent for 
T2DM. However, due to the progressive nature of T2DM, many subjects may have poor 
glycemic control despite metformin monotherapy.  Since ertugliflozin improves glycemic 
control via a mechanism independent of insulin, it could potentially represent a valuable 
therapy across the typical disease progression of T2DM, including individuals with
inadequate glycemic control on metformin monotherapy.
In addition, this study will assess changes in bone mineral density (BMD) by dual-energy 
X-ray absorptiometry (DXA), and so provide important information on the bone safety of 
ertugliflozin. 
1.3. 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 who were receiving metformin monotherapy, the following 
placebo-adjusted mean (80% confidence interval [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 placebo-adjusted mean reductions in 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. 
1.4. Safety Information for Ertugliflozin and Other SGLT2 Inhibitors
Several SGLT2 inhibitors are in clinical development and as of August 2013, one SGLT2 
inhibitor is approved in the U.S. (canagliflozin) and another (dapagliflozin) is approved in 
the European Union.  Based on available clinical trial data with dapagliflozin and 
canagliflozin, 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).  In some clinical trials with SGLT2 inhibitors, the reported rate of UTI was 
slightly higher in subjects treated with an SGLT2 inhibitor compared to those receiving 
placebo.
SGLT2 inhibition leads to an increase in urinary excretion of glucose and sodium, a diuretic 
effect and a decrease in blood pressure similar to that reported with other agents with a 
diuretic action.  In clinical trials with other SGLT2 inhibitors, this diuretic effect led to a 
higher frequency of adverse events such as pollakiuria, thirst and polyuria, but these events 
were typically of mild severity and usually did not lead to discontinuation.  However, certain 
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populations of subjects (eg, elderly or renal insufficient) may be at risk for 
hypovolemia-related adverse events from this mechanism.  As SGLT2 inhibition can lead to 
volume depletion, there is also a potential concern for decreased estimated glomerular 
filtration rate (eGFR) on a hemodynamic basis.  In subjects with moderate renal impairment, 
there was a slightly higher incidence of renal-related adverse events reported in subjects 
receiving SGLT2 inhibitors than controls in clinical trials with other SGLT2 inhibitors.  
Small initial decreases in the estimated glomerular filtration rate (eGFR) were seen, which 
returned toward baseline levels over time with continued treatment and/or upon 
discontinuation of therapy, consistent with a reduction in plasma volume.  The reversibility 
with continued treatment or with discontinuation of treatment is consistent with a 
hemodynamic (plasma volume) mechanism.  
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.  As of August 2013, a total of 479 subjects have 
been exposed to ertugliflozin in six completed Phase 1 and two completed Phase 2 studies.  
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 well tolerated with a safety profile 
supporting continued development. 
As of August 2013, there have been no deaths, and a total of 11 Serious Adverse Events 
(SAEs) were reported in 9 subjects.  Across the program, a total of 10 subjects (1.5%) were 
withdrawn due to adverse events (AEs).  The most frequent AEs reported with ertugliflozin
use in the Phase 1 studies have been headache, constipation, diarrhea and nausea.  In the two 
Phase 2 studies, upper respiratory, urinary tract and genital fungal infections, diarrhea, 
arthralgia and headache were most frequently reported.  The incidences of these AEs 
however, were low.  UTI was reported at a frequency of 3.3% for all ertugliflozin doses 
combined, versus 5.4% for placebo.  The frequency of genital fungal infection was noted to 
be numerically higher in males and females receiving ertugliflozin treatment compared to 
placebo, and currently this AE is the only event considered to be an adverse drug reaction 
(ADR) for ertugliflozin.  Overall, there was no clear dose-related increase in frequency of 
AEs with increasing dose of ertugliflozin.
In Phase 2 study B1521004, a mild diuretic effect was observed with ertugliflozin 
(ie, increase in 24-hour urinary volume) though there was a lack of a dose-response 
relationship across the doses of ertugliflozin.  In susceptible individuals, this diuretic effect 
from ertugliflozin could lead to volume depletion and related adverse events such as 
hypotension or dizziness, and these events will be monitored in the Phase 3 studies. 
In Phase 2, there were small increases observed in hemoglobin and hematocrit, suggestive of 
hemoconcentration, and a small increase in blood-urea-nitrogen (BUN) but no change in 
serum creatinine, at Week 12 relative to Baseline. Given the small magnitude of the 
increases in BUN, and hemoglobin/hematocrit, these changes are unlikely to have clinical 
consequence.  Small mean increases in serum calcium, serum phosphate and serum 
magnesium, and intact parathyroid hormone (iPTH) all within the laboratory reference range, 
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were observed following 12 weeks of dosing with ertugliflozin.  There was a suggestion of 
changes in markers of bone resorption, though there did not appear to be a clear 
dose-dependent effect with increasing dose of ertugliflozin.  In totality, the clinical relevance 
of these findings remains unclear.  However, the effect of ertugliflozin on BMD will be 
evaluated in this trial, and all clinical fractures will be adjudicated throughout the Phase 3 
program by an independent committee and will be included in a pooled analysis.
In the clinical program to date, no clinically significant changes from baseline in serum 
aminotransferases (ALT and AST) have been observed. 
Phase 3 clinical trial data from another SGLT2 inhibitor, dapagliflozin, revealed a numerical 
imbalance in the rates of breast and bladder cancer in dapagliflozin-treated subjects 
compared to control.11 The causal relationship to dapagliflozin for this finding is uncertain 
given the small number of events and the absence of any preclinical signal (ie, no reported 
increase in either tumor in carcinogenicity studies) with dapagliflozin.  Moreover, in the 
larger clinical program of another SGLT2 inhibitor, canagliflozin, no cancer imbalance, 
including in breast or bladder cancer events, was reported.  Because thorough evaluation of 
malignancies is important in the development program of all investigational medications, 
detailed information will be collected for subjects who develop a malignancy.  This 
information could include but is not limited to relevant medical history, biopsy, or operative 
reports, etc.
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 
(PF-04971729). 
1.5. Rationale for Study and Design
SGLT2 inhibitors lower blood glucose in an insulin-independent manner.  Consequently, 
glucose lowering should be observed across the typical continuum of T2DM progression,
ranging from subjects treated with diet and exercise alone to subjects receiving insulin. 
This trial will assess the efficacy and safety of ertugliflozin added to the regimen of subjects 
who have inadequate glycemic control on metformin monotherapy at or near maximally 
effective doses (ie, 1500 mg per day). Subjects already on metformin monotherapy at 
protocol-specified doses (1500 mg per day) for at least 8 weeks at Screening Visit 1 and 
who meet other enrollment criteria, will go directly from Screening Visit 1 to Screening 
Visit 3 to enter the 2-week single-blind placebo run-in period.
In addition to subjects with inadequate control on metformin monotherapy at 
protocol-specified doses, a broader range of subjects will be screened for the study, including 
subjects on metformin in combination with another allowable single AHA agent, or 
metformin at a dose below the protocol-specified dose (ie, <1500 mg per day). Other 
potentially eligible subjects, not yet on metformin monotherapy at protocol-specified doses,
will be switched at Screening Visit 2 to a regimen of metformin monotherapy and need to 
attain a dose of 1500 mg per day and then enter a dose stable period, including at least 
8 weeks on a stable dose of metformin monotherapy prior to Screening Visit 3, where they 
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will enter a 2 week single-blind placebo run-in period. These subjects will have HbA1c 
measured again at Screening Visit 3 to determine if they qualify for enrollment. 
Beyond the effects of ertugliflozin mentioned above on electrolytes and bone biomarkers 
from Phase 2, a small decrease in BMD, of unclear significance, was observed in a clinical 
trial of one agent in the SGLT2 class (canagliflozin), but not in another (dapagliflozin). 
SGLT2-induced urinary caloric loss produces body weight loss, which may potentially 
reduce BMD.18 Based upon these observations, this trial will assess the effect of ertugliflozin 
on BMD, and also obtain data on the effect of ertugliflozin on bone biomarkers.
Approximately 50% of the population enrolled in the trial will be women who have been 
post-menopausal for 3 years or more (at least 3 years since their last menstrual period [LMP] 
or bilateral oophorectomy performed 3 years or more prior to screening), and the 
randomization will be stratified based on this post-menopausal status (as well as geographical 
region – primarily to facilitate drug supply logistics).  Details on the stratification factors for 
randomization are provided in Section 4.3.
The population to be enrolled in this study represents subjects appropriate to assess the 
primary and secondary objectives in the study.  Collecting BMD data with this mechanism is 
important in subjects with T2DM regardless of age or sex, and particularly important in a 
population of post-menopasual women. Subjects with a lumbar spine, femoral neck, total hip
or distal forearm regions BMD T-score of less than -2.5 as measured at Screening will be 
excluded given that this trial prohibits the use of concomitant bone-active medications such 
as bisphosphonates, which would likely be used by such a population.  Subjects receiving 
other medications affecting bone turnover, such as estrogen receptor modulators, are also 
excluded from this trial as potentially these medications may confound the interpretation of 
any potential effect of ertugliflozin on BMD.  Due to concerns regarding the quality of bone 
imaging, subjects with a BMI >40.0 kg/m2 will be excluded from this trial.
1.5.1. Rationale for Dose Selection of Ertugliflozin
The proposed ertugliflozin doses to be 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 FPG) from study 
B1521006 as well as 24-hour urinary glucose excretion (mechanism biomarker) in T2DM 
subjects from study B1521004.  For these end points, the 5 mg and 15 mg doses consistently 
elicit a response that is >80% and >90% of the maximum response, respectively (Table 2). 
Table 2.
Estimated Percent Maximum Response for Various Endpoints
Ertugliflozin 
Dose
UGE – T2DM
(ED50=0.78 mg)
HbA1C
(ED50=1 mg)
FPG
(ED50=1.1 mg)
5 mg
87%
83%
82%
15 mg
95%
94%
93%
ED50= dose achieving 50% of maximum response
UGE= urinary glucose excretion
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In addition, the dose-response modeling of 24-hour urinary glucose excretion (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 (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.
1.5.2. Rationale for Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on whole blood deoxyribonucleic 
acid (DNA), plasma and serum specimens collected during this clinical trial.  This research 
may include genetic analyses (DNA), gene expression profiling [ribonucleic acid (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
In subjects with T2DM and inadequate glycemic control, on a stable dose of metformin
monotherapy, the following are primary objectives and hypotheses of the trial:
1. Objective:  At Week 26, to assess the effect on HbA1c of 15 mg ertugliflozin as 
compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in HbA1c for 15 mg 
ertugliflozin is greater than that for placebo.
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2. Objective:  At Week 26, to assess the effect on HbA1c of 5 mg ertugliflozin as 
compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in HbA1c for 5 mg 
ertugliflozin is greater than that for placebo.
3. Objective:  To assess the safety and tolerability of ertugliflozin.
The secondary objectives and hypotheses of the trial are:
1. Objective:  At Week 26, to assess the effect on fasting plasma glucose (FPG) of 
15 mg ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in FPG for 15 mg 
ertugliflozin is greater than that for placebo.
2. Objective:  At Week 26, to assess the effect on FPG of 5 mg ertugliflozin as 
compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in FPG for 5 mg 
ertugliflozin is greater than that for placebo.
3. Objective:  At Week 26, to assess the effect on body weight of 15 mg ertugliflozin 
as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in body weight for 
15 mg ertugliflozin is greater than that for placebo.
4. Objective:  At Week 26, to assess the effect on body weight of 5 mg ertugliflozin 
as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in body weight for 5 mg 
ertugliflozin is greater than that for placebo.
5. Objective:  At Week 26, to assess the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 15 mg ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 15 mg ertugliflozin is greater than that for placebo.
6. Objective:  At Week 26, to assess the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 5 mg ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the proportion of subjects with an HbA1c <7% 
(53 mmol/mol) treated with 5 mg ertugliflozin is greater than that for placebo.
7. Objective:  At Week 26, to assess the effect on systolic blood pressure of 15 mg 
ertugliflozin as compared with placebo.
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Hypothesis:  At Week 26, the mean reduction from baseline in systolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.
8. Objective:  At Week 26, to assess the effect on systolic blood pressure of 5 mg 
ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in systolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.
9. Objective:  At Week 26, to assess the effect on diastolic blood pressure of 15 mg 
ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in diastolic blood 
pressure for 15 mg ertugliflozin is greater than that for placebo.
10. Objective:  At Week 26, to assess the effect on diastolic blood pressure of 5 mg 
ertugliflozin as compared with placebo.
Hypothesis:  At Week 26, the mean reduction from baseline in diastolic blood 
pressure for 5 mg ertugliflozin is greater than that for placebo.
11. Objective: At Week 26, to assess the proportion of subjects with anHbA1c 6.5%, 
incidence of subjects requiring glycemic rescue therapy, and time to initiation of 
glycemic rescue therapy for each ertugliflozin arm compared with placebo.
12. Objective: At Week 52, to assess the change from baseline in efficacy endpoints 
relating to HbA1c, FPG; proportion of subjects with an HbA1c <7%;proportion of 
subjects with an HbA1c 6.5%; incidence of subjects requiring glycemic rescue 
therapy; and time to initiation of glycemic rescue therapy for each of the two 
ertugliflozin arms.
13. Objective: At Week 52, to assess the change from baseline in efficacy endpoints 
relating to body weight, and the change from baseline in systolic and diastolic 
blood pressure.
14. Objective: At Week 104, to assess the change from baseline in efficacy endpoints 
relating to HbA1c, FPG; proportion of subjects with anHbA1c <7%; proportion of 
subjects with anHbA1c 6.5%, incidence of subjects requiring glycemic rescue 
therapy; and time to initiation of glycemic rescue therapy for each of the two 
ertugliflozin arms.
15. Objective: At Week 104, to assess the change from baseline in efficacy endpoints 
relating to body weight, and the change from baseline in systolic and diastolic 
blood pressure.
16. Objective:  To descriptively summarize pharmacokinetics of ertugliflozin in this 
study and provide PK data for potential population PK analysis.
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Secondary objectives related to bone safety are:
17. Objective: At Week 26, to assess the effect on BMD as measured by DXA at the 
lumbar spine (L1-L4), femoral neck, total hip, and distal forearm for each of the two 
ertugliflozin arms ertugliflozin as compared with placebo.
18. Objective: At Week 26, to assess the effect on bone biomarkers of each of the two 
doses of ertugliflozin as compared with placebo.
19. Objective: At Week 52, to assess the change from baseline in BMD as measured 
by DXA at the lumbar spine (L1-L4), femoral neck, total hip and distal forearm for 
each of the two ertugliflozin arms.
20. Objective: At Week 52, to assess the change from baseline in bone biomarkers for 
each of the two ertugliflozin arms.
21. Objective: At Week 104, to assess the change from baseline in BMD as measured 
by DXA at the lumbar spine (L1-L4), femoral neck, total hip and distal forearm for 
each of the two ertugliflozin arms. 
22. Objective: At Week 104, to assess the change from baseline in bone biomarkers for 
each of the two ertugliflozin arms.
2.2. Endpoints
2.2.1. Primary Endpoint

Change in HbA1c from Baseline to Week 26.
2.2.2. Secondary Endpoints

Change in FPG from Baseline to Week 26.

