A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 26-Week Multicenter Study to Evaluate the Efficacy and Safety of Ertugliflozin in Asian Subjects With Type 2 Diabetes Mellitus and Inadequate Glycemic Control on Metformin Monotherapy (VERTIS-ASIA)
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 26-
Week Multicenter Study To Evaluate The Efficacy And Safety 
Of Ertugliflozin In Asian Subjects With Type 2 Diabetes 
Mellitus And Inadequate Glycemic Control On Metformin 
Monotherapy
NCT number: 
NCT02630706 
Document Date: 
09 March 2014

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CLINICAL PROTOCOL 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
26-WEEK MULTICENTER STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ERTUGLIFLOZIN IN ASIAN 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:
Not Applicable
European Clinical Trial Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
MK-8835-012-00 (Merck Protocol Number)
B1521045 (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
09 March 2014
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 Asian subjects with T2DM who have inadequate glycemic 
control on metformin monotherapy.  The results of this study are intended to support the 
registration of ertugliflozin in China.
Objectives and Hypotheses:
The objectives listed below will be assessed in the overall study population and also in the 
China subpopulation (ie, subjects enrolled from China) in parallel. All hypotheses will be 
tested in the overall population; the primary hypotheses and secondary hypotheses 1-4 will 
also be tested in the China subpopulation (see Statistical Section 9.2.1 and 9.2.2).
In subjects with T2DM and inadequate glycemic control on metformin monotherapy, the 
following are primary objectives and hypotheses of the trial, after 26 weeks:
1. Objective: To assess the effect on HbA1c of 15 mg ertugliflozin relative to placebo.
Hypothesis:  The mean reduction from baseline in HbA1c for 15 mg ertugliflozin is 
greater than that for placebo.
2. Objective:  To assess the effect on HbA1c of 5 mg ertugliflozin relative to placebo.
Hypothesis:  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, after 26 weeks:
1. Objective:  To assess the effect on fasting plasma glucose (FPG) of 15 mg 
ertugliflozin relative to placebo.
Hypothesis:  The mean reduction from baseline in FPG for 15 mg ertugliflozin is 
greater than that for placebo.
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2. Objective:  To assess the effect on FPG of 5 mg ertugliflozin relative to placebo.
Hypothesis:  The mean reduction from baseline in FPG for 5 mg ertugliflozin is 
greater than that for placebo.
3. Objective:  To assess the effect on body weight of 15 mg ertugliflozin relative to
placebo.
Hypothesis:  Ertugliflozin 15 mg reduces body weight relative to placebo.  
4. Objective:  To assess the effect on body weight of 5 mg ertugliflozin relative to
placebo.
Hypothesis:  Ertugliflozin 5 mg reduces body weight relative to placebo.  
5. Objective:  To assess the proportion of subjects with an HbA1c <7.0% 
(53 mmol/mol) treated with 15 mg ertugliflozin relative to placebo.
Hypothesis:  The proportion of subjects with an HbA1c <7.0% (53 mmol/mol) 
treated with 15 mg ertugliflozin is greater than that for placebo.
6. Objective:  To assess the proportion of subjects with an HbA1c <7.0% 
(53 mmol/mol) treated with 5 mg ertugliflozin relative to placebo.
Hypothesis:  The proportion of subjects with an HbA1c <7.0% (53 mmol/mol) 
treated with 5 mg ertugliflozin is greater than that for placebo.
7. Objective:  To assess the effect on systolic blood pressure of 15 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in systolic blood pressure for 15 mg 
ertugliflozin is greater than that for placebo.
8. Objective:  To assess the effect on systolic blood pressure of 5 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in systolic blood pressure for 5 mg 
ertugliflozin is greater than that for placebo.
9. Objective:  To assess the effect on diastolic blood pressure of 15 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in diastolic blood pressure for 15 mg 
ertugliflozin is greater than that for placebo.
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10. Objective:  To assess the effect on diastolic blood pressure of 5 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in diastolic blood pressure for 5 mg 
ertugliflozin is greater than that for placebo.
11. Objective: To assess the proportion of subjects with an HbA1c <6.5% treated with
ertugliflozin (for each dose) relative to placebo.
12. Objective: To assess the proportion of subjects requiring glycemic rescue therapy, 
and the time to initiation of glycemic rescue therapy with ertugliflozin (for each dose) 
relative to placebo.
13. Objective: To descriptively summarize pharmacokinetics of ertugliflozin and 
provide population PK [(pharmacokinetic(s)] analysis in this study.
Study Population:
Asian 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 stable dose of 
1500 mg/day, for 8 weeks. In a country where the minimum age for consent and
enrollment is 21 years of age, this age criterion should be followed.
Study Design:
This trial is a Phase 3 multi-center, randomized, parallel-group study with a 26-week, 
double-blind, placebo-controlled treatment period followed by a 2-week phone follow-up 
after the last dose of investigational product in Asian subjects with T2DM and inadequate 
glycemic control on metformin monotherapy.
The trial includes a fixed, 2-week single-blind 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.
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 wash-off of another allowable 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;
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
Combination therapy with metformin and one of the following allowable oral AHAs: 
sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, meglitinide, or alpha-
glucosidase inhibitor. 
Subjects receiving metformin in combination with another allowable AHA (as listed above) 
must discontinue the non-metformin AHA beginning at the Screening Visit 2 (S2) and 
remain off the non-metformin AHA for the duration of this trial, while they are receiving 
investigational product.
The following table provides information on the inclusion 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 S1
HbA1c Inclusion 
Criterion at S1
Change in Background Diabetes Therapy 
and Duration of Metformin Monotherapy 
Dose-Stable Period Prior to Placebo Run-
in S3
Metformin monotherapy, 
1500 mg/day, and stable dose for 
8 weeks
7.0%–10.5% (53-91 
mmol/mol), inclusive
None.  Subjects proceed directly to a 
combined Screening Visit 2 and 3 (S2/S3).
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 non-metformin 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.
** metformin can be uptitrated over a period of up to 4 weeks.
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The trial is designed with two phases:
Met=Metformin
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1. Screening phase including discontinuation of background diabetes therapy other 
than metformin (if applicable) and a single-blind 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. Treatment Phase: Randomized, double-blind, placebo-controlled treatment period 
(Visits V4 through V8) - a 26-week treatment period for assessment of primary efficacy 
and safety endpoints along with secondary efficacy endpoints.  At entry into the double-
blind treatment phase, subjects will be randomized to ertugliflozin 5 mg, ertugliflozin 
15 mg, or placebo, while maintaining metformin at a stable dose (1500 mg/day).  
Glycemic rescue therapy with open-label glimepiride will be initiated in subjects with 
glucose values exceeding protocol-specified values as provided in Section 5.6.  Dosing 
and titration of open-label glimepiride rescue therapy will be at the Investigator’s 
discretion.  After initiation of rescue therapy, background metformin (same dose and 
regimen) and blinded investigational product will continue to be taken by the subject.  
Each randomized subject should have a follow-up phone call 14 days after the last dose 
of investigational product to assess for AE (adverse event)s, SAE (serious adverse 
event)s and collect information on clinical events per Section 7.6, if applicable. 
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 Asian adult subjects with T2DM and inadequate glycemic control 
on metformin monotherapy. 
Approximately 495 Asian subjects will be randomized into three trial arms in a 1:1:1 ratio 
(165 subjects/arm for ertugliflozin 5 mg, 15 mg and placebo respectively).  
Glycemic Rescue Therapy:
Subjects will be prescribed rescue therapy in the form of open-label glimepiride, if they meet 
specific glycemic criteria with glucose values exceeding protocol-specified values as 
provided in Section 5.6.  Dosing and titration of open-label glimepiride rescue therapy will 
be at the Investigator’s discretion. 
Endpoints:
Primary Endpoint: 