Change in body weight from Baseline to Week 26.

Incidence of HbA1c of <7% (53 mmol/mol) at Week 26.

Change in systolic and diastolic blood pressure from Baseline to Week 26.

Change in HbA1c, FPG, and body weight from Baseline to Weeks 52 and 104.

Incidence of HbA1c <7% (53 mmol/mol) at Weeks 52 and 104.

Incidence of HbA1c 6.5% (48 mmol/mol) at Weeks 26, 52 and 104.

Change in systolic and diastolic blood pressure from Baseline to Weeks 52 and 104.

Proportion of subjects requiring glycemic rescue therapy up to Weeks 26, 52 and 104.
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
Time to glycemic rescue therapy up to Weeks 26, 52 and 104.

Endpoints related to pharmacokinetics of ertugliflozin.
Secondary endpoints related to bone safety are:

Change in BMD as measured by DXA at the lumbar spine (L1-L4), femoral neck, total 
hip and distal forearm from Baseline to Week 26.

Change in BMD as measured by DXA at the lumbar spine (L1-L4), femoral neck, total 
hip and distal forearm from Baseline to Weeks 52 and 104.

Change from baseline in bone biomarkers at Weeks 26, 52 and 104.
As part of a large Phase 3 program for ertugliflozin, this protocol will contribute safety data
to a program-wide meta-analysis of clinical cardiovascular events.  Additional detail is 
provided in Section 7.8.1.
To maintain the ability of the trial to provide information on long-term safety data, subjects 
who discontinue investigational product and do not withdraw consent will thereafter be 
contacted via telephone by the Investigator/qualified designee according to the same 
schedule as if the subject were still taking investigational product (ie, according to Section 
the Schedule of Activities and Section 6).  Such subjects will be asked to return to the clinic 
at the time of the Week 104 visit.  Additional details are provided in Section 6.7.
This trial will utilize an external Data Monitoring Committee (E-DMC) to periodically 
review safety data.
3. STUDY DESIGN
This trial is a Phase 3 multi-center, randomized, parallel-group study with a 26-week, 
double-blind, placebo-controlled treatment period (Phase A) followed by a 78-week 
double-blind, extension period (Phase B) in subjects with T2DM and inadequate glycemic 
control on metformin in monotherapy.
The trial includes a 1-week screening period, a variable interval for metformin titration (if 
needed), and at least an 8-week metformin stable dose period when subjects will discontinue 
and remain off any previous allowable background diabetes therapy (except for metformin), 
and a 2-week single-blind placebo run-in period prior to randomization.  A follow-up phone 
call will take place 2 weeks after the last dose of investigational product. Subjects could 
participate in the trial for approximately up to 119 weeks. 
The fixed, 2-week placebo run-in from Screening Visit 3 (S3) to Day 1/Visit 4 which has the 
explicit purpose of familiarizing the subjects with the study treatment regimen and excluding 
subjects who are not compliant with the blinded placebo prior to randomization. 
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The trial is designed to include subjects taking a variety of baseline diabetes therapy 
regimens at the Screening visit by incorporating a period of metformin titration and dose 
stabilization, and washoff of another anti-hyperglycemic agent if necessary, prior to placebo 
run-in.  Subjects will be eligible to screen for this trial if they are receiving one of the 
following diabetes therapy regimens at the time of Screening Visit 1 (S1):

Metformin monotherapy.

Combination therapy with metformin and one of the following oral 
anti-hyperglycemic agents (AHAs): sulfonylurea, DPP-4 inhibitor, meglitinide, or 
alpha-glucosidase inhibitor.
Subjects receiving metformin in combination with another allowable AHA must discontinue 
the other AHA beginning at the Screening Visit 2 (S2) and remain off the other AHA for the 
duration of this trial.
The following table provides information on the allowable HbA1c levels at S1 based upon 
the background diabetes therapy.  In addition, the table includes the subsequent actions to be 
taken based on the background diabetes regimen.
Table 3.
Background Diabetes Therapy at Screening Visit 1 (S1), HbA1c Initial 
Inclusion and Appropriate Changes in Background Diabetes Therapy
Diabetes Therapy at Screening 
Visit (S1)
HbA1c Inclusion 
Criterion at S1
Change in Background Diabetes Therapy 
Prior to Placebo Run-in (S3)
Metformin monotherapy, 
1500 mg/day for 8 weeks
7.0%–10.5% (53-91
mmol/mol), inclusive
None.  Subjects proceed directly to a 
combined S2/S3 Visit
Metformin monotherapy, 
1500 mg/day for <8 weeks
7.0%–10.5% (53-91
mmol/mol), inclusive
Maintain metformin dose 1500 mg/day so 
subject has 8 weeks on stable dose.
Metformin monotherapy, 
<1500 mg/day
7.5% - 11.0% (58-97
mmol/mol),  inclusive
Titrate metformin to 1500 mg/day. The 
dose stable period must be 8 weeks.
Metformin + another single 
allowable AHA*
6.5%–9.5%
(48-80 mmol/mol),
inclusive
Discontinue the other AHA.  Titrate 
metformin to 1500 mg/day (if needed).  
The dose stable period for metformin 
monotherapy must be 8 weeks.
HbA1c = Glycosylated hemoglobin; AHA = Anti-hyperglycemic agent; S1 = Initial screening visit; 
S2/S3 = Combined Screening Visit 2 and 3.
*allowable AHA agents are sulfonylurea, DPP-4 inhibitor, meglitinide, or alpha-glucosidase inhibitor.
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Figure 1 summarizes the overall trial scheme.
Figure 1.
Trial Scheme
Met=Metformin 
The trial consists of three phases:
1. Screening phase including discontinuation of background diabetes therapy other 
than metformin (if applicable) and a placebo run-in period (Visits S1 up to V4): - the 
length of this standardization period will vary depending on the diabetes therapy of 
subjects at S1 (metformin monotherapy 1500 mg/day for 8 weeks or for <8 weeks, 
metformin monotherapy <1500 mg/day or metformin + another single allowable AHA) 
as shown in Table 3.
2. Phase A: Randomized, double-blind, placebo-controlled treatment period (Visits V4 
though V8) - a 26-week treatment period for assessment of primary and secondary safety 
and efficacy endpoints.  At entry into Phase A, subjects will be randomized to 
ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo, while maintaining metformin at a 
dose 1500 mg/day.  Glycemic rescue therapy with open-label glimepiride and basal 
insulin should be initiated in subjects with glucose values exceeding protocol-specified 
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values as mentioned in Section 5.6. Dosing and titration of open-label glimepiride rescue 
therapy is at the discretion of the Investigator.
3. Phase B: Double-Blind, extension period (Visits V8 through V15) – a 78-week, 
double-blind extension period where subjects randomized to ertugliflozin will remain on 
their randomized treatment; subjects randomized to placebo will have the addition of 
treatment with glimepiride (if they were not rescued during Phase A), maintaining the 
double-blinding; this is accomplished by the use of blinded glimepiride or matching 
placebo, as described below: 

Subjects randomized to ertugliflozin (5 or 15 mg) are continued on their randomized
dose of ertugliflozin, and

If not rescued in Phase A: will be started on the addition of placebo matching 
glimepiride (and with mock uptitration using glimepiride placebo tablets 
matching 1 or 2 mg tablets, as determined appropriate by the investigator).

If rescued in Phase A: will not be started on placebo matching glimepiride, and 
open-label glimepiride will be continued into Phase B.

Subjects randomized to the placebo treatment group will continue on the placebo
tablets matching ertugliflozin and

If not rescued in Phase A: will be started on the addition of glimepiride (1 mg), 
with titration with 1 or 2 mg tablets (to maximum allowed dose [6 or 8 mg] based 
upon the local label]) as determined appropriate by the investigator.

If rescued in Phase A: will not be started on glimepiride, and open label rescue 
glimepiride will be continued into Phase B.
Note: subjects whose Week 26 visit fasting fingerstick glucose is <110 mg/dL 
(6.1 mmol/L) will not have the glimepiride or matching placebo initiated at the 
Week 26 visit. At each subsequent scheduled study visit, if the FFSG is 110 mg/dL, 
glimepiride or matching placebo tablets may be initiated (unless not considered 
appropriate by the investigator based upon the risk of hypoglycemia). 
During Phase B, glycemic rescue therapy with basal insulin should be initiated in subjects 
with glucose values or HbA1c values exceed protocol-specified values (See Section 5.6). 
A follow-up phone call will take place 14 days after the last dose of investigational product. 
This trial is designed to evaluate the efficacy, safety and tolerability of both the 5 mg and 
15 mg oral doses of ertugliflozin on glycemic control, body weight, and blood pressure 
following a 26-week dosing period in adult subjects with T2DM and inadequate glycemic 
control on background treatment with metformin monotherapy.
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It is also designed to evaluate the longer-term efficacy, safety and tolerability of ertugliflozin 
during the entire 104-week treatment period, which includes a 78-week double-blind
extension period. A key purpose of this 78-week double-blind, extension period is to collect 
additional safety data of ertugliflozin on BMD.  The effect of ertugliflozin on BMD will be 
assessed by DXA. All DXA data throughout the trial will be forwarded to a Central 
Evaluation Facility to ensure standardization.  
Approximately 600 subjects will be randomized to ensure that a minimum of 480 subjects 
(160 per arm) provide HbA1c data at the Week 26 primary timepoint.  Given the plans not to 
replace those subjects who are withdrawn early, the 600 subjects randomized will control for 
the approximate 20% premature withdrawal rate for HbA1c data to allow for withdrawn 
subjects who will still be included in the analysis, but will not necessarily have Week 26 data 
available.  However, a 15% premature withdrawal or non-evaluable rate has been assumed 
for the BMD data, as this will not be censored if glycemic rescue therapy is taken prior to 
Week 26.  So, the post glycemic rescue therapy data from subjects who require rescue 
therapy prior to Week 26 will be censored from primary and secondary efficacy analyses. 
For the bone safety endpoints (BMD and bone biomarkers), all data will be included 
(including results after glycemic rescue initiation). After the Week 26 visit, Phase A data 
will be unblinded for limited staff from the Sponsor but not for the Investigator and the 
subject, or any study team members involved in the day-to-day running of the trial, including 
site and central monitoring staff.
4. SUBJECT SELECTION
This trial can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol 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 study team before subjects are included in the trial. 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial:
1. Subjects 18 years of age at the time of the initial Screening Visit (S1) with a 
diagnosis of T2DM in accordance with American Diabetes Association (ADA) 
guidelines.12
2. Receiving one of the following diabetes therapy regimens at the time of Screening 
Visit 1 (S1) and with an HbA1c within the following range:
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Diabetes Medication at Screening Visit (S1)
HbA1c Inclusion Criterion at S1
Metformin monotherapy, 1500 mg/day
7.0%–10.5%, ( 53-91 mmol/mol) 
inclusive
Metformin monotherapy, <1500 mg/day
7.5% - 11.0% (58-97 mmol/mol inclusive
Dual combination therapy with metformin + 
sulfonylurea, DPP-4 inhibitor, meglitinide, or 
alpha-glucosidase inhibitor
6.5%–9.5% (48-80 mmol/mol),
Inclusive
3. Subjects taking metformin monotherapy for less than 8 weeks at S1 or who require 
a change to their diabetes regimen at the S2 visit to remain eligible to participate
(including subjects discontinuing AHA therapy at S2) must have an HbA1c of 
7.0-10.5% (53-91 mmol/mol) at S3 after at least 8 weeks on a regimen of 
metformin in monotherapy.
4. Body Mass Index (BMI) 18.0-40.0 kg/m2. 
5. Evidence of a personally signed and dated informed consent document indicating 
that the subject (or 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.
6. Subjects who, in the opinion of the Investigator, are willing and able to comply 
with scheduled visits, treatment plan, laboratory tests, and other study procedures.
7. Subject meets one of the following criteria:
a.
Is a male.
b. Is a female not of reproductive potential defined as one who (See Sections 4.4.4.1
and 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 Screening Visit 1 (S1).
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 for subjects participating in clinical trials), 
or
2. Agrees to use (or have their partner use) acceptable contraception to prevent 
pregnancy within the projected duration of the trial and for 14 days after the 
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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 intra-uterine device
(IUD).  As an exception, medroxyprogesterone acetate (Depo Provera) is 
not permitted. 

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). 
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the trial:
1. History of type 1 diabetes mellitus or a history of ketoacidosis or subject assessed 
by the Investigator as possibly having type 1 diabetes confirmed with a C-peptide 
<0.7 ng/mL (0.23 nmol/L).  Note: Only subjects assessed by the Investigator as 
possibly having type 1 diabetes should have C-peptide measured at Screening 
Visit 1 (S1).
2. History of secondary types of diabetes (eg, genetic syndromes, secondary 
pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, 
and post-organ transplant).
3. Subjects who are <80% compliant based on pill count with the Placebo Run-in 
medication.
4. History of myocardial infarction, unstable angina, arterial revascularization, stroke, 
transient ischemic attack, or New York Heart Association (NYHA) functional class 
III-IV heart failure within 3 months of Screening Visit 1 (S1).
5. 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 
Screening Visit 1 (S1), confirmed via 1 repeat triplicate set at Screening Visit 1 
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(S1) if deemed necessary.  For subjects with a confirmed mean triplicate value of 
sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure 
>90 mm Hg at the S1 visit, the Investigator and/or treating physician is allowed to 
adjust background blood pressure medication(s) to improve blood pressure control 
in order for the subject to be re-assessed for eligibility. 
6. Subject has a clinically significant electrocardiogram (ECG) abnormality at 
Screening Visit (S1) that requires further diagnostic evaluation or intervention 
(eg, new, clinically significant arrhythmia or a conduction disturbance).
7. Subject has active, obstructive uropathy or indwelling urinary catheter.
8. 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.
9. 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.
10. Any clinically significant malabsorption condition.
11. Meets any of the following criteria:

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.
Note: Weight-stable is defined as <5% change in body weight in the last 6 months.
12. Subject who had bariatric surgery at any time in the past.
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13. Subjects with a gender-specific BMD T-score of <-2.5 at any site assessed at 
Screening Visit 3. 
14. Subjects with a documented history of osteoporosis (prior documented BMD 
T-score of <-2.5).
15. Subjects with rheumatoid arthritis.
16. Subjects with any other illness that could impact BMD assessment such as inherited 
bone disorders, metabolic bone disease or autoimmune endocrinopathies.
17. Subjects with bilateral hip prosthesis or subjects who have fewer than 3 vertebrae 
which are evaluable by DXA at Screening Visit 3 (S3). 
18. Subjects with hyperparathyroidism defined as a parathyroid hormone (PTH) value 
at Screening Visit 1 that exceeds the upper limit of the reference range of the 
central laboratory.
19. Subjects with previously diagnosed atraumatic vertebral fracture or high and low 
impact fracture of the hip or wrist.
20. Subjects with a known hypersensitivity or intolerance to any SGLT2 inhibitor.
21. Subjects who have previously been randomized in a trial with ertugliflozin.
22. Subjects with a known hypersensitivity or intolerance to glimepiride. 
23. Screening fasting plasma or finger-stick glucose >270 mg/dL (15 mmol/L), 
confirmed by a single repeat following counseling on exercise and diet. This will 
be assessed at each of the screening visits (as applicable).
24. Fasting serum triglyceride >600 mg/dL (6.8 mmol/L) at Screening Visit 1 (S1), 
confirmed by a single repeat if deemed necessary.  For subjects with confirmed 
fasting triglycerides >600 mg/dL, the Investigator and/or treating physician is 
allowed to adjust the background lipid altering medication(s) to lower fasting 
triglycerides in order for the subject to be re-assessed for eligibility. 
25. Subjects taking blood pressure or lipid altering medications that have not been on a 
stable dose for at least 4 weeks prior to randomization. 
26. Subjects currently being treated for hyperthyroidism or subjects on thyroid 
replacement therapy that has not been on a stable dose for at least 6 weeks prior to 
randomization and/or subjects who have a thyroid-stimulating hormone (TSH)
outside of the laboratory reference range at Screening Visit 1 (S1). 
27. Male subjects with a serum creatinine 1.3 mg/dL (115 mol/L) or female 
subjects with a serum creatinine 1.2 mg/dL (106 mol/L) or subjects with an 
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eGFR <55 mL/min/1.73m2 according to the 4-variable Modification of Diet in 
Renal Disease (MDRD) equation at Screening Visit 1 (S1). 
28. An aspartate transaminase (AST) or alanine transaminase (ALT) >2 X the upper 
limit of normal (ULN) range at Screening (S1), or a total bilirubin >1.5 X the ULN 
unless the subject has a history of Gilbert’s syndrome. 
29. 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.
30. Use of the following prohibited therapeutic agents.  These agents are not to be used 
from 12 weeks prior to Screening Visit 1 (S1) through the completion of the trial:

Insulin of any type (except for short-term use during hospitalization or use of 
basal insulin as glycemic rescue therapy).

Other injectable anti-hyperglycemic agents (eg, pramlintide, exenatide, 
liraglutide).

Another SGLT2 inhibitor.

Bromocriptine (Cycloset).

Colesevelam (Welchol).

Any other anti-hyperglycemic therapy with the exception of the protocol-
approved agents.
31. The following therapeutic agents are prohibited for the duration of the trial.  
Specific time length restrictions for each medication/drug class are as follows:

Bisphosphonates (eg, alendronate, risedronate, ibandronate, etc): Subjects must 
not have received a bisphosphonate for at least 2 years prior to Screening Visit 1 
(S1). The exception to this is subjects who used an oral bisphosphonate for 
<1 month in total so long as the use was not within 12 months of S1.
Note: As an exception, bisphosphonates and other bone active products may be 
allowed during the study if subjects meet specific rescue criteria related to loss of 
BMD as described in Section 7.6.1.1.

Any other medication or products affecting bone turnover, including but not 
limited to: calcitonin, parathyroid hormone (teriparatide), estrogen (locally acting 
estrogen creams are acceptable), testosterone, tamoxifen, raloxifene, bazedoxifene
(or another selective estrogen receptor modulators [SERM]), tibolone, 
denosumab, aromatase inhibitor, strontium, or corticosteroid treatment (oral, 
inhaled, parenteral at any dose) within 12 months of S1.
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
Pioglitazone or rosiglitazone within 12 months of S1 visit.

Growth hormone within 12 months of S1 visit.

Phenytoin or Phenobarbital within 12 months of S1 visit.

Medroxyprogesterone acetate (Depo Provera) within 24 months of S1.
32. 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 Placebo Run-in Period (S3/Day -14) to the 
completion of the trial. 
Note: Topical corticosteroids and physiological replacement doses of adrenal steroids 
are permitted. 
33. 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 or Merck employees directly involved 
in the conduct of the trial.
34. Participation in any other trials involving investigational drug(s) (Phase 1-4) within 
30 days before Screening Visit 1 (S1) and/or during study participation.
35. Subjects who have undergone a surgical procedure within 6 weeks prior to signing 
informed consent or have planned major surgery during the trial.  Note: A subject 
who has undergone minor surgery within the 6 weeks prior to Screening Visit (S1) 
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.
36. At the randomization visit, 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 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.
37. 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. 
38. 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 
investigational product.
39. Subjects who have donated blood or blood products within six weeks of Screening 
Visit (S1) or who plan to donate blood or blood products at any time during the 
trial.
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40. Subjects with:

Known history of Human Immunodeficiency Virus (HIV).

Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells.
41. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator, would make the subject 
inappropriate for entry into this trial.
4.3. Randomization Criteria 
The randomization will be stratified based on post-menopausal status (as well as
geographical region -primarily to facilitate drug supply logistics). Approximately 50% of the 
population enrolled in the trial will be women who have been post-menopausal for 3 years or 
more (at least 3 years since their last menstrual period [LMP] or bilateral oophorectomy 
performed 3 years or more prior to screening), and the randomization will be stratified based 
on this post-menopausal status.  The stratification factor will have 4 levels: 

Men.

Premenopausal women.

Women who are perimenopausal or post-menopausal for less than 3 years after LMP
or bilateral oophorectomy performed less than 3 years prior to screening, 

Women who are post-menopausal for 3 years or more after LMP or women with a 
history of bilateral oophorectomy performed 3 years or more prior to screening. 
Randomization to the men, premenopausal women, perimenopausal or <3 years 
post-menopausal women groups will be capped at approximately 50% overall, to ensure 
approximately 50% of randomized subjects are in the group of women who have been 
post-menopausal for 3 years or more after LMP, or with a history of bilateral oophorectomy 
performed 3 years or more prior to screening.
Subjects will be assigned a unique identifier via an Interactive Voice Response System 
(IVRS) at Screening Visit (S1), which will be retained throughout the duration of their 
participation in the trial. Subjects who have discontinued a diabetes medication at S2 or 
needed a change in their metformin dose at S2 or who were not on metformin 1500 mg/day 
for 8 weeks at S2 are required to have an HbA1c measurement at S3 to determine eligibility 
as defined in the inclusion criteria. These subjects will start the placebo run-in at S3 but can 
only be randomized on Day 1 (V4) if the S3 HbA1c meets the entry requirement. Subjects 
will be randomized into the study at V4, provided that they have satisfied all subject 
eligibility criteria.  Eligibility criteria are outlined in Sections 4.1 and 4.2 and should be 
verified at S1, S2 and S3 as applicable. A computer-generated randomization code using the 
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method of random permuted blocks will be utilized to assign on Day 1 (V4) subjects to 1 of 
the 3 treatment regimens (ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo).  The same 
randomization code will then be used to assign blinded glimepiride/placebo therapy for 
Phase B.
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 collections for clinical laboratory tests, fasting glucose monitoring, 
and the start of pharmacokinetic assessments.

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 visits to the site, subjects must be instructed to arrive without having 
taken the dose of investigational product, open-label metformin, rescue therapy (if 
applicable), or blinded glimepiride/placebo.  Other medications may be administered 
prior to the clinic visit if they can be administered without food. 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 activity (SOA).  

Subjects will be counseled on appropriate dietary and lifestyle guidelines for T2DM 
at S2 and asked to maintain these guidelines throughout participation in the trial.  
Counseling on dietary guidelines should be in accordance with local medical 
standards of care for subjects with T2DM.
4.4.2. Physical Activities
Subjects must not engage in physically strenuous exercise (for example: heavy lifting, weight 
training, calisthenics, and aerobics) within 48 hours before each blood sample collection for 
clinical laboratory tests for the duration of participation in the trial.
4.4.3. Alcohol, Caffeine and Tobacco

Intake of alcohol should be limited (refer to exclusion 9 for acceptable amount of 
alcohol consumption).

Ingestion of caffeine will be prohibited for at least 30 minutes prior to scheduled 
electrocardiograms and blood pressure determinations.

Ingestion of nicotine-containing products will be prohibited for at least 30 minutes 
prior to the scheduled electrocardiogram and blood pressure determinations.
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4.4.4. Female Contraception
Only female subjects of non-childbearing potential, 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:

Postmenopausal: defined as at least 12 months with no menses in women 45 years 
of age, or 

Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation 
or occlusion at least 6 weeks prior to Screening Visit (S1).
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. 
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. As an exception, medroxyprogesterone acetate (Depo Provera) 
is not permitted. 