Change in HbA1c from Baseline to Week 26.
Secondary Endpoints:

Change in FPG from Baseline to Week 26.

Change in body weight from Baseline to Week 26.
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
Proportion of subjects with HbA1c of <7.0% (53 mmol/mol) at Week 26.

Change in systolic blood pressure from Baseline to Week 26.

Change in diastolic blood pressure from Baseline to Week 26.

Proportion of subjects with HbA1c <6.5% (48 mmol/mol) at Week 26.

Proportion of subjects requiring glycemic rescue therapy by Week 26.

Time to glycemic rescue therapy.

Endpoints related to pharmacokinetics of ertugliflozin.
Statistical Methods:
All efficacy and safety analyses will be performed for the overall study population, as well as 
for the China subpopulation using the analysis methods described in Sections 9.2 and 9.3. 
Sample Size: The sample size determination is based on the primary endpoint, reduction in 
HbA1c from baseline to Week 26, within the subjects enrolled from China. Assuming a 
standard deviation (SD) of 1.0%, the sample size of 105 Chinese subjects per group (total of 
315 Chinese subjects) provides approximately 95% power to detect a difference in HbA1c of 
0.5% between each ertugliflozin dose and placebo (and approximately 90% power for 
detecting this difference for both doses vs. placebo) using a two-sided 0.05 alpha level test.
To control the overall Type I error rate at 0.05 within each population (ie, within the overall 
study population and within the China subpopulation) 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. Assuming a drop-out rate of 20% by Week 26 
(ie, either subjects who discontinue from the study, discontinue administration of IP
(Investigational Product), or subjects who take rescue medication and are censored), 
approximately 396 subjects from China (132 per group) will be randomized. Additionally, 
this study will have approximately 99 subjects from at least two other Asian countries.  The 
total sample size for this study is approximately 495 randomized subjects.
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 the trial, including baseline and 
post-baseline time points.  The post glycemic rescue therapy data from subjects who receive
rescue therapy will be censored from primary and secondary endpoint efficacy analyses.
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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 country (China, Other), treatment, visit, treatment by visit 
interaction, AHA status at study entry (binary) and Baseline eGFR (estimated glomerular 
filtration rate).  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 within each population (overall study population and China subpopulation ).  
Within each of these two populations, 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. The model 
utilized for the China subpopulation will not include country as a term.
Analysis of Secondary Endpoints: 
The proportion of subjects with an HbA1c <7.0% (53 mmol/mol) at Week 26 will be 
analyzed using a logistic regression model with terms for country (categorical), treatment 
(categorical), baseline HbA1c (continuous), AHA status at study entry (binary) and Baseline 
eGFR (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.
For the overall study population, the secondary efficacy endpoints of FPG, proportion of 
subjects achieving an HbA1c <7.0% (53 mmol/mol), 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. For the 
China subpopulation, due to smaller sample size, which limits the power for other secondary 
endpoints, only FPG and body weight endpoints will be tested for each ertugliflozin dose 
versus placebo using a multiple testing procedure that strongly controls the Type I error rate 
at 0.05, within the China subpopulation (ie, first FPG will be tested, and if both ertugliflozin 
doses are significant (p< 0.05), then body weight will be tested for each dose sequentially). 
The 95% CI with nominal p values will be provided for other secondary endpoints in the 
China subpopulation.
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j.
ECGs scheduled in the trial are initially assessed at the investigative site for subject safety and then submitted to be read centrally. ECGs should be obtained 
prior to the nominal time assessment of blood pressure, and pulse rate as well as prior to blood collection.
k.
Samples collected for urinalysis will be sent to the central laboratory for dipstick analysis (not including urinary glucose assessment) and microscopy if the 
laboratory performed dipstick is positive for blood, nitrites, leukocytes and/or protein. 
l.
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.  
m. If fasting fingerstick glucose (FFSG) <120 mg/dL (6.7 mmol/L) or >270 mg/dL (15.0 mmol/L) AND the investigator believes that the value is not consistent 
with the subject’s current self-monitoring blood glucose (SMBG) values, the subject should not be excluded at this time.  The subject should be rescheduled 
for Visit 4/Day 1 within 7 days.  FFSG should be re-tested at rescheduled Visit 4 and only those whose re-test FFSG is eligible can proceed into the study.  
In such cases, the sites will need to repeat all Visit 4/Day 1 procedures (See Section 6.3.1).  
n.
Includes total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, non-HDL-C and triglycerides at all time points noted 
above.  
o.
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.
p.
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 their non-metformin AHA therapy at S2) must have an HbA1c of 7.0-10.5% (53-91 mmol/mol) at S3 in order to 
be randomized.  
q.
HbA1c should not be obtained if ET or rescue visit occurs within 6 weeks of randomization.
r.
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).
s.
Subjects will be seen by a dietician or qualified healthcare professional for dietary and exercise counseling at S2 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.
t.
Subjects should be educated on the symptoms of hyperglycemia (eg, polyuria, polydipsia) at S2.
u.
At Week 26 visit, only need to collect and review Hypoglycemia Assessment and Self-Monitoring Blood Glucose logs, there is no dispensing of additional 
logs at this visit.
v.
Assess AEs, SAEs, hypoglycemia assessment log as well as potential clinical events for adjudication (See Section 7.4.6, 7.6, 8 for additional detail).
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................18
LIST OF FIGURES .................................................................................................................19
1. INTRODUCTION ...............................................................................................................23
1.1. Indication.................................................................................................................23
1.2. Background .............................................................................................................23
1.3. Efficacy of Ertugliflozin..........................................................................................24
1.4. Safety Information for Ertugliflozin and Other SGLT2 Inhibitors.........................24
1.5. Rationale for Study and Design ..............................................................................26
1.5.1. Rationale for Dose Selection of Ertugliflozin ............................................27
2. STUDY OBJECTIVES, HYPOTHESES AND ENDPOINTS ...........................................28
2.1. Objectives and Hypotheses .....................................................................................28
2.2. Endpoints.................................................................................................................29
2.2.1. Primary Endpoint........................................................................................29
2.2.2. Secondary Endpoints ..................................................................................30
3. STUDY DESIGN.................................................................................................................30
4. SUBJECT SELECTION......................................................................................................33
4.1. Inclusion Criteria.....................................................................................................33
4.2. Exclusion Criteria....................................................................................................35
4.3. Randomization ........................................................................................................39
4.4. Life Style Guidelines...............................................................................................40
4.4.1. Subject Management Prior to Scheduled Visits .........................................40
4.4.2. Dietary Counseling.....................................................................................40
4.4.3. Physical Activities ......................................................................................40
4.4.4. Alcohol, Caffeine and Tobacco ..................................................................40
4.5. Female Contraception .............................................................................................40
4.5.1. Females– Non-childbearing Potential.........................................................41
4.5.2. Females of Childbearing Potential..............................................................41
4.6. Sponsor Qualified Medical Personnel.....................................................................41
5. STUDY TREATMENT.......................................................................................................42
5.1. Allocation to Treatment ..........................................................................................42
5.2. Breaking the Blind ..................................................................................................42
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5.3. Drug Supplies..........................................................................................................43
5.3.1. Formulation and Packaging........................................................................43
5.3.2. Placebo Run-in............................................................................................43
5.3.3. Concomitant Metformin .............................................................................43
5.3.4. Administration of Double-Blind Investigational Product...........................44
5.3.5. Compliance.................................................................................................44
5.4. Drug Storage and Drug Accountability...................................................................45
5.5. Concomitant Medication(s).....................................................................................45
5.6. Glycemic Rescue Therapy ......................................................................................46
5.6.1. Drug Supplies for Glycemic Rescue Therapy ............................................47
6. STUDY PROCEDURES .....................................................................................................47
6.1. Instructions to Subjects ...........................................................................................47
6.1.1. Dispense Hypoglycemia Assessment Log and Instruct on 
Hypoglycemia Symptoms and Management ...................................................48
6.1.2. Diet and Exercise Counseling.....................................................................49
6.2. Screening.................................................................................................................49
6.2.1. Screening Visit 1 (S1).................................................................................49
6.2.2. Screening Visit 2 (S2).................................................................................50
6.2.3. Placebo Run-in (Visit S3 or Combined S2/S3) ..........................................51
6.3. Double-Blind, Placebo-Controlled Treatment Period (Visits 4 through 8) ............52
6.3.1. Day 1 (Visit 4) ............................................................................................52
6.3.2. Week 6 (Visit 5)..........................................................................................54
6.3.3. Week 12 (Visit 6)........................................................................................55
6.3.4. Week 18 (Visit 7)........................................................................................56
6.3.5. Week 26 (Visit 8) – Final Study Visit / Early Termination Visit...............57
6.4. Follow-up Phone Call..............................................................................................58
6.5. Rescue Visit, if applicable.......................................................................................58
6.6. Subject Withdrawal.................................................................................................59
6.6.1. Reasons for Discontinuation from Investigational Product or from 
the Trial............................................................................................................60
6.6.1.1. Follow-up for Subjects who Discontinue Due to 
Decreased Renal Function.................................................................62
7. ASSESSMENTS..................................................................................................................63
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7.1. Pregnancy Testing...................................................................................................63
7.2. Body Weight ...........................................................................................................63
7.3. Physical Examinations ............................................................................................64
7.4. Safety.......................................................................................................................64
7.4.1. Clinical Laboratory Tests ...........................................................................64
7.4.1.1. Lipid Panel ................................................................................65
7.4.1.2. Urinary Albumin:Creatinine Ratio............................................65
7.4.2. Vital Signs (Sitting Blood Pressure and Pulse Rate)..................................66
7.4.3. Postural (Orthostatic) Blood Pressure and Pulse Rate................................66
7.4.4. Electrocardiogram, (12-lead ECG).............................................................67
7.4.5. Review of Self-Monitoring Glucose Logs..................................................67
7.4.6. Review of Hypoglycemia Assessment Logs ..............................................68
7.4.6.1. Management of Hypoglycemia .................................................68
7.4.7. Assessment of Infections............................................................................69
7.4.7.1. Urinary Tract Infections............................................................69
7.4.7.2. Genital Fungal Infections..........................................................70
7.5. Pharmacokinetics of Ertugliflozin...........................................................................70
7.5.1. Plasma for PK Analysis..............................................................................70