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).
4.5. Sponsor Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list provided to each site. 
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To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. 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 help desk 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 help desk 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 study 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 help desk 
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 TREATMENT
5.1. Allocation to Treatment
Approximately 600 subjects will be randomized in a 1:1:1 ratio to receive ertugliflozin 5 mg,
ertugliflozin 15 mg, or placebo once daily. 
Allocation of subjects to treatment groups will proceed through the use of a computerized 
Interactive Voice Response System (IVRS) that is accessible 24 hours per day, 365 days per 
year. The dispenser will be required to enter or select information as will be specified by the 
IVRS user manual. Subject information will be entered into the system starting at S1 when 
the subject will be assigned a unique identifier which will be retained throughout the duration 
of participation in the trial. On Day 1 (V4), once the inclusion, exclusion and randomization 
criteria have been verified, each subject will be assigned 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 
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 (ie, when the unblinding information is 
considered clinically necessary for appropriate subject management).  Whenever possible, 
the Investigator or sub-Investigator should consult with a member of the Sponsor study team 
prior to breaking the blind.  When the blinding code is broken, the reason must be fully 
documented and entered in the source documents.
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Phase A of this trial is subject-, Investigator-, and sponsor-blinded. Following completion of 
Phase A (defined as database lock), treatment assignment for subjects in Phase A of the trial 
will become available to limited staff from Pfizer/Merck and their delegates to permit 
authoring of the clinical study report.  Phase B of the trial will be blinded to the subject, 
Investigator, and Sponsor or Sponsor-designate personnel responsible for study monitoring 
activities (including all site monitoring activities).
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 in Phases A and B.  Tablets will be 
packaged into bottles or blister cards.
Pfizer will provide Investigator sites with sufficient amounts of blinded investigational 
product to accommodate expected recruitment.  Blinded investigational product will be 
assigned to subjects via an IVRS or equivalent. 
All investigational product containers dispensed to subjects should be returned to the 
Investigator site at the next clinic visit for the assessment of subject compliance and drug 
accountability.
5.3.2. Placebo Run-in
A single-blind placebo run-in will be administered starting at Day -14/Visit S3 where 
subjects will be instructed to take 1 tablet of placebo ertugliflozin 5 mg and 1 tablet of 
placebo ertugliflozin 10 mg each day from the bottles or blister card(s) provided for this 
period. The last dose of placebo run-in investigational product should be taken on the day 
prior to Day 1.  Subjects should not be informed that they are taking placebo during this 
period. Subjects who are <80% compliant based on pill count with the Placebo Run-in 
medication will be ineligible for randomization.
5.3.3. Concomitant Metformin
Subjects will use the background metformin prescribed by their physician and provided in 
the local commercial packaging.  Immediate Release (IR) and Extended Release (ER) forms 
are allowed in the study, provided that the same subject remains on the same formulation (IR 
or ER) from S2 to the Week 104 visit. 
Metformin titration will be required for some subjects between Screening Visit 2 (S2) and 
Screening Visit 3 (S3), prior to the placebo run-in period. This will occur in subjects who 
have been receiving metformin monotherapy at a dose <1500 mg/day at S1 or who have been 
receiving metformin at a dose <1500 mg/day plus another AHA at S1. 
The metformin dose should generally be increased by 500 mg per week (or as standard 
practice per the Investigator) to achieve the maximally approved/tolerated dose referring to 
the label, which must be 1500 mg/day. Metformin should generally be taken with meals.  
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Those subjects will enter the placebo run-in period at S3 after the metformin monotherapy 
dose of 1500 mg/day has been kept stable for at least 8 weeks. 
The metformin dose will not be changed from Screening Visit 3 until the end of the trial
(V15), except if medically necessary. In that case, all efforts should be made to get the 
subject back to the previous dose.
5.3.4. Administration (Ertugliflozin/Placebo)
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 will be dispensed 2 bottles or blister cards and given 
clear dosing instructions. They will be instructed to take 2 tablets per day of 
ertugliflozin/placebo, one from each bottle or blister card. Subjects randomized to 
ertugliflozin 5 mg will receive 1 ertugliflozin 5 mg tablet and 1 placebo ertugliflozin 10 mg 
tablet per day.  Subjects randomized to ertugliflozin 15 mg will receive 1 ertugliflozin 5 mg 
tablet and 1 ertugliflozin 10 mg tablet per day.  Subjects randomized to placebo will receive 
1 placebo ertugliflozin 5 mg tablet and 1 placebo ertugliflozin 10 mg tablet per day. 
The investigational product should be taken orally at approximately the same time of day in 
the morning from Day 1 through to Week 104 or early termination.  In addition, subjects will 
be instructed to delay the self-administration of investigational product on the day 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, he/she should be 
instructed to take it as soon as the subject remembers unless it is time for the next dose.  
Subjects should be instructed not to "make up" for the missed dose by taking two doses at the 
same time.
5.3.5. Drug Supplies for Phase B
The Sponsor will supply blinded glimepiride and matching placebo for glimepiride, for oral 
administration, as 1 mg and 2 mg strength over-encapsulated tablets or matching placebo.  
Blinded glimepiride and matching placebo for glimepiride will only be provided to subjects 
who were not rescued in Phase A with open-label glimepiride. At entry into Phase B,
non-rescued subjects in the placebo treatment group will receive blinded glimepiride in 
addition to placebo for ertugliflozin while non-rescued subjects in the ertugliflozin groups 
will receive a matching placebo for glimepiride.
Glimepiride/placebo will be supplied in bottles for dispensing at each visit containing 
sufficient supplies to permit dosing until the next scheduled visit.  Glimepiride/placebo 
should be stored in accordance with the label. All blinded glimepiride and matching placebo 
for glimepiride containers dispensed to subjects should be returned to the Investigator site at 
the next clinic visit for the assessment of subject compliance and drug accountability.
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5.3.5.1. Administration of Glimepiride/Matching Placebo
The dose of glimepiride/matching placebo will be initiated at 1 mg/day (or matching placebo 
for 1 mg tablet) starting on the day of the Week 26 visit for subjects who were not rescued in 
Phase A, and only if subject’s fasting fingerstick glucose (FFSG) at Week 26 visit is 
110 mg/dL (6.1 mmol/L). 
If the subject’s FFSG at Week 26 visit is <110 mg/dL (6.1 mmol/L), the subject will not 
receive glimepiride/matching placebo at the Week 26 visit.
All subjects will continue with investigational product (ertugliflozin/placebo) during 
Phase B, regardless of whether a subject does or does not initate glimepiride/matching 
placebo at Week 26.
For subjects started on glimepiride/matching placebo 1 mg at Week 26, at the Week 30 visit, 
the dose of glimepiride/matching placebo will be increased to 2 mg once daily (QD), if 
deemed appropriate by the Investigator based on the subject’s self-monitoring blood glucose 
measurements and assessment of risk of hypoglycemia.  Assessment of glimepiride dosing 
will then take place at subsequent clinic visits (ie, Weeks 39, 52, 65, 78, and 91).  Further 
up-titration of glimepiride will be made in increments of 2 mg/day, with the maximum dose 
(6 or 8 mg QD) based upon the local label of glimepiride.  Subjects may remain on 1 mg/day 
if appropriate based on finger-stick glucose monitoring.  
Subjects who did not have glimepiride/matching placebo initiated at the Week 26 visit may 
have glimepiride/matching placebo initiated (with 1 mg dose) at any subsequent visit, if their 
FFSG is no longer <110 mg/dL (6.1 mmol/L), and subsequently uptitrated, as described 
above. Down-titration is allowed at any time during the trial, as needed, in order to avoid 
hypoglycemia. 
It is recommended that the dose of glimepiride be administered with breakfast or the first 
main meal of the day. 
If any adjustment in the administration of glimepiride/matching placebo is necessary between 
scheduled visits, an unscheduled visit to the site should be performed. 
In case of hypoglycemia:
If a subject experiences episodes of unexplained hypoglycemia (ie, not explained by missed 
meals or excess physical activity), the subject’s glimepiride/matching placebo should be 
down-titrated to a dose determined appropriate by the Investigator.  In general, glimepiride 
should be down-titrated by 2 mg/day (eg, 6 mg to 4 mg or 4 mg to 2 mg), or more rapidly, as 
considered appropriate by the Investigator. In subjects receiving 2 mg/day the dose should 
be reduced to 1 mg/day in case of hypoglycemia.  Subjects on glimepiride/matching placebo 
1 mg who experience unexplained hypoglycemia should interrupt glimepiride/matching 
placebo and may continue in the trial off of glimepiride/matching placebo.  If unexplained 
hypoglycemia continues to occur after glimepiride/matching placebo is interrupted, the 
subject should be considered for discontinuation from the blinded investigational product 
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according to Section 6.7.2 – Reason for Discontinuation from Investigational Product or 
From the Study.
If a subject has had glimepiride/matching placebo interrupted or down-titrated, and 
re-initiation or up-titration of therapy is considered appropriate, then re-initiation and/or 
up-titration of glimepiride/matching placebo may be performed through the end of Phase B
according to the guidelines used for initial up-titration.
Note: If glimepiride/matching placebo is re-initiated, the dose should not be up-titrated 
beyond the dose at which hypoglycemia originally occurred.
5.3.6. Compliance
Subjects will be directed to bring any used and unused bottles or blister cards to each visit.  
The Investigator must maintain a complete and current accountability record for the 
investigational product.
Compliance with the placebo run-in medication should be monitored by study personnel at 
the site, at the end of the placebo run-in (Day 1/Visit 4), by comparing the returned 
investigational product with the amount dispensed and the information reported by the 
subject.  The number of tablets issued minus the number of tablets returned will be used to 
calculate tablets taken.  From this information, compliance will be calculated as:
Compliance = 100 x (tablets dispensed–tablets returned)/No. of days between visits x No. of 
tablets taken per day
Subjects who are <80% compliant based on pill count with the Placebo Run-in medication 
are ineligible for randomization.
During the remainder of the trial, compliance for subjects must be assessed for the 
ertugliflozin/matching placebo, and blinded glimepiride/placebo therapy (if applicable) by 
taking the subject’s report. 
The Investigator or designee will counsel subjects who report taking <80% of the prescribed 
medication (s) described above following randomization.  The Investigator or designee will 
determine factors that resulted in <80% compliance with these medication(s) and will take 
steps to improve compliance.  Subjects will continue these medications but will be counseled 
on the importance of taking their medication(s) 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 the drug label and applicable 
regulatory requirements.
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Storage conditions stated in the SRSD [Investigator Brochure’s (IB)] will be superseded by 
the label storage.
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 AHAs taken by the subject at any time prior to S1, and any other medications taken 
within 8 weeks prior to S1, will be recorded on the appropriate electronic case report form
(eCRF).  The site may rely on subject report for this information.  Concomitant medications 
taken during the trial must also be recorded.  All subjects must be questioned about 
concomitant medication according to the Schedule of Activities.
Medications that are indicated as prohibited in the Exclusion Criteria must not be used prior 
to or during the trial as specified in Section 4.2.
Subjects who are not on a stable dose of blood pressure or lipid altering medications at S1 
can be scheduled appropriately for S3 and Day 1 to ensure they have a stable dose for at least 
4 weeks prior to randomization per exclusion criterion 25.  To the extent that is reasonable, 
the Investigator should make all efforts to modify these regimens in advance of 
randomization to avoid the need to change after randomization.  However, the Investigator or 
subject’s physician/health care provider is permitted to make adjustments in blood pressure 
or lipid altering background therapy throughout the trial if clinically warranted. 
Subjects who are receiving calcium supplementation upon entry into the trial should continue 
to receive these medications at the same doses throughout the trial.  The concentration of 
25-hydroxyvitamin D will be measured at S3. Based on the results, the Investigator will be 
allowed to supplement subjects with vitamin D according to local practices or country dietary 
guidelines and if clinically necessary.
Initiation of a weight-loss medication during the study (eg, orlistat, phentermine, topiramate, 
lorcaserin) is prohibited.  Note: Subjects who are on treatment with a weight-loss medication 
or other medication associated with weight changes (eg, anti-psychotic agents) and who are 
weight-stable (ie, <5% change in body weight within 6 months of S1) are eligible to 
participate in the study and permitted to continue these medications during the study.
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5.6. Glycemic Rescue Therapy
Subjects will be prescribed open-label glycemic rescue therapy and dosed according to 
physician judgment, if they meet specific, progressively more stringent, glycemic thresholds
based on a repeated, confirmed FPG or HbA1c measured by the central lab according to 
the directions below:
Table 4.
Glycemic Thresholds
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 26:
FPG >200 mg/dL (11.1 mmol/L)
After Week 26:
FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.0% 
(64 mmol/mol)
Subjects who meet the glycemic rescue thresholds detailed in Table 4 should have the repeat 
FPG measurement performed as early as possible (within 7 days following the receipt of test 
results).
During Phase A, subjects exceeding pre-specified glycemic thresholds after randomization 
will have glycemic rescue therapy initiated with open-label glimepiride. Glycemic rescue 
therapy must be initiated at a rescue visit which is either a scheduled or an unscheduled visit 
at the investigational site, and not by a telephone visit. Dosing will be at the Investigator’s 
discretion and the Investigator will be responsible for managing the initiation and titration of 
the glimepiride rescue therapy according to the country-specific product label. At the rescue 
visit, immediately prior to initiation of glycemic rescue therapy, subjects meeting rescue 
criteria must undergo the procedures described in Section 6.6.
Subjects requiring glycemic rescue therapy during Phase A and entering into Phase B are to 
remain in the trial up to the end, and will continue to receive investigational product 
(ertugliflozin/placebo) in a blinded fashion as well as open-label glimepiride.  These subjects 
will not receive blinded glimepiride/placebo therapy during Phase B.
Additional glycemic rescue therapy with basal insulin should be initiated as follows:
During Phase A (prior to Week 26 visit): 

Subjects who were initiated on open-label glimepiride rescue therapy, and who 
reached the maximum allowed dose (or tolerated dose, if lower), who meet glycemic 
rescue FPG criteria (after at least 2 weeks on maximum dose of glimepiride), will 
have basal insulin initiated and managed as considered appropriate by the investigator 
(ie, including selection of agent and starting dose, timing of administration, and 
uptitration). 
During Phase B:

Subjects who were initiated on open-label glimepiride rescue therapy in Phase A, 
who meet glycemic rescue criteria after at least 2 weeks on maximum dose of 
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open-label glimepiride for FPG criteria or at least 8 weeks for HbA1c criteria, will 
have basal insulin initiated and managed as considered appropriate by the investigator 
(ie, including selection of agent and starting dose, timing of administration, and 
uptitration).

Subjects not on Phase A open-label glimepiride rescue therapy who meet glycemic 
rescue criteria after at least 2 weeks on maximum dose of blinded glimepiride or 
matching placebo for FPG criteria or at least 8 weeks for HbA1c criteria will have 
basal insulin initiated and managed as considered appropriate by the investigator 
(ie, including selection of agent and starting dose, timing of administration, and 
uptitration).
Basal insulin must be initiated at a rescue visit which is either a scheduled or an unscheduled 
visit at the investigational site, and not by a telephone visit. Consideration should be given to
reducing the dose of glimepiride (either open-label, for rescued subjects, or blinded 
glimepiride or matching placebo, for non-rescued subjects) as basal insulin treatment is 
initiated and up-titrated. 
5.6.1. Drug Supplies for Glycemic Rescue Therapy
During Phase A, subjects requiring glycemic rescue therapy will receive treatment with 
open-label glimepiride. Open-label glimepiride will be provided locally by the trial site or 
subsidiary, depending on local country operational or regulatory requirements. 
For subjects requiring rescue therapy with basal insulin (eg, insulin glargine, insulin detemir, 
NPH insulin, degludec), basal insulin will be provided locally by the trial site or subsidiary, 
depending on local country operational or regulatory requirements. 
6. STUDY PROCEDURES 
For the procedures described below, where multiple procedures are scheduled at the same 
time point(s) relative to dosing, 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.

Visit windows for this trial are recommended and not required.
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6.1. Instructions to Subjects
At the S2 visit, subjects will be given the following instructions/guidance to be complied 
with for the duration of participation in the trial and provided the following or similar items 
to aid in management of their T2DM (provided to the sites by the Sponsor):

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 be undertaken in the event subjects 
experience symptoms of hyperglycemia or hypoglycemia.
6.1.1. Dispense Hypoglycemia Assessment Log and Instruct on Hypoglycemia 
Symptoms and Management
At S2, 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, palpitation, 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 episodes he or she believes may represent hypoglycemia.  If a fingerstick 
glucose has been obtained before or shortly (ie, within a few minutes) after treating, the value 
should be recorded in the log.  In addition, subjects will be instructed to record in the log any 
fingerstick glucose values 70 mg/dL (3.9 mmol/L) regardless of the presence of 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 on the log.  Each episode should be evaluated 
by the Investigator.  For episodes determined to be hypoglycemia (symptomatic or 
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asymptomatic), and for all glucose values 70 mg/dL (3.9 mmol/L) regardless of whether 
they are considered an adverse event, the hypoglycemia assessment (HA) electronic case 
report form (eCRF) must also be completed.  Each event of symptomatic hypoglycemia must 
be reported as an adverse event on the adverse event eCRF.  Each episode of asymptomatic 
hypoglycemia considered by the Investigator to be an adverse event should also be reported 
on the adverse event eCRF.
6.1.2. Diet and Exercise Counseling
Subjects will be seen by a dietician or qualified healthcare professional for dietary and 
exercise counseling at S2 visit only; monitoring at other visits may be done by other 
appropriate site personnel evaluating the subject.
At S2, the subject will receive counseling on diet consistent with the local guidelines of the 
country of the investigational site. At each subsequent visit, the subject will be asked about 
their diet and exercise.  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 (S1)
As subjects must be fasting for the S1 visit, it is permissible that the Informed Consent 
Document is signed by the subject prior to the S1 visit.  Because some of the laboratory data 
at S1 can be repeated (see Exclusion Criteria), the S1 visit may actually occur over several 
days.
Subjects will be instructed to arrive at the site after a minimum 10-hour fast (except water) 
for S1.  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).  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.

Provide subject with Study Contact Card.

Collect demography, medical history including smoking status as well as prior 
medications used.

Measure body weight and height in duplicate [refer to Section 7.2].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].
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
Obtain blood and urine specimens for clinical laboratory tests; chemistry, 
hematology, urinalysis [refer to Section 7.4.1].

HbA1c, fasting plasma glucose (FPG), fasting triglycerides, TSH, PTH. 

Urine pregnancy test for women of childbearing potential.

Fasting C-peptide (only for subjects assessed by the Investigator as possibly having 
type 1 diabetes).

Perform an optional fingerstick HbA1c assessment while at the site. The fingerstick 
HbA1c cannot substitute for a central laboratory measurement to determine subject 
eligibility.

Review of eligibility criteria.
Subjects must be instructed to continue their background oral AHA; no changes to 
background oral AHA (if applicable) will be made until the S2 Visit.
6.2.2. Screening Visit 2 (S2)
A separate S2 visit is required for subjects taking metformin monotherapy for less than 
8 weeks at the S1 visit and for those who require a change to their diabetes regimen 
(including subjects who need to discontinue their AHA therapy). Subjects whose HbA1c at 
S1 is 7.0-10.5% (53-91 mmol/mol), and are on metformin monotherapy 1500 mg/day for 
8 weeks or more at S1 can proceed with a combined S2/S3 Visit. For combined visits, all 
procedures from each individual visit must be performed at the one combined visit.
Approximately 1 week following the S1 visit, subjects will return to the site after a minimum 
10-hour fast (except water) for the S2 visit. The following procedures should be completed:

Conduct inquiry about any spontaneously reported adverse events by asking the 
subjects to respond to a non-leading question such as “how do you feel?”

Obtain supine, single, standard, 12-lead ECG [refer to Section 7.4.4].  

Subjects will be given a sponsor-provided glucose meter, a self-monitoring blood 
glucose log and needed supplies to enable them to perform finger stick blood glucose 
monitoring at home. Subjects should be instructed on how to complete the log.

As a means of confirming subjects' understanding of the instructions, subjects will 
perform a fasting finger stick blood glucose assessment while at the site. 

Subjects will be educated on the symptoms of hyperglycemia (eg, polyuria, 
polydipsia) and instructed to call the site should these symptoms occur and/or worsen 
before next visit (ie, S3).
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
Subjects will be provided with a hypoglycemia assessment log that they must use to 
track the incidence of hypoglycemia. Subjects should be educated on the symptoms 
of hypoglycemia [refer to Section 6.1.1] and instructed to call the site should these 
symptoms occur and/or worsen before next visit (ie, S3). 

Subjects will be counseled by a dietician or qualified health care provider on 
appropriate dietary and lifestyle guidelines for T2DM. Counseling on dietary 
guidelines will be in accordance with local medical standards of care for patients with 
T2DM. 

Review and update concomitant medications since last visit.