7.6. Clinical Event Adjudication....................................................................................70
7.6.1. Clinical Cardiovascular Events, Venous Thromboembolic Events 
and All Deaths..................................................................................................70
7.6.2. Fractures .....................................................................................................72
7.6.3. Pancreatitis..................................................................................................72
7.6.4. Liver Injury.................................................................................................72
7.6.5. Renal Failure...............................................................................................72
8. ADVERSE EVENT REPORTING......................................................................................73
8.1. Assessing and Recording Adverse Events ..............................................................73
8.2. Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor................................................................................................................73
8.3. Reporting of Pregnancy and Lactation to the Sponsor............................................74
8.4. Immediate Reporting of Adverse Events to the Sponsor ........................................74
8.4.1. Serious Adverse Events ..............................................................................74
8.5. Evaluating of Adverse Events.................................................................................75
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8.6. Events of Clinical Interest.......................................................................................79
8.7. Management of Subjects with Elevated Liver Enzymes (ALT or AST 3X 
ULN)..........................................................................................................................79
8.8. Serious Adverse Events Exempt from Expedited Reporting by the Sponsor .........83
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................84
9.1. Sample Size Determination.....................................................................................84
9.2. Efficacy Analysis ....................................................................................................85
9.2.1. Analysis of Primary Endpoint ....................................................................85
9.2.2. Analysis of Secondary Endpoints...............................................................86
9.2.3. Endpoints Related to Pharmacokinetics of Ertugliflozin............................88
9.3. Safety Analysis........................................................................................................88
9.4. Data Monitoring Committee ...................................................................................89
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................89
11. DATA HANDLING AND RECORD KEEPING .............................................................89
11.1. Case Report Forms/Electronic Data Record .........................................................89
11.2. Record Retention...................................................................................................90
12. ETHICS..............................................................................................................................90
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............90
12.2. Ethical Conduct of the Study ................................................................................91
12.3. Subject Information and Consent..........................................................................91
12.4. Subject Recruitment ..............................................................................................91
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................91
13. DEFINITION OF END OF TRIAL...................................................................................92
14. SPONSOR DISCONTINUATION CRITERIA ................................................................92
15. PUBLICATION OF STUDY RESULTS..........................................................................92
15.1. Communication of Results by the Sponsor...........................................................92
15.2. Publications by Investigators ................................................................................93
16. REFERENCES ..................................................................................................................94
LIST OF TABLES
Table 1.
Background Diabetes Therapy at Screening Visit 1 (S1), HbA1c Initial 
Inclusion and Appropriate Changes in Background Diabetes Therapy..................6
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Table 2.
Estimated Percent Maximum Response for Various Endpoints...........................27
Table 3.
Background Diabetes Therapy at Screening Visit 1 (S1), HbA1c Initial 
Inclusion and Appropriate Changes in Background Diabetes Therapy................31
Table 4.
Glycemic Thresholds............................................................................................46
Table 5.
Clinical/Safety Central Laboratory Tests .............................................................65
Table 6.
Evaluating Adverse Events...................................................................................76
LIST OF FIGURES
Figure 1.
Trial Scheme.........................................................................................................32
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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
ASaT
All Subjects as Treated
AST
aspartate transaminase
AUC
area under the concentration-time curve
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
CV
cardiovascular
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram
ECI
event of clinical interest
ED50
dose achieving 50% of maximum response
eGFR
estimated glomerular filtration rate
ER
Extended Release
ET
early termination of the study
FDA
Food and Drug Administration
FFSG
fasting fingerstick glucose
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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
IP
Investigational Product
IR
Immediate Release
IRB
institutional review board
IUD
Intra-uterine device
IVRS
interactive voice response system
LDL-C
low density lipoprotein cholesterol
MACE
major adverse cardiovascular events
Met
metformin
MDRD
Modification of Diet in Renal Disease
N/A
Not applicable
NOAEL
no observed adverse effect level
NYHA
New York Heart Association
PK
pharmacokinetic(s)
PR interval
time from the beginning of the P wave to the end of the QRS 
complex on electrocardiogram
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
S1
Screening Visit 1
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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
SGLT1
Sodium Glucose co-Transporter 1
SGLT2
Sodium Glucose co-Transporter 2
SLC5A
Sodium Glucose co-Transporter gene family
SMBG
Self-monitoring blood glucose
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reactions
T2DM 
type 2 diabetes mellitus
TIA
Transient ischemic attack
TSH
thyroid-stimulating hormone
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 In China, the 
population with T2DM was reported as 90 million in the year 2011with a prevalence of 9.3%.
It is estimated that by 2030, the prevalence of T2DM in China will increase to 12.1% and the 
total T2DM population in China will be around 129.7 million.2,3 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
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 Asian subjects with T2DM who have inadequate glycemic control on 
metformin monotherapy.  
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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.
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 January 2014, two SGLT2 
inhibitors (dapagliflozin and canagliflozin) are approved in the U.S. and 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 
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 
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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.  At the completion of Phase 2, a total of 
479 subjects had 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 December 2013, there were 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 the 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.  
In the clinical program to date, no clinically significant changes from baseline in serum 
aminotransferases [ALT (alanine transaminase) and AST (aspartate transaminase))] have 
been observed. 
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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.9 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. 
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 Asian 
subjects who have inadequate glycemic control on metformin monotherapy at or near 
maximally effective doses (ie, 1500 mg/day).  Subjects already on metformin monotherapy 
at protocol-specified doses (1500 mg/day) for at least 8 weeks at S1 and who meet other 
enrollment criteria will go directly from S1 to S2/3 to enter the 2-week single-blind placebo 
run-in period.
In addition to subjects with inadequate control on metformin monotherapy at 1500 mg/day
for 8 weeks, a broader range of subjects will be screened for the study. This includes
subjects who have been on a stable dose of metformin 1500 mg/day for <8 weeks, or 
metformin monotherapy at a dose <1500 mg/day as well as subjects on metformin in 
combination with another allowable single AHA agent. Subjects not yet on a stable dose of 
metformin monotherapy 1500 mg/day for at least 8 weeks will enter a dose stable period at 
S2, so that they have received at least 8 weeks of a stable dose of metformin monotherapy 
prior to S3, where they will enter a 2 week single-blind placebo run-in period. Subjects 
receiving metformin and another allowable single AHA will discontinue the non-metformin 
AHA at S2 and enter a metformin monotherapy period (uptitrate metformin dose to 1500 
mg/day if applicable ) and reach a stable dose of 1500 mg/day for at least 8 weeks prior to 
S3.  With the exception of subjects who at S1 are already receiving metformin monotherapy 
1500 mg/day for at least 8 weeks, subjects on other allowable diabetes medications at S1 
will have HbA1c measured again at S3 to determine if they qualify for enrollment. 
The population to be enrolled in this study represents subjects appropriate to assess the 
primary and secondary objectives in the study.
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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
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).  Data from study B1521009 provide 
support for study of 5 mg and 15 mg doses of ertugliflozin in Asian subjects in study 
B1521045.  In study B1521009, the pharmacokinetics and pharmacodynamics of 
ertugliflozin were studied in healthy Japanese subjects following administration of single (1, 
5 and 25 mg) and multiple (25 mg once daily for 7 days) oral doses of ertugliflozin.  Western 
healthy subjects were included in the single dose portion of this study for comparison of 
pharmacokinetics and pharmacodynamics between healthy Japanese and Western subjects.  
Results from this study suggest that clinically meaningful differences between Asian and 
Western subjects in ertugliflozin pharmacokinetics and pharmacodynamics are not likely to 
exist.  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.
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2. STUDY OBJECTIVES, HYPOTHESES AND ENDPOINTS
2.1. Objectives and Hypotheses
The objectives listed below will be assessed in the overall study population and also in the 
China subpopulation (subjects enrolled from China) in parallel. All hypotheses will be tested 
in the overall population; the primary hypotheses and secondary hypotheses 1-4 will also be 
tested in the China subpopulation (see Statistical Sections 9.2.1 and 9.2.2).
In subjects with T2DM and inadequate glycemic control on metformin monotherapy, the 
following are primary objectives and hypotheses of the trial, after 26 weeks:
1. Objective: To assess the effect on HbA1c of 15 mg ertugliflozin relative to placebo.
Hypothesis:  The mean reduction from baseline in HbA1c for 15 mg ertugliflozin is 
greater than that for placebo.
2. Objective:  To assess the effect on HbA1c of 5 mg ertugliflozin relative to placebo.
Hypothesis:  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, after 26 weeks:
1. Objective:  To assess the effect on fasting plasma glucose (FPG) of 15 mg 
ertugliflozin relative to placebo.
Hypothesis:  The mean reduction from baseline in FPG for 15 mg ertugliflozin is 
greater than that for placebo.
2. Objective:  To assess the effect on FPG of 5 mg ertugliflozin relative to placebo.
Hypothesis:  The mean reduction from baseline in FPG for 5 mg ertugliflozin is 
greater than that for placebo.
3. Objective:  To assess the effect on body weight of 15 mg ertugliflozin relative to
placebo.
Hypothesis:  Ertugliflozin 15 mg reduces body weight relative to placebo.  
4. Objective:  To assess the effect on body weight of 5 mg ertugliflozin relative to
placebo.
Hypothesis:  Ertugliflozin 5 mg reduces body weight relative to placebo.  
5. Objective:  To assess the proportion of subjects with an HbA1c <7.0% 
(53 mmol/mol) treated with 15 mg ertugliflozin relative to placebo.
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Hypothesis:  The proportion of subjects with an HbA1c <7.0% (53 mmol/mol) 
treated with 15 mg ertugliflozin is greater than that for placebo.
6. Objective:  To assess the proportion of subjects with an HbA1c <7.0% 
(53 mmol/mol) treated with 5 mg ertugliflozin relative to placebo.
Hypothesis:  The proportion of subjects with an HbA1c <7.0% (53 mmol/mol) 
treated with 5 mg ertugliflozin is greater than that for placebo.
7. Objective:  To assess the effect on systolic blood pressure of 15 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in systolic blood pressure for 15 mg 
ertugliflozin is greater than that for placebo.
8. Objective:  To assess the effect on systolic blood pressure of 5 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in systolic blood pressure for 5 mg 
ertugliflozin is greater than that for placebo.
9. Objective:  To assess the effect on diastolic blood pressure of 15 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in diastolic blood pressure for 15 mg 
ertugliflozin is greater than that for placebo.
10. Objective:  To assess the effect on diastolic blood pressure of 5 mg ertugliflozin 
relative to placebo.
Hypothesis:  The mean reduction from baseline in diastolic blood pressure for 5 mg 
ertugliflozin is greater than that for placebo.
11. Objective: To assess the proportion of subjects with an HbA1c <6.5% treated with
ertugliflozin (for each dose) relative to placebo.
12. Objective: To assess the proportion of subjects requiring glycemic rescue therapy, 
and the time to initiation of glycemic rescue therapy with ertugliflozin (for each dose) 
relative to placebo.
13. Objective: To descriptively summarize pharmacokinetics of ertugliflozin and 
provide population PK analysis in this study.
2.2. Endpoints
2.2.1. Primary Endpoint