Review of eligibility criteria.
Subjects receiving metformin in combination with one other allowable AHA must 
discontinue this other AHA beginning at the S2 visit and remain off this other AHA for the 
duration of this trial.
6.2.3. Placebo Run-in (Visit S3 or Combined S2/S3)
A separate S3 visit is required for subjects taking metformin monotherapy for less than 
8 weeks at the S1 visit and for those who require a change to their diabetes regimen 
(including subjects who need to discontinue their AHA therapy).  Subjects whose HbA1c at 
S1 is 7.0-10.5% (53-91 mmol/mol), and are on metformin monotherapy 1500 mg/day for 
8 weeks or more at S1 can proceed with a combined S2/S3 Visit. If visit is combined S2/S3, 
all procedures from each individual visit must be performed at the one combined visit.
Subjects will return to the site after a minimum 10-hour fast (except water) for S3 or 
combined S2/S3. The following procedures should be completed:

Update concomitant medications since last visit.

Measure HbA1c to assess eligibility for subjects taking metformin monotherapy for 
less than 8 weeks at the S1 visit and for those who required a change to their diabetes 
regimen at the S2 visit (including subjects who have discontinued their AHA therapy 
at the S2 visit).

Conduct inquiry about any spontaneously reported adverse events by asking the 
subjects to respond to a non-leading question such as “how do you feel?”

DXA of lumbar spine, total hip, femoral neck and distal forearm [refer to 
Section 7.6]. DXA should be performed on the same day as the S3 visit.  However, if 
it cannot be performed on this day, the DXA will need to be conducted sometime 
between S3 and at least ten days before the Day 1 visit in order that the results will be 
available prior to Day 1. 

Perform complete physical examination [refer to Section 7.3].
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
Obtain duplicate orthostatic blood pressure and pulse rate measurement (supine 
standing) [refer to Section 7.4.3].

Measure body weight in duplicate [refer to Section 7.2].

Obtain blood sample for 25-hydroxyvitamin D measurement.

Urine pregnancy test for women of childbearing potential.

Perform a fasting finger stick blood glucose assessment at the clinic.

Diet and exercise monitoring (see Section 6.1.2).

Review self-monitoring blood glucose and Hypoglycemia Assessments logs
completed by the subjects (refer to Section 7.4.6).

Review of eligibility criteria.
Following completion of the above procedures:

Contact IVRS.

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.

Placebo for placebo run-in will be dispensed and first dose should be administered 
and witnessed in clinic [refer to Section 5.3.2]. 
6.3. Phase A: Double-Blind, Placebo-Controlled Treatment Period (Visits 4 through 8)
6.3.1. Day 1 (Visit 4)
At 14 days 5 days relative to S3 (or combined S2/S3 visit), subjects will return to the site 
after a minimum 10-hour fast (except water) for the Day 1 (V4). At this visit, the following 
procedures will be completed prior to administration of investigational product:

Assessment of pill count on the returned bottles or blister card(s) dispensed at the 
previous visit (S3) will be undertaken.

Assess treatment compliance.  If non-compliance to the blinded placebo is identified 
(ie, <80% of placebo run-in medication taken by subject), the subject must not be 
randomized.

Update concomitant medications since last visit.

Measure body weight in duplicate [refer to Section 7.2].

Obtain supine, single, standard, 12-lead ECG [refer to Section 7.4.4].
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
Obtain duplicate orthostatic blood pressure and pulse rate measurement (supine 
standing) [refer to Section 7.4.3].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Conduct inquiry about any spontaneously reported AEs by asking the subject to 
respond to a non-leading question such as “how do you feel?”

Review self-monitoring blood glucose and Hypoglycemia Assessment logs completed 
by the subject [refer to Section 7.4.6].

Diet and exercise monitoring (see Section 6.1.2).

Review of eligibility criteria.

Register/randomize subject into trial using IVRS [refer to Sections 4.3 and 5.1].

Obtain blood and urine specimens for:

Clinical laboratory tests [refer to Section 7.4.1] including chemistry, hematology, 
urinalysis, urinary albumin/creatinine ratio, urine pregnancy test (where 
applicable) [refer to Section 7.1], lipid panel, apolipoproteins, HbA1c, FPG, and 
whole blood (DNA), plasma and serum for Future Biomedical Research (FBR) 
[refer to Schedule of Activities Table and Appendix 1]. 
Note: The FBR sample for DNA analysis should be obtained pre-dose, at 
Day 1/Visit 4, 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).

Bone Biomarkers (CTX, P1NP) and PTH [refer to Section 7.7].
Following completion of the above procedures:

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.

Supply of investigational product will be dispensed and first dose from the new 
supply should be administered and witnessed in clinic [refer to Section 5.3.4]. 
6.3.2. Week 6 (Visit 5)
At 6 weeks 7 days relative to Day 1 (V4), subjects will return to the site after a minimum 
10-hour fast (except water) for V5. At this visit, the following procedures will be 
completed:
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
Update concomitant medications since last visit.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Measure body weight in duplicate [refer to Section 7.2].

Obtain duplicate orthostatic blood pressure and pulse rate measurement (supine 
standing) [refer to Section 7.4.3].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?”Assess potential clinical 
events for adjudication [refer to Section 7.8].

Diet and exercise monitoring (see Section 6.1.2).

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Obtain blood and urine specimens for:

Clinical laboratory tests [refer to Section 7.4.1] including chemistry, urine 
pregnancy test (where applicable) [refer to Section 7.1], HbA1c, and FPG.

Pharmacokinetics of ertugliflozin (on a plasma sample) [refer to Section 7.5.1] 
including collection of date/time of blood draw and date/time of last dose of 
investigational product.  PK sample is to be collected approximately 24 hr 
following the prior day's dose and before administration of the current day's dose.
Following completion of the above procedures:

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.

Contact IVRS.

Dispense glycemic rescue therapy, if applicable.

Dispense investigational product.
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6.3.3. Week 12 (Visit 6)
At 12 weeks 7 days relative to Day 1 (V4), subjects will return to the site after a minimum 
10-hour fast (except water) for V6. At this visit, the following procedures will be 
completed:

Update concomitant medications since last visit.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Measure body weight in duplicate [refer to Section 7.2].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?” Assess potential 
clinical events for adjudication [refer to Section 7.8].

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Diet and exercise monitoring (see Section 6.1.2).

Obtain blood and urine specimens for:

Clinical laboratory tests [refer to Section 7.4.1] including chemistry, hematology, 
urine pregnancy test (where applicable) [refer to Section 7.1], lipid panel, HbA1c, 
and FPG. 

Pharmacokinetics of ertugliflozin (on a plasma sample) [refer to Section 7.5.1] 
including collection of date/time of blood draw and date/time of last dose of 
investigational product.  PK samples are to be collected approximately 24 hr 
following the prior day's dose and before administration of the current day's dose.
Following completion of the above procedures:

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.

Collect a PK sample 1 h after dose administration of double-blind investigational 
product for ertugliflozin/placebo (with an allowable time window up to 3 hours post 
dose).

Contact IVRS.
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
Dispense glycemic rescue therapy, if applicable.

Dispense investigational product.
6.3.4. Week 18 (Visit 7)
At 18 weeks 7 days relative to Day 1 (V4), subjects will return to the site after a minimum 
10-hour fast (except water) for V7. At this visit, the following procedures will be 
completed:

Update concomitant medications since last visit.

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Measure body weight in duplicate [refer to Section 7.2].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?” Assess potential 
clinical events for adjudication [refer to Section 7.8].

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Diet and exercise monitoring (see Section 6.1.2). 

Obtain blood and urine specimens for:

Clinical laboratory tests [refer to Section 7.4.1] including chemistry, urine 
pregnancy test (where applicable) [refer to Section 7.1], HbA1c, and FPG.

Pharmacokinetics of ertugliflozin (on a plasma sample) [refer to Section 7.5.1] 
including collection of date/time of blood draw and date/time of last dose of 
investigational product.  PK sample is to be collected approximately 24 hr 
following the prior day's dose and before administration of the current day's dose.
Following completion of the above procedures:

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.

Collect a PK sample 1 h after dose administration of double-blind investigational 
product for ertugliflozin/placebo (with an allowable time window up to 3 hours post 
dose).
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
Contact IVRS.

Dispense glycemic rescue therapy, if applicable.

Dispense investigational product.
6.3.5. Week 26 (Visit 8)
At Week 26 7 days relative to Day 1 (V4), subjects will return to the site after a minimum 
10-hour fast (except water) for V8.  Completion of the Week 26 (V8) visit marks the end of 
the subjects' participation in Phase A and entry into Phase B (double-blind extension). At 
this visit, the following procedures will be completed prior to administration of 
investigational product:

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed.

Review and update concomitant medications since last visit.

Measure body weight in duplicate [refer to Section 7.2].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Conduct brief physical examination which includes assessment of heart, lungs, 
abdomen, extremities and skin.

Obtain triplicate orthostatic blood pressure and pulse rate measurement (supine 
standing [refer to 7.4.3].

Obtain supine, single, standard, 12-lead ECG [refer to Section 7.4.4].

Perform DXA of lumbar spine, total hip, femoral neck and distal forearm [refer to 
Section 7.6]. If the DXA can’t be performed at Week 26 visit, it can be obtained 
7 days from the scheduled visit date. 

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?”Assess potential clinical 
events for adjudication [refer to Section 7.8].

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Perform a fasting finger stick blood glucose assessment at the clinic.

Diet and exercise monitoring (see Section 6.1.2).
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
Obtain blood and urine specimens for:

Clinical laboratory tests [refer to Section 7.4.1] including chemistry, hematology, 
urinalysis, urinary albumin/creatinine ratio, urine pregnancy test (where 
applicable) [refer to Section 7.1], lipid panel, apolipoproteins, HbA1c, FPG and 
FBR plasma and serum samples Appendix 1.

Bone Biomarkers (CTX and P1NP) and PTH [refer to Section 7.7].
Following completion of the above procedures:

Contact IVRS.

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.

Subjects will be dispensed drug supplies to last them to the next visit:

Double-blind investigational product for ertugliflozin/placebo; AND

Blinded glimepiride/placebo therapy only to subjects NOT receiving open-label 
glimeperide for glycemic rescue and whose fasting fingerstick glucose (FFSG) at 
Week 26 visit is 110 mg/dL (6.1 mmol/L). 

Week 26 dose of double-blind ertugliflozin/placebo will be administered from new 
supply of investigational product and witnessed in clinic.

Dispense glycemic rescue therapy, if applicable.
6.4. Phase B: Double-Blind Extension Period (Visits 8 through 15)
This blinded (sponsor-open), double-blind extension period starts after the completion of the 
Week 26 assessments for Phase A (V8) and includes Visits 9 through 15 conducted at 
Weeks 30, 39, 52, 65, 78, 91, and 104.
6.4.1. Week 30 (Visit 9)
At 30 weeks 7 days relative to Day 1 (V4), subjects will return to the site after a minimum 
10-hour fast (except water) for V9.  At this visit, the following procedures will be 
completed:

Contact IVRS.

Update concomitant medications since last visit.

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?” Assess potential 
clinical events for adjudication [refer to Section 7.8].
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
Perform a fasting finger stick blood glucose assessment at the clinic.

Obtain plasma sample for pharmacokinetics of ertugliflozin [refer to Section 7.5.1] 
including collection of date/time of blood draw and date/time of last dose of 
investigational product.  PK sample is to be collected approximately 24 hr following 
the prior day's dose and before administration of the current day's dose.

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Subjects will be dispensed the following drug supply to last them to the next visit:

Blinded glimepiride/placebo therapy (applicable only to subjects who are NOT 
receiving open-label glimeperide for glycemic rescue).
6.4.2. Week 39 (Visit 10) through Week 91 (Visit 14)
Visits following Week 30 have a visit window of 14 days relative to Day 1. The procedures 
for Visits 10-14 are described in this section. 
Additional procedures are required for Week 52 (V11), which are further defined in 
Section 6.4.3, respectively.
Following the preceding visit and within the corresponding visit window, subjects will return 
to the site after a minimum 10-hour fast (except water) for V9-14.  At these visits, the 
following procedures will be completed:

Update concomitant medications since last visit.

Assess treatment compliance with investigational product and blinded 
glimepiride/placebo therapy (if applicable), and counsel subject for non-compliance, 
as needed. 

Measure body weight in duplicate [refer to Section 7.2].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?” Assess potential 
clinical events for adjudication [refer to Section 7.8].

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Diet and exercise monitoring (see Section 6.1.2).
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
Perform a fasting finger stick blood glucose assessment at the clinic.

Obtain blood and urine specimens for:

Clinical laboratory tests [refer to Section 7.4.1] including chemistry; hematology
(only at Week 52 and Week 78); urinalysis (only at Week 52 and Week 78); urine 
pregnancy test (where applicable) [refer to Section 7.1]; HbA1c; and FPG.
Following completion of the above procedures:

Contact IVRS.

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.

Subjects will be dispensed drug supplies to last them to the next visit:

Double-blind investigational product for ertugliflozin/placebo; AND

Blinded glimepiride/placebo therapy (applicable only to subjects who are NOT 
receiving open-label glimeperide for glycemic rescue).

Dispense glycemic rescue therapy, if applicable.
6.4.3. Week 52 (Visit 11)
At Week 52 14 days relative to Day 1 (V4), after a minimum 10-hour fast (except water), 
the following procedures will be completed in addition to those previously listed in 
Section 6.4.2:

Conduct brief physical examination which includes assessment of heart, lungs, 
abdomen, extremities and skin.

Obtain supine, single, standard, 12-lead ECG [refer to Section 7.4.4].

Perform DXA of lumbar spine, femoral neck, total hip, and distal forearm [refer to 
Section 7.6]. If the DXA can’t be performed at Week 52 visit, it can be obtained 7 
days from the scheduled visit date. 

Obtain blood and urine specimens for:

Urinalysis, urinary albumin/creatinine ratio, lipid panel.

Bone Biomarkers and PTH [refer to Section 7.7].
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6.4.4. Week 104 (Visit 15) – Final Study Visit/Early Termination Visit
At Week 104 14 days relative to Day 1 (V4) or at Early Termination (ET), subjects will 
return to the site after a minimum 10-hour fast (except water). 
Completion of the Week 104 (V15) visit marks the end of the subject’s participation in 
Phase B. Subjects who complete the trial and those who discontinue from the trial
prematurely, should complete the procedures listed below:

Contact IVRS.

Update concomitant medications since last visit.

Assess treatment compliance with investigational product and blinded 
glimepiride/placebo therapy (if applicable).

Measure body weight in duplicate [refer to Section 7.2].

Collect triplicate measurements of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Obtain supine, single, standard, 12-lead ECG [refer to Section 7.4.4].

DXA of lumbar spine, total hip, femoral neck and distal forearm [refer to 
Section 7.6]. If the DXA can’t be performed at Week 104 visit, it can be obtained in 
a 7 days window prior to Week 104. In case of discontinuation of investigational 
product during Phase A, a DXA scan will be performed if the discontinuation occurs 
between Week 12 and Week 26.  In case of discontinuation of investigational product 
during Phase B, a DXA scan will be performed if the discontinuation occurs at least 
12 weeks from the previous scan.  

Conduct brief physical examination which includes assessment of heart, lungs, 
abdomen, extremities and skin.

Conduct inquiry about any spontaneously reported AEs by asking the subjects to 
respond to a non-leading question such as “how do you feel?” Assess potential 
clinical events for adjudication [refer to Section 7.8].

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Perform a fasting finger stick blood glucose assessment at the clinic.

Diet and exercise monitoring (see Section 6.1.2).

Obtain blood and urine specimens for:
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
Clinical laboratory tests [refer to Section 7.4.1] including chemistry, hematology, 
urinalysis, urinary albumin/creatinine ratio, urine pregnancy test (where 
applicable) [refer to Section 7.1], lipid panel, HbA1c (only if visit is at least 
6 weeks after randomization), apolipoproteins (at early termination visit only),
FPG, FBR plasma and serum samples (Appendix 1).

Bone Biomarkers (CTX, P1NP) and PTH [refer to Section 7.7].
Subjects, who discontinue from the trial prematurely, should be reminded that they will be 
contacted via telephone by the Investigator/qualified designee according to the same 
schedule as if they were still taking investigational product and will be asked to return for a 
visit at the week 104 visit unless they withdraw consent per Section 6.7.
6.5. 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 per 
Section 7.8, if applicable.  The phone call should be completed within a 3 day window. 
6.6. Rescue Visit, if applicable
Subjects who require rescue therapy per Section 5.6 must have glycemic rescue therapy 
initiated at either a scheduled or unscheduled visit and not by a telephone call. If subjects 
require glycemic rescue therapy prior to Week 6, a rescue visit should occur.  The following 
procedures are to be completed at a rescue visit:

Assess treatment compliance with investigational product and counsel subject for 
non-compliance, as needed. 

Measure body weight in duplicate [refer to Section 7.2].

Collect triplicate measurement of sitting blood pressure and pulse rate [refer to 
Section 7.4.2].

Obtain duplicate orthostatic blood pressure and pulse rate measurement (supine 
standing) [refer to Section 7.4.3] only if the Rescue Visit occurs in Phase A.

Conduct brief physical examination which includes assessment of heart, lungs, 
abdomen, extremities and skin.

Obtain blood specimens for clinical laboratory tests [refer to Section 7.4.1] including 
chemistry, hematology, urinalysis, lipid panel, HbA1c (only if visit is at least 6 weeks 
after randomization), apolipoproteins, FPG and FBR plasma and serum samples. 

Conduct inquiry about any spontaneously reported AEs by asking the subject to 
respond to a non-leading question such as “how do you feel?”
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
Review self-monitoring blood glucose and Hypoglycemia Assessment logs completed 
by the subject.

Diet and exercise monitoring (see Section 6.1.2).

Dispense glycemic rescue therapy as appropriate.  Dosing of open-label glimepiride
and basal insulin is at the Investigator’s discretion.

Distribute glucose meter and supplies, as needed.
6.7. Subject Withdrawal
Subjects may withdraw from the trial 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. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  For withdrawn subjects, the Investigator should inquire about the reason for 
withdrawal, request the subject return all unused investigational product, request the subject 
to return for an early termination visit, and follow up with the subject regarding any 
unresolved adverse events (AEs).
If the subject withdraws from the trial, 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. 
If a subject indicates his or her intention to stop active participation (ie, chooses to no longer 
attend visits at the investigational site, take blinded investigational product, and have other 
study-related procedures conducted at the investigational site) in the trial or if the 
Investigator has recommended stopping the investigational product, the Investigator must 
clarify with the subject if he/she is willing to continue in the study with contact at intervals to 
provide a brief and focused update on health status (eg, SAEs and events eligible for 
adjudication [see Section 7.8]).  It will be important for the subject to understand the 
importance of complete collection of information, and also the limited requirements for 
continuing to provide this information (ie, a brief telephone contact, occurring at the time of 
the originally planned study visits).  Thus, subjects may discontinue study drug and continue 
in the study with clinic visits or allow continued site contacts without clinic visits, or they 
may indicate that they do not wish to have further contact with the site. 
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 
collection of information on clinical cardiovascular events.  This may include contacting 
family members and health care providers and, when applicable, using subject location 
services.  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 
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reach the subject via certified letter.  All attempts to contact a subject and information 
received during contact attempts must be documented in the subject’s medical record.  In any 
circumstance, every effort should be made to document subject outcome, if possible. 
Subjects who are discontinued from investigational product but agree to continue to 
participate in the trial by providing follow-up information can have medical and diabetes 
management by their managing physician or Investigator, as appropriate.  These subjects 
may initiate any other therapy as needed (previously prohibited medications may be used).  
After discontinuation of investigational product, Pfizer or its designee will continue to 
reimburse/supply (as specified in Section 5.6.1), glimepiride or insulin (for those rescued) 
until trial completion.  The Investigator should ensure that the subject has enough open-label 
rescue medication until the next scheduled in clinic visit.  Procurement of any other oral 
AHAs, is the responsibility of the subject. 
6.7.1. Withdrawal from Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.  Subjects may withdraw consent at any time by 
contacting the principal Investigator for the main trial.  If medical records for the main trial 
are still available, the Investigator will contact the Sponsor using the designated mailbox 
, and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the Investigator confirming the destruction.  It is the 
responsibility of the Investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (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.
6.7.2. Reasons for Discontinuation from Investigational Product or from the Trial
Reasons for protocol-specified discontinuation from the investigational product or from the 
trial are listed, but not limited, 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 delegate] assessment) for any laboratory safety test 
abnormality resulting in discontinuation from investigational product.
Withdrawal from the Trial

Subject requests discontinuation from the trial (ie, refuses to continue to be contacted 
to provide further health information).
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
Death.
Discontinuation of Investigational Product
1. Subject meets protocol-specified hyperglycemia criteria as specified below:
Subject continues to exceed glycemic rescue criteria for at least 3 weeks despite maximal 
adjustment of basal insulin therapy, without a reasonable explanation (eg, intercurrent 
illness or medication omission).  Subjects who don’t agree to start basal insulin will have 
investigational product discontinued.  
2. Hypoglycemia: Repeated (2 or more episodes since the prior visit) FPG or fingerstick 
glucose <50 mg/dL (<2.8 mmol/L) with or without symptoms of hypoglycemia or 
70 mg/dL (3.9 mmol/L) with symptoms of hypoglycemia, and without a reasonable 
explanation (such as increased physical activity or skipped meal).
Note: For subjects rescued with glimepiride and/or basal insulin, the protocol-specified 
discontinuation criteria for hypoglycemia only apply after the subject has interrupted 
glycemic rescue medication.  Similarly, for subjects who were started on Phase B blinded 
glimepiride or matching placebo, the hypoglycemia criteria only applies when subject is 
off of blinded glimepiride or matching placebo.
3. Abnormal liver function tests meeting criteria specified in Section 8.7. 
4. Parameters of Renal Function:

Serum creatinine concentrations consistently 1.5 mg/dL (133 mol/L) in men or 
1.4 mg/dL (123 mol/L) in women.
OR

Subjects with eGFR consistently <45 mL/min/1.73 m2 (MDRD formula). 
Note: A consistent value is defined as a repeat measurement performed within 7 days of 
notification from the central laboratory. If the eGFR or serum creatinine value continues 
to meet discontinuation criterion but demonstrates improvement relative to the prior 
result, an additional repeat may be performed.  See Section 6.7.2.1 for guidance on 
following subjects who discontinue due to decreased renal function or renal-related 
adverse events.  
5. Requirement for one of the prohibited medications listed in Section 4.2.
6. For subjects who are on glycemic rescue medication, if such a subject develops any 
condition for which the rescue medication is contraindicated in accordance with the local 
drug label of the country where the subject is participating.
7. Pregnancy.
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Note: A positive urine pregnancy test requires immediate interruption of investigational 
product until serum -hCG can be performed and found to be negative.  Subject must be 
permanently discontinued, and pregnancy should be reported and followed per 
Section 7.1 if pregnancy is confirmed by a positive serum pregnancy test.
8. 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. 
9. Subjects undergoing bariatric surgery.
10. The Investigator or subject are unblinded to randomized assignment (eg, unblinding 
information obtained through IVRS or inadvertently obtained).
If a subject discontinues investigational product, he/she should complete all Early 
Termination Visit procedures as described in Section 6.4.4 and listed in Schedule of 
Activities.  Unless the consent to follow the subject is specifically withdrawn, a subject will 
be contacted via telephone by the Investigator/qualified designee according to the same 
schedule as if he/she were still taking investigational product and will be asked to return for a 
visit at Week 104.  Such subjects may initiate other AHA therapy as indicated (prohibited 
medications described in Section 5.5 will not apply to these subjects.)
6.7.2.1. Follow-up for Subjects who Discontinue Due to Decreased Renal Function
Subjects who discontinue blinded investigational product for eGFR/creatinine 
discontinuation criteria (see Section 6.7.2) or renal-related adverse events should have a 
repeat eGFR/creatinine performed 1 week after the last dose of Investigational Product.  This 
post-treatment visit may occur at the Discontinuation visit (if the Discontinuation visit occurs 
1 week after the last dose of Investigational Product) or at an unscheduled 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, angiotensin-converting enzyme (ACE) inhibitors, 
diuretic agents, etc), and clinical assessment of volume status (eg, measurement of orthostatic 
heart rate [HR] and blood pressure [BP], and physical examination focused on assessment of 
volume status); additional evaluations, including renal ultrasound, 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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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 study team will be informed of these incidents in a timely fashion.
All biological samples will be assayed, by a sponsor-identified central laboratory, using a 
validated analytical method in compliance with the Sponsor’s standard and validated 
methodologies, and 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.
7.1. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at both the S1 and S3 Screening Visits and before 
investigational product administration at the Baseline visit 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 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 withdrawn from investigational product 
but may continue to be contacted according to the same schedule as if he/she were still taking 
investigational product and will be asked to return for a visit at the Week 104 visit.  
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local 
regulations.
7.2. 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 are 
allowed to weigh subjects in light clothing. 

Subjects should be instructed to step gently onto the scale, place both feet together in 
the center of the scale and stand straight with eyes directed ahead.  Subjects should be 
instructed to stand still and not sway.  Measurement will be recorded after the weight 
has stabilized.
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
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 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 
conduct accuracy checks on the scale, the study 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 must 
be conducted monthly, and the accuracy check record must be sent to the Sponsor at 
the end of the trial.
7.3. Physical Examinations
A complete physical examination will be performed at the S3 Visit.  A brief physical 
examination including assessment of the heart, lungs, abdomen, extremities, and skin will be 
performed at other times as listed in the Schedule of Activities. Abnormalities considered 
clinically significant should be reported as AEs.  Other body systems may be evaluated as per 
the judgment of the Investigator or as needed to evaluate adverse events.
7.4. Safety
7.4.1. Clinical Laboratory Tests
The tests outlined in Table 5 will be performed at the pre-specified time points outlined in the 
Schedule of Activities following an overnight fast of at least 10 hours (except water). 
The FPG and HbA1c results from the central laboratory will be masked at randomization and 
throughout the duration of the trial for both the sponsor and investigative site unless the 
results meet pre-specified alert criteria.  A confirmatory plasma glucose value from the 
central laboratory on a new plasma sample will be required to make a final determination as 
to whether a subject meets the criteria for glycemic rescue or discontinuation.  If it is 
confirmed a subject meets glycemic rescue or discontinuation criteria, FPG and HbA1c will 
be unmasked for the remainder of the trial.
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Table 5.
Clinical/Safety Central Laboratory Tests
Hematology
Chemistry
Urinalysisa, e
Others
Hemoglobin
Hematocrit
RBC Count
Platelet Count
WBC Count
Total Neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Serum Creatinine
Ca++ (total)
Na+
K+
Cl-
Total CO2 (Bicarbonate)
Mg++
Phosphate
Uric Acid
AST (SGOT)
ALT (SGPT)
Alkaline Phosphatase
Total bilirubin
Direct (conjugated) bilirubinb
Indirect (unconjugated) bilirubinc
Albumin
Total Protein
pH
Protein (qual)
Blood (qual)
Ketones
Leukocyte esterase
Nitrites
Microscopyd
At S1 only:
- Fasting triglycerides/TSH
At selected visits, only (refer to 
Schedule of Activities):
- PTH, CTX, PINP
- 25-hydroxyvitamin D
-HbA1c
- FPG
- C-peptide 
- Urinary albumin/creatinine ratioe
- Pregnancy tests (where 
applicable)
- Lipid panel (ie, total cholesterol, 
HDL, LDL, triglycerides)
- Apolipoproteins (ApoB, and 
ApoA-1)
a.
Routinely collected samples for urinalysis will be sent to the central laboratory for dipstick analysis and microscopy if 
needed, see [d].  
b.
Direct bilirubin measured only when total bilirubin is greater than upper limit of normal.
c.
Indirect bilirubin measured only when total bilirubin is greater than upper limit of normal.
d.
Microscopy to be performed by 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. 
e.
Urine sample(s) for urinalysis and albumin:creatinine ratio 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.  Under these 
circumstances, the subject should provide a urine sample for evaluation at an unscheduled visit.
7.4.1.1. Lipid Panel and Apolipoproteins
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, low density lipoprotein cholesterol (LDL-C), high density 
lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides. 

ApoB and ApoA-1 will also be included at Day 1 and Week 26 visits as well as the 
glycemic rescue visit and early termination visit.
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.
7.4.1.2. Urinary Albumin:Creatinine Ratio
A urine sample will be collected at the times listed in the Schedule of Activities (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 
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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.
7.4.2. Vital Signs (Sitting Blood Pressure and Pulse Rate)
Vital sign measurements include a triplicate measurement of sitting blood pressure and pulse 
rate.  Blood pressure and pulse rate will be measured using an automated, oscillometric blood 
pressure measuring device at all time points noted in the Schedule of Activities.  Site 
personnel should use the same blood pressure measuring device throughout the trial for each 
subject.
The following method should be used to record sitting blood pressure and pulse rate for 
subjects in triplicate:

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 CRFs. 

Assessment of pulse rate can be manual (rather than using an automated device); 
however, when done manually, pulse rate must be measured in the brachial/radial 
artery for at least 30 seconds. 
Other procedures should not be performed during the time of the blood pressure and pulse 
rate measurements.
7.4.3. Postural (Orthostatic) Blood Pressure and Pulse Rate
On the S3, Day 1, Week 6 and Week 26 visits, 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 (except for S3 visit).  
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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:

Subject in supine position for a minimum of 5 minutes.

Measure blood pressure and pulse rate in the supine position in duplicate (at least 
1 minute apart).

Stand subject and measure blood pressure and pulse rate in the standing position in 
duplicate according to the following instructions.  The first measurement of standing 
blood pressure and pulse rate will be measured after at least 1 minute of standing.  
The second measurement of standing blood pressure and pulse rate will be measured 
after the subject has been standing for at least 3 minutes. 
7.4.4. Electrocardiogram, (12-lead ECG)
Single, supine 12-lead ECGs 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 procedure.