Change in HbA1c from Baseline to Week 26.
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2.2.2. Secondary Endpoints

Change in FPG from Baseline to Week 26.

Change in body weight from Baseline to Week 26.

Proportion of subjects with HbA1c of <7.0% (53 mmol/mol) at Week 26.

Change in systolic blood pressure from Baseline to Week 26.

Change in diastolic blood pressure from Baseline to Week 26.

Proportion of subjects with HbA1c <6.5% (48 mmol/mol) at Week 26.

Proportion of subjects requiring glycemic rescue therapy by Week 26.

Time to glycemic rescue therapy.

Endpoints related to pharmacokinetics of ertugliflozin.
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 followed by a 2-week phone follow-up 
after the last dose of investigational product in Asian subjects with T2DM and inadequate 
glycemic control on metformin monotherapy.
The trial includes a fixed, 2-week placebo run-in from 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.
The trial is designed to accommodate subjects taking a variety of baseline diabetes therapy 
regimens at S1 by incorporating a period of metformin dose titration and stabilization, and 
wash off of another allowable 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 S1: 

Metformin monotherapy;

Combination therapy with metformin and one of the following allowable oral AHAs: 
sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, meglitinide, or alpha-
glucosidase inhibitor. 
Subjects receiving metformin in combination with another allowable AHA (as listed above)
must discontinue the non-metformin AHA beginning at S2 and remain off the non-metformin
AHA for the duration of this trial, while they are receiving investigational product.
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The following table provides information on the inclusion 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 S1
HbA1c Inclusion 
Criterion at S1
Change in Background Diabetes Therapy 
and Duration of Metformin Monotherapy 
Dose-Stable Period Prior to Placebo Run-
in S3
Metformin monotherapy, 
1500 mg/day, and stable dose for 
8 weeks
7.0%–10.5% (53-91 
mmol/mol), inclusive
None.  Subjects proceed directly to S2/S3.
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 non-metformin 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.
** metformin can be uptitrated over a period of up to 4 weeks.
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Figure 1 summarizes the overall trial scheme.
Figure 1.
Trial Scheme
Met=Metformin
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The trial is designed with two phases:
1. Screening phase including discontinuation of background diabetes therapy other 
than metformin (if applicable) and a single-blind 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. Treatment Phase: Randomized, double-blind, placebo-controlled treatment period 
(Visits V4 through V8) - a 26-week treatment period for assessment of primary efficacy 
and safety endpoints along with secondary efficacy endpoints.  At entry into double-blind 
treatment phase, subjects will be randomized to ertugliflozin 5 mg, ertugliflozin 15 mg, 
or placebo, while maintaining metformin at a stable dose (the metformin dose at which 
the subject entered the metformin dose-stable run-in period).  Glycemic rescue therapy 
with open-label glimepiride will be initiated in subjects with glucose values exceeding 
protocol-specified values as provided in Section 5.6.  Dosing and titration of open-label 
glimepiride rescue therapy will be at the Investigator’s discretion.  After initiation of 
rescue therapy, background metformin (same dose and regimen) and blinded 
investigational product will continue to be taken by the subject.  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 7.6, if 
applicable.
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 Asian adult subjects with T2DM and inadequate glycemic control 
on metformin monotherapy. 
Approximately 495 Asian subjects including approximately 396 subjects from China,
99 subjects from at least two other Asian countries will be randomized (165 subjects to 
ertugliflozin 5mg, 15mg and placebo respectively). This sample size accounts for an 
approximate 20% premature withdrawal rate (ie, either subjects who discontinue from the 
study or IP, or subjects who take rescue medication and are censored) and ensures an 
adequate number of subjects have evaluable data for the primary endpoint of HbA1c at Week 
26.
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. 
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Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial:
1. Asian subject 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.19 In a country where the minimum age for consent and enrollment is 21 
years of age, this age criterion should be followed.  
2. Subject receiving one of the following diabetes therapy regimens at the time of S1 and 
with an HbA1c within the following range:
Diabetes Medication at 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 non-metformin AHA therapy at S2 or requiring metformin dose 
titration) must have an HbA1c of 7.0-10.5% (53-91 mmol/mol) at S3 after at least 8 
weeks on a stable dose regimen of metformin monotherapy 1500 mg/day.  Subjects 
receiving a stable dose of metformin monotherapy 1500 mg/day for at least 8 weeks 
prior to S1 and meeting eligibility, do not need to have an HbA1c performed at S3.
4. Body Mass Index (BMI) 18.0 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.   
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 4.5.1
and 4.5.2 for reference on childbearing potential):
1. Is postmenopausal defined as at least 12 months with no menses in women 
45 years of age, or 
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2. Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal 
ligation or occlusion at least 6 weeks prior to S1.
c.
Is a female of reproductive potential and:
1. Agrees to remain abstinent from heterosexual activity*, 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 
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).  

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). 
*Abstinence can be used as the sole method of contraception if it is in line with the subject’s 
preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
ethics committees. Periodic abstinence (eg, calendar, ovulation, sympto-thermal, 
postovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
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.
2. History of other specific types of diabetes (eg, genetic syndromes, secondary 
pancreatic diabetes, diabetes due to endocrinopathies, drug-or chemical-induced, and 
post-organ transplant).
3. Subjects who are <80% compliant based on pill count with the Placebo Run-in 
medication.
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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 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 S1, 
confirmed via 1 repeat triplicate set at S1 if deemed necessary by investigator’s 
judgement.  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 
have blood pressure re-measured to determine study eligibility. 
6. Subject has a clinically significant electrocardiogram (ECG) abnormality at S3 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.
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12. Subject who had bariatric surgery within 12 months of S1 or bariatric surgery >12 
months from S1 but is not weight stable.
13. Subjects with a known hypersensitivity or intolerance to any SGLT2 inhibitor.
14. Subjects who have previously been randomized in a trial with ertugliflozin.
15. Screening fasting plasma or finger-stick glucose >270 mg/dL (15 mmol/L), 
confirmed by a single repeat following counseling on exercise and diet. This will be 
assessed at each of the screening visits (S1, S2 and S3 as applicable per flowchart 
[FPG or finger-stick measurement]).  
16. At the Day 1 visit (Visit 4), subject has a fasting finger-stick glucose (FFSG) <120 
mg/dL (6.7 mmol/L) or >270 mg/dL (15.0 mmol/L).
Note: If the subject meets this exclusion criterion AND the investigator believes that 
the value is not consistent with the subject’s current self-monitoring blood glucose 
(SMBG) values and S3/Week -2 FFSG value, the subject should not be excluded at 
this time. This visit should be changed to an Unscheduled Visit and the subject 
should be rescheduled for Visit 4/Day 1 within 7 days. Additional single-blind 
placebo run-in medication should be dispensed if needed. If the subject meets this 
FFSG exclusion criterion at the rescheduled Visit 4/Day 1, the subject MUST be 
excluded.
17. Fasting serum triglyceride >600 mg/dL (6.8 mmol/L) at S1, confirmed by a single 
repeat if deemed necessary by investigator’s judgement.  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)/regimen to lower fasting 
triglycerides in order for the subject to having fasting triglycerides re-measured to 
determine study eligibility.  
18. Subjects taking blood pressure or lipid altering medications that have not been on a 
stable dose for at least 4 weeks prior to randomization. 
19. Subjects who are currently being treated for hyperthyroidism.
20. Subjects who are on thyroid replacement therapy and who have 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 S1. 
21. 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 eGFR 
<55 mL/min/1.73m2 according to the 4-variable Modification of Diet in Renal 
Disease (MDRD) equation at S1. 
22. An aspartate transaminase (AST) or alanine transaminase (ALT) >2X the upper limit 
of normal (ULN) range at S1, or a total bilirubin >1.5 X the ULN unless the subject 
has a history of Gilbert’s. 
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23. 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.
24. Use of the following prohibited therapeutic agents.  These agents are not to be used 
from 12 weeks prior to S1:

Insulin of any type (except for short-term use during concomitant illness or other 
stress).

Other injectable anti-hyperglycemic agents (eg, pramlintide, exenatide, 
liraglutide).

Another SGLT2 inhibitor.

Bromocriptine.

Colesevelam.

Rosiglitazone or pioglitazone.

Any other anti-hyperglycemic therapy with the exception of the protocol-
approved agents.
25. Subject is on or likely to require treatment for 14 consecutive days or repeated 
courses of pharmacologic doses of corticosteroids. These medications are not to be 
used from the time of the start of the Placebo Run-in Period (S3/Day -14) to the last 
dose of investigational product. 
Note: Inhaled, nasal, and topical corticosteroids and physiological replacement doses 
of adrenal steroids are permitted. 
26. 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.
27. Participation in any other trials involving investigational drug(s) (Phase 1-4) within 
30 days before S1 and/or has plan of participating any other trials during study 
participation.
28. 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 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.
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29. 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.
30. 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. 
31. 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.
32. Subjects who have donated blood or blood products within six weeks of S1 or who 
plan to donate blood or blood products at any time during the trial.
33. Subjects with Human Immunodeficiency Virus (HIV) assessed by medical history.
34. Subjects with:

Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells, 
or

Clinically important hematological disorders (such as aplastic anemia, 
myeloproliferative or myelodyplastic syndromes, thrombocytopenia).
35. 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
Subjects who meet eligibility criteria will be assigned a unique identifier via an Interactive 
Voice Response System (IVRS) at S1, which will be retained throughout the duration of their 
participation in the trial.  A computer-generated randomization code using the method of 
random permuted blocks will be utilized to assign subjects on Day 1 (V4) to 1 of the 
3 treatment regimens (ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo).
There will be two stratification groups at randomization – ‘China’ and ‘Other’.
Randomization to the China stratum will be capped at approximately 396 subjects. and 
randomization to the ‘Other countries’ stratum will be capped at approximately 99 subjects.
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4.4. Life Style Guidelines 
4.4.1. Subject Management Prior to Scheduled Visits

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 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, or rescue therapy (if 
applicable).  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.  
4.4.2. Dietary Counseling
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.
4.4.3. 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.
4.4.4. Alcohol, Caffeine and Tobacco

Intake of alcohol should be limited (refer to exclusion 9 for acceptable amount of 
alcohol consumption).

Ingestion of caffeine and nicotine-containing products will be prohibited for at least 
30 minutes prior to scheduled electrocardiograms and blood pressure determinations.
4.5. 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 4.5.2 will 
be allowed to enroll in this trial.
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4.5.1. 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 S1.
4.5.2. 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 while the subject is 
receiving investigational product 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.

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).
4.6. 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. 
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 
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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 495 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 if 
required for urgent subject management.  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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5.3. Drug Supplies
5.3.1. Formulation and Packaging
Ertugliflozin 5 mg, ertugliflozin 10 mg, and matching placebos will be supplied as 
immediate-release tablets for oral administration.  Tablets will be packaged into bottles.
Pfizer will provide Investigator sites with sufficient amounts of blinded investigational 
product to accommodate expected recruitment.  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 tablet run-in will be administered starting at Day -14/Visit S3 where 
subjects will be instructed to take 1 tablet of placebo matching ertugliflozin 5 mg and 1 tablet 
of placebo matching ertugliflozin 10 mg each day from the bottles 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) or Extended Release (ER) forms 
are allowed in the study. Subjects should remain on the same formulation (IR or ER) of 
metformin from S2 to the Week 26 visit.
Metformin titration will be required for some subjects between S2 and 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.  
Those subjects will enter the placebo run-in period at S3 after the monotherapy dose of 
1500 mg/day has been kept stable for at least 8 weeks.
The metformin dose will not be changed from S3 until the end of the trial (V8), except if 
medically necessary. In that case, all efforts should be made to get the subject back to the 
dose at randomization.
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5.3.4. Administration of Double-Blind Investigational Product
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 and given clear dosing 
instructions. They will be instructed to take 2 tablets per day of double-blind investigational 
product, one from each bottle, as follows. 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 26 (last dose taken the morning prior to the Week
26 visit) 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. On Day 1, Week 12 and Week 18 
visit days, subjects will take the dose of double-blind investigational product in the clinic
after visit assessments.
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. Compliance
Subjects