12-lead ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position.
12-lead ECGs should be obtained prior to the nominal time assessment of blood pressure, 
and pulse rate as well as prior to blood collection.
The screening ECG should be read and interpreted at the investigative site.  ECGs performed 
at Day 1 and time points after randomization 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.
Subject demographic information will be made available to the central scoring site that will 
provide results on heart rate (beats per minute [BPM]), overall interpretation, rhythm type, 
and heart rate intervals PR, QRS, QT, QTcB, and QTcF (msec), along with any comments. 
7.4.5. 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 S2 visit. 
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7.4.6. Review of Hypoglycemia Assessment Logs
The site must review the hypoglycemia assessment logs completed by the subjects at each
site visit subsequent to the S2 visit.  Based on this information, an assessment of any 
symptomatic occurrence of hypoglycemia must be undertaken and appropriate decisions 
should be made by the Investigator.
7.4.6.1. 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, 
palpitation, 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.
A subject should be discontinued from the investigational product if they have repeated (2 or 
more episodes since the prior visit) FPG or fingerstick glucose <50 mg/dL (<2.8 mmol/L) 
with or without symptoms of hypoglycemia or 70 mg/dL (3.9 mmol/L) with symptoms of 
hypoglycemia, and without a reasonable explanation (such as increased physical activity or 
skipped meal).
Any episode of hypoglycemia must be captured on the Hypoglycemic Adverse Event Form 
of the CRF (refer to Section 6.1.1).  For definition of hypoglycemic episode and severity 
categorization, refer to Section 7.4.6.1.1 below.
7.4.6.1.1. Definition and Severity Categorization of Hypoglycemic Events
Based on review of the subject completed hypoglycemia assessment logs at each outpatient 
visit to the site, the Investigator must assess the glucose values as well as any symptoms 
documented.  Each hypoglycemic event will be reported by the Sponsor according to the 
following categories.  
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.  Finger-stick 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 finger-stick 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 finger-stick or plasma glucose concentration 70 mg/dL 
(3.9 mmol/L). 
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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 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. 
7.4.6.1.2. 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 finger-stick or plasma glucose value 70 mg/dL 
(3.9 mmol/L) from either a fingerstick or central laboratory sample 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).
7.4.7. Assessment of Infections
7.4.7.1. Urinary Tract Infections
Any subject presenting with symptoms considered to be a urinary tract infection should be 
recorded as having an adverse event with the term as considered appropriate by the 
investigator (eg, cystitis, pyelonephritis, urinary tract infection). The site should collect urine 
for culture performed by their local laboratory, but urine dipstick should not be performed by 
the site or local laboratory. If a urinalysis is clinically necessary, a microscopic urinalysis 
ONLY and not a dipstick urinalysis should be performed. If symptoms are reported outside 
of a routine scheduled study visit, clinical assessment and urine testing should be done 
promptly at an unscheduled visit. The investigator or treating physician should initiate 
antibiotic treatment as considered clinically appropriate; if possible, a locally obtained 
culture and sensitivity should be obtained. 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 (excluding urine dipstick 
results) and treatment provided, and this information should be recorded.
7.4.7.2. 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. 
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7.5. Pharmacokinetics of Ertugliflozin
7.5.1. Plasma for PK Analysis
On the morning of any visit that includes pharmacokinetic sampling, investigational product 
dosing (if applicable) will occur after the pre-dose sample is taken.
Blood samples (approximately 4 mL) to provide approximately 2 mL of plasma for 
pharmacokinetic analysis will be collected at visits specified in the "Schedule of Activities".  
Pre-dose samples will be collected at Weeks 6, 12, 18 and 30. In addition, post-dose samples 
will be collected at Weeks 12 and 18, 1 hour after administration of investigational product
(but with an allowable window up to 3 hours). The exact date and time of the blood draw 
and the date and time of the last dose of investigational product reported by the subject prior 
to the blood draw should be captured on the CRF.
Samples will be centrifuged at approximately 1700 g for about 10 minutes at 4C (if a 
refrigerated centrifuge is not available, place sample in an ice water bath for at least 
10 minutes before centrifugation).  The plasma will be stored in appropriately labeled 
screw-capped polypropylene tubes at approximately -20C within 1 hour of collection. 
Detailed instructions for the preparation and shipment of the samples can be found in the 
Laboratory Manual supplied by the central laboratory.
As part of understanding the pharmacokinetics of the investigational product, samples may 
be used for metabolite identification and/or evaluation of the bioanalytical method.  These 
data will be used for internal (ie, Sponsor) exploratory purposes and will not be included in 
the clinical study report.
7.6. Dual-Energy X-Ray Absorptiometry (DXA)
7.6.1. Bone Mineral Densitometry
Bone densitometry will be performed in facilities qualified and approved by the Sponsor or 
its designee. 
DXA scanning procedures will be standardized and all the scans will be monitored and 
centrally analyzed by a Central Evaluation Facility according to a specific protocol. 
Procedures to be followed by the bone densitometry facilities to maintain quality control will 
be provided in a separate manual.  The hardware used should remain the same for the 
duration of the trial.  Software upgrades to DXA equipment must be approved in advance by 
the Central Evaluation Facility.
BMD of lumbar spine (L1-L4), femoral neck, and total hip and distal forearm will be 
measured by DXA at all time-points as mentioned in the Schedule of Activities.  The left hip 
should be evaluated unless prevented by pathology, in which case the right hip will be 
evaluated throughout the trial.
Screening DXA scan should be performed at Screening Visit 3, or sometime between S3 and 
at least ten days before the Day 1 visit.  These scans will be submitted to the Central 
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Evaluation Facility for assessment of eligibility.  Assessment of eligibility will be returned to 
the site before Day 1 visit and results of the Screening DXA must be available prior to 
subject randomization.
Follow up DXA scans will be performed at Week 26, 52 and 104 visits and submitted to the 
Central Evaluation Facility for assessment.  Follow-up scans should be obtained in a 14 day 
window from the scheduled Week 26, 52 visits and in a 14 day window prior to the 
Week 104 visit.  Investigators will remain blinded to the results of these follow up scans, 
unless the subject meets criteria for rescue criteria as provided below.
In case of discontinuation of investigational product during Phase A, a DXA scan will be 
performed if the discontinuation occurs between Week 12 and Week 26.  In case of 
discontinuation of investigational product during Phase B, a DXA scan will be performed if 
the discontinuation occurs at least 12 weeks from the previous scan. 
7.6.1.1. Rescue Criteria Related to Loss of BMD
Rescue criteria will be put into place for subjects who exhibit a significant reduction in BMD 
according to the protocol-defined criteria. Subjects with a reduction in BMD from baseline 
of >7% at any anatomical site together with a T-score <-2.5 at the Week 26 or Week 52 
follow-up scans, will have a complete unscheduled DXA performed. If these values are 
confirmed based on a repeat, complete unscheduled DXA the Investigator or treating 
physician will be permitted to start any bone active therapy. In these cases, subjects should 
continue to receive ertugliflozin or matching placebo.  The repeat, confirmatory DXA should 
be performed within 4 weeks from the initial reading.
7.7. Bone Biomarkers, PTH 
Blood will be collected for analysis of biochemical markers of bone turnover.  The following 
biomarkers will be measured during the study at the times listed in the Schedule of Activities.

Carboxy-terminal cross-linking telopeptides of Type I collagen (CTX); measured as a 
biomarker of bone resorption.

Procollagen type I N-terminal propeptide (P1NP); measured as a marker of bone 
formation.
Parathyroid hormone (PTH) will also be measured according to the times in the Schedule of 
Activities.
The sample(s) for measurement of bone biomarkers and PTH should not be collected if the 
investigational product has been discontinued for >7 days prior to the collection of the 
sample(s).
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7.8. Clinical Event Adjudication
7.8.1. Clinical Cardiovascular Events, Venous Thromboembolic Events and All Deaths
The identification of a potential clinical cardiovascular event, venous thrombo embolic event 
and all deaths 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.
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 Endpoint Adjudication Committee (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.
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Pfizer or designee will provide a listing of specific documents needed to support adjudication 
by the EAC.  Obtaining documentation will be the responsibility of 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.
The composite of adjudicated events of cardiovascular death, non-fatal myocardial infarction, 
non-fatal stroke (often referred to as major cardiovascular events [MACE]), plus 
hospitalization for unstable angina will contribute to a meta-analysis of cardiovascular safety 
of ertugliflozin across the Phase 2 and 3 programs.  Events of venous 
thromboembolism/pulmonary embolism and hospitalized congestive heart failure (CHF) will 
be separately tabulated across the Phase III clinical development program, and are not 
included in the cardiovascular composite of MACE plus hospitalized unstable angina.
7.8.2. Fractures
Spontaneously reported fractures will be adjudicated by an independent and blinded external 
fracture adjudication committee (FAC) comprised of radiologists.  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 the FAC.  The FAC 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 FAC members 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 
FAC charter will describe the precise mandates and procedures to be used for the 
adjudication of clinical fractures.
7.8.3. 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 be blinded to treatment 
assignment. A Pancreatitis Adjudication Charter will describe the precise mandates and 
procedures to be used for the adjudication of pancreatitis.
7.8.4. 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.
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7.8.5. Acute Renal Failure
Ertugliflozin, an SGLT2 inhibitor, increases urinary glucose excretion leading to an osmotic 
diuresis, and has the potential to reduce estimated glomerular filtration rate (eGFR). 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 describe the precise mandates 
and procedures to be used for assessing renal failure and assigning causality.
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 during the course of the use of the Sponsor's product in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in clinical 
practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
All adverse events will be recorded from the time the consent form is signed through 14 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets.
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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.
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 Pfizer or designee either by electronic media or paper.  Appropriate 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 Pfizer or designee either by electronic media 
or paper.  Appropriate 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;
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
Is a congenital anomaly/birth defect;

Is a cancer;

Is associated with an overdose;

Is another important medical event.
Refer to Table 6 for additional details regarding each of the above criteria.
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause that occurs to any subject from the time the consent is signed through 14 days 
following cessation of treatment, whether or not related to the Sponsor's product, must be
reported within 24 hours to Pfizer or designee either by electronic media or paper.  
Appropriate 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 Pfizer or designee. 
All subjects with serious adverse events must be followed up for outcome.
8.5. Evaluating of Adverse Events
An Investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 6. The Investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 6 for instructions in evaluating adverse events.
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Table 6.
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual 
activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the Investigator, at immediate risk of death from the event as it occurred [Note: This 
does not include an adverse event that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of 
stay, even if the hospitalization is a precautionary measure for continued observation.  (Note:  Hospitalization for an elective procedure to treat 
a pre-existing condition that has not worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of a Merck product and is documented in the patient’s medical history); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer; 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 †).
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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.)
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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 Pfizer or designee either by electronic media or paper.  
Appropriate 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, that is not associated 
with clinical symptoms or abnormal laboratory results. 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or equal 
to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab 
value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The trial site guidance for assessment and 
follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent).
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. 
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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.

ALT or AST 8X ULN or 3X ULN with symptoms consistent with liver injury and 
without an established etiology.

ALT or AST 5X ULN for 2 weeks.
Section II: Guidance for Assessment of Potential Etiology
Questions to Assess Etiology
Investigate potential causes for the subject’s elevated liver enzymes using the questions 
below.  Answers to the questions should be recorded in the subject’s source documents and 
appropriate eCRFs. 
1. Has the subject recently:

Had a change in his/her pattern of alcohol use?  Investigate historic pattern of 
alcohol use as well.

Administered an illegal drug(s) (including intravenous drugs)?

Been exposed to a chemical agent or other environmental toxin?

Consumed any unusual foods (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)?
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3. Does the subject have a relevant medical history (eg, autoimmune disorder, cancer, 
Gilbert’s syndrome, obesity, Wilson’s disease, Non-alcoholic 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)?
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 by the Sponsor
All adverse events meeting SAE criteria (see Section 8.4.1 above) must be reported to the 
Sponsor within 24 hours of when the site is notified of the event.  The following refers to 
Sponsor processing of SAEs, but does not impact Investigator responsibilities for reporting 
of any SAE.
Potential pre-specified cardiovascular SAEs will be submitted for adjudication to an 
independent EAC (see Section 7.8.1 for details). 
The following potential cardiovascular SAEs will not be subject to expedited reporting by the 
Sponsor, even 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.
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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. 
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
Detailed methodology for summary and statistical analyses of the data collected in this trial
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
With respect to the primary endpoint of reduction in HbA1c from Baseline to Week 26 and 
assuming an SD of 1.0%,11 the sample size of approximately 600 subjects (200 per arm) 
provides at least 99% power to detect a difference of 0.5% between each ertugliflozin dose 
and placebo (and 98% power for detecting this difference for both doses vs placebo) using a 
two-sided 0.05 alpha level test, allowing for a dropout rate of up to 20%. To control the 
overall Type I error rate at 0.05 a sequential testing approach will be used across the primary 
and secondary efficacy endpoints for which hypotheses will be tested, and for the two doses 
of ertugliflozin.
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The sample size for this trial also provides adequate precision for the comparisons of 
ertugliflozin versus placebo with respect to the changes in BMD from Baseline to Week 26.  
In a recent study of another SGLT2 inhibitor (dapagliflozin) in subjects with inadequately 
controlled T2DM on metformin, the largest variability for the change from baseline in BMD 
was at the total hip site, with a standard deviation (SD) of approximately 3.3% after 
50 weeks.13 Assuming that the SD of the change in BMD increases over time, 3.3% was 
taken as a conservative estimate of the variability at 26 weeks for precision calculations and 
also to ensure adequate precision for all BMD sites.
Assuming an SD of 3.3% and allowing for a dropout rate of up to 15% at Week 26, the 
half-width of the 95% confidence interval for the between-treatment difference is expected to 
be 0.7% from the point estimate for the overall study population, and also of approximately 
1.0% for the post-menopausal for 3 years sub-group which will be analyzed separately 
(approximately 50% of the overall study population). These CI half-widths would be precise 
enough to rule out clinically relevant changes in BMD, both for the overall study population 
and the 3 years post-menopausal subgroup. This is based on changes in BMD that are 
approximately 50% of the average changes from baseline to Week 80 observed for 
thiazolidinediones, which are known to be associated with significant bone loss and an 
increased risk of fracture.19
BMD data will not be censored at the point of a subject taking glycemic rescue therapy, so
the dropout rate assumed for precision calculation (15%) is lower than that assumed for the 
HbA1c power calculation (20%).  However BMD data will be censored at the point of a 
subject taking BMD rescue therapy.
9.2. Efficacy Analysis
The primary analysis population for efficacy analyses will be the Full Analysis Set (FAS), 
which is defined separately for each analysis endpoint to include all randomized subjects 
who have received at least one dose of investigational product and have at least one 
measurement of the respective endpoint at any time during Phase A of the trial including 
baseline and post-baseline time points.  The post-glycemic rescue therapy data from subjects 
who require rescue therapy prior to week 26 will be censored from primary and secondary 
endpoint efficacy analyses. 
9.2.1. Analysis of Primary Endpoint 
The primary endpoint of HbA1c will be analyzed using a constrained longitudinal data 
analysis (cLDA) model with the following terms:

Treatment (categorical), 

Visit (categorical), 

Treatment by visit interaction,

Menopausal Status randomization stratum. 
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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.16 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 between each dose of ertugliflozin and placebo in terms of mean change 
from baseline at the primary time point of Week 26 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 performed to assess the robustness of the primary model.  
ANCOVA will be conducted utilizing the last observation carried forward as the dependent 
variable and including fixed factors for treatment (categorical), randomization stratum 
(categorical), and baseline value (continuous).  A per protocol analysis will also be pre-
specified in the statistical analysis plan.  Descriptive and graphical summaries by treatment 
group and time point will also be presented.  Other additional analyses to explore the 
robustness of results to regions and other factors will also be performed.
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. 
9.2.2. Analysis of Secondary Endpoints
The proportion of subjects achieving an HbA1c <7% (53 mmol/mol) at Week 26 will be 
analyzed using a logistic regression model with terms for treatment (categorical), 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. 
The secondary endpoints of fasting plasma glucose, body weight, systolic blood pressure and 
diastolic blood pressure will be analyzed separately by fitting constrained longitudinal data 
analysis models similar to that used for the primary endpoint.  Sitting blood pressure 
collected in triplicate will be used for assessment of blood pressure as a secondary endpoint.
The secondary efficacy endpoints of FPG, proportion of subjects achieving an HbA1c <7%, 
body weight, systolic blood pressure and diastolic blood pressure will be tested for each 
ertugliflozin dose versus placebo using a multiple testing procedure that strongly controls the 
overall Type I error rate at 0.05.  A step-down hierarchical, sequential testing approach will 
be used, as follows:
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Order
Endpoint (Change from 
Baseline to Week 26*)
Arm Comparison
1
HbA1c
15 mg ertugliflozin arm to placebo
2
HbA1c
5 mg ertugliflozin arm to placebo
3
FPG
15 mg ertugliflozin arm to placebo
4
FPG
5 mg ertugliflozin arm to placebo
5
Body Weight
15 mg ertugliflozin arm to placebo
6
Body Weight
5 mg ertugliflozin arm to placebo
7 
HbA1c <7.0% at Wk 26
15 mg ertugliflozin arm to placebo
8 
HbA1c <7.0% at Wk 26
5 mg ertugliflozin arm to placebo
9
Systolic BP
15 mg ertugliflozin arm to placebo
10
Systolic BP
5 mg ertugliflozin arm to placebo
11
Diastolic BP
15 mg ertugliflozin arm to placebo
12
Diastolic BP
5 mg ertugliflozin arm to placebo
*Except for HbA1c <7.0% at Wk 26 endpoint
Starting with the first hypothesis, the test will conducted at a 5% level of significance.  If the 
hypothesis test is significant, then the next hypothesis will be tested at a 5% level of 
significance.  Otherwise, testing ceases within this hierarchy.
9.2.3. Analysis of Other Secondary Endpoints
9.2.3.1. Analysis of BMD
The changes in BMD from Baseline to Week 26 at the lumbar spine, femoral neck, total hip, 
and distal forearm will be key safety endpoints.  A BMD analysis set will be defined to 
include all randomized subjects who have received at least one dose of investigational 
product and have at least one measurement of BMD at any time during Phase A of the trial 
including baseline and post-baseline time points.  For analyses of changes in BMD, 
measurements obtained post glycemic rescue therapy will be utilized if available; however 
BMD measurements will be censored at the point of a subject taking BMD rescue therapy. 
Changes from Baseline to Week 26 in BMD will be analyzed by fitting a constrained 
longitudinal data analysis model with terms for treatment, visit, treatment by-visit interaction 
and menopausal status randomization stratum.  Least-squares means and 95% confidence 
intervals will be used to estimate the treatment effect (difference between ertugliflozin and 
placebo) at Week 26.
Analyses of BMD will also be conducted separately for the male and female subgroups and 
also for subjects who completed 20 weeks of study treatment. Another sub-group analysis 
will be conducted separately for women post-menopausal for 3 years after LMP
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(approximately 50% of the overall study population).  Descriptive statistics will also be 
provided for each of the four randomization strata.
Changes from baseline in other continuous endpoints (including bone biomarkers) will be 
summarized descriptively (including 95% confidence intervals for BMD endpoints) by 
treatment group (for all treatment arms in each phase) and time point. Categorical endpoints 
will be summarized using frequency tables for each treatment group and time point.
Bone biomarker data and PTH data will be censored from the analysis if the samples were 
collected >7 days from the last dose of investigational product.  Data for these markers will 
also be censored for subjects who initiate rescue medication with any bone-active 
medication.
9.2.4. Endpoints Related to Pharmacokinetics of Ertugliflozin
Details on the pharmacokinetic analysis may be found in the Statistical Analysis Plan.  The 
pharmacokinetic data from this trial may be combined with data from other studies for 
population pharmacokinetic analysis using nonlinear mixed effects modeling.  If data permit, 
estimates of population pharmacokinetic parameters such as CL/F as well as estimates of 
inter-individual and residual variability will be determined.  In addition, effects of 
demographic or physiologic factors (eg, age, race, weight, gender, renal function) on 
pharmacokinetic parameters will be assessed.  The results will be summarized in a separate 
report.
9.3. Safety Analysis
The safety analysis population will consist of all treated subjects, ie, all subjects who 
received at least one dose of investigational product.
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify all 
adverse events (AEs) with respect to system organ class and preferred term.  Summaries of 
AEs will include treatment-emergent AEs according to treatment group.
To avoid the confounding influence of rescue therapy, the primary approach for most safety 
analyses will exclude data from the period following the initiation of rescue therapy. A 
secondary approach will include data following the initiation of rescue therapy. For serious 
AEs and discontinuations due to AEs, the approach that includes data following the initiation 
of rescue therapy will be considered primary. 
Descriptive statistics will be used to summarize results and changes from baseline in clinical 
laboratory tests and in vital signs.  The number and percentage of subjects with abnormal 
findings from ECGs will be tabulated by treatment group.
Furthermore, a 3-tier approach will be used to summarize AEs.  Tier-1 consists of 
pre-specified adverse events of interest, and will include AEs or collections of AEs related to 
urinary tract infection, genital mycotic infection, hypoglycemia and hypovolemia.  Where 
available, standard MedDRA queries will 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 
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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 are provided for 
screening purposes only.  Tier-2 AEs are those that are not Tier-1, but are common, 
occurring in 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.  The confidence intervals are for estimation purposes 
only.  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.
9.4. Planned Analyses
The results of Phase A will be analyzed, and a clinical study report for Phase A will be 
written while Phase B is on-going.  The results of Phase A will not be used to make any 
changes to the design or conduct of Phase B.  An unblinding plan will be developed and put 
into place in order to limit the extent of sponsor unblinding that takes place during the 
reporting of Phase A and to ensure that sponsor staff who interact with clinical sites do not 
have access to treatment assignments during Phase B. 
No formal interim analyses are planned (other than in support of the independent DMC 
regular review of safety), but may be conducted if necessary in support of Regulatory filings 
or requests. 
9.5. Data Monitoring Committee 
This trial will use an external Data Monitoring Committee (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 E-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 communications between these organizations. The Sponsor will 
forward such decisions, which may include summaries of aggregate analyses of endpoint 
events and of safety data which are not endpoints, to regulatory authorities, as appropriate. 
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 CRFs is 
accurate.  The Investigator and institution will allow Pfizer/Merck monitors/auditors or its 
agents and appropriate regulatory authorities direct access to source documents to perform 
this verification.
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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 trial.
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.
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 
informed consent documents, 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), 
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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 trial 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, informed consent documents, 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.
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.
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The informed consent document 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 trial 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.
12.3.1. 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. 
12.4. Subject Recruitment
Advertisements approved by ethics committees and Investigator databases may be used as 
recruitment procedures.
12.5. 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.
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 trial 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 trial in that Member State.
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13.2. End of Trial in all Other Participating Countries
End of Trial in all other participating countries is defined as last subject last visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this trial 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, Pfizer/Merck retains the right to discontinue development of ertugliflozin at any 
time.
If a trial 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
The Sponsor fulfills its commitment to publicly disclose clinical trial results through posting 
the results of studies on http://www.clinicaltrials.gov/ (ClinicalTrials.gov). The Sponsor 
registers study protocols and posts Basic Results on ClincialTrials.gov for Sponsor 
interventional studies in human subjects that evaluate the safety and/or efficacy of 
ertugliflozin. 
The results are posted in a tabular format called Basic Results. 
For studies involving ertugliflozin, the timing of the posting depends on whether ertugliflozin
is approved for marketing in any country at the time the trial is completed:

For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, FDA-approved products, the 
Sponsor posts results within one year of the primary completion date (PCD).  For 
studies involving products approved in any country, but not FDA approved, the 
Sponsor posts results one year from last subject, last visit (LSLV).

For studies involving products that are not yet approved in any country, the Sponsor
posts the results of already-completed studies within 30 days of US regulatory 
approval, or one year after the first ex-US regulatory approval of the product (if only 
submitted for approval ex-US).

For studies involving products whose drug development is discontinued before 
approval, the Sponsor posts the results within one year of discontinuation of the 
program (if there are no plans for outlicensing or within two years if outlicensing 
plans have not completed).
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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 trial concluded according to the pre-specified protocol or was 
terminated.
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.
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.
International Diabetes Federation. Diabetes Atlas. Fifth Edition. Brussels, Belgium. 
2011.
2.
American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. 
Diabetes Cares 2013: 1-14.
3.
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 
Diabetes Control and Prevention, 2011. 
4.
Mokdad AH, Ford ES, Bowman BA, Diez WH, Vinicor F, Bales VS, Marks JS. 
Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001. 
JAMA 2003: 289: 76-79. 
5.
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.
6.
Sttratton IM, Adler AI, Neil HA, et al. Association of glycemia with macrovascular 
complications of type 2 diabetes (UKPDS35): prospective observational study. BMJ 
2000;321:405-12. 
7.
Isaji M. Sodium-glucose cotransporter inhibitors for diabetes. Current Opinion in 
Investigational Drugs 2007;8(4):285-92.
8.
Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption : A novel 
strategy for achieving glucose control in type 2 diabetes mellitus. Endocrine Practice 
2008;14:782-90.
9.
Bays H. Review: From victim to ally: the kidney as an emerging target for the treatment 
of diabetes mellitus. Current Medical Research and Opinion 2009;25:671-81.
10.
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.
11.
Baily CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on 
to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, 
double-blind, placebo-controlled 102-week trial. BMC Medicine 2013, 11:43.. 
12.
American Diabetes Association. Executive summary: Standards of medical care in 
diabetes – 2012. Diabetes Care 2012;35(Suppl.1):S4-S10.
13.
Ljunggren O, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjostrom CD, Sugg J, 
Parikh S.  Dapagliflozin has no effect on markers of bone formation and resorption or 
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bone mineral density in patients with inadequately controlled type 2 diabetes mellitus 
on metformin.  Diabetes, Obesity and Metabolism 2012; 14:990-999.
14.
Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde A, Sugg J, and 
Parikh S. Effects of Dapagliflozin on Body Weight, Total Fat Mass, and Regional 
Adipose Tissue Distribution in Patients with Type 2 Diabetes Mellitus with Inadequate 
Glycemic Control on Metformin J Clin Endocrinol Metab, March 2012, 97(3):1020–
1031.
15.
Stenlöf K, Cefalu WT, Kim K-A, Alba M, Usiskin K, Tong C, Canovatchel W, 
Meininger G. Efficacy and safety of canagliflozin 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.
Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or 
dependent variable in analyses of change from baseline in clinical trials? Statist Med 
2009; 28:2509-2530.
17.
Janssen Research & Development, LLC Endocrinologic and Metabolic Drugs Advisory 
Committee’.
18.
Ricci TA, Heymsfield SB, Pierson RN Jr, Stahl T, Chowdhury HA, Shapses SA. 
Moderate energy restriction increases bone resorption in obese postmenopausal women. 
Am J Clin Nutr 2001; 73:347-352.
19.
Borges JLC, Bilezikian JP, Jones-Leone AR, Acusta AP, Amberty PD, Nino AJ, Grosse 
M, Fitzpatrick LA, and Cobitz AR. A randomized, parallel group, double-blind, 
multicentre study comparing the efficacy and safety of Avandamet 
(rosiglitazone/metformin) and metformin on long-term glycaemic control and bone 
mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus 
patients. Diabetes, Obesity and Metabolism 2011; 13:1036-1046.
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Appendix 1. Collection and Management of Specimens for Future Biomedical Research
1. 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.
2. 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.
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research sub-study.
b. Informed Consent
                                                
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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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 discontinued 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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4. Confidential Subject Information for Future Biomedical Research
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical 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, EMEA, 
FDA), whereby this information would be directly transferred to the health authority.
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5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the highly 
validated conditions usually associated with regulatory approval of diagnostics.  The scope of 
research performed on these specimens is limited to the investigation of the variability in 
biomarkers that may correlate with a clinical phenotype in subjects.
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.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.  Subjects may withdraw consent at any time by 
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 
 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 can not be processed. 
7. Retention of Specimens
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental 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.
8. 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.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
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 
subjects may pursue clinical diagnostic testing if they wish to do so.
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10. Gender, Ethnicity, and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical trials 
for future biomedical research.  When 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.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized.  Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen will 
be obtained at the time of routine blood specimens drawn in the main 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.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-reported 
ethnicity.  Subjects who do not wish to provide this data may still participate in future 
biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
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Appendix 2. Biomarker Brochure
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Ertugliflozin (MK-8835/PF-04971729)
MK-8835-007-00/B1521017
Final Protocol, 20 September 2013
PFIZER CONFIDENTIAL
Page 128
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03MLK7
 
 
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Ertugliflozin (MK-8835/PF-04971729)
MK-8835-007-00/B1521017
Final Protocol, 20 September 2013
PFIZER CONFIDENTIAL
Page 129
090177e1848ce2dd\Approved\Approved On: 23-Sep-2013 15:48 
 
 
03MLK7
PPD
 
 
04W782


Ertugliflozin (MK-8835/PF-04971729)
MK-8835-007-00/B1521017
Final Protocol, 20 September 2013
PFIZER CONFIDENTIAL
Page 130
090177e1848ce2dd\Approved\Approved On: 23-Sep-2013 15:48 
 
 
03MLK7
 
 
04W782


Ertugliflozin (MK-8835/PF-04971729)
MK-8835-007-00/B1521017
Final Protocol, 20 September 2013
PFIZER CONFIDENTIAL
Page 131
090177e1848ce2dd\Approved\Approved On: 23-Sep-2013 15:48 
 
 
03MLK7
 
 
04W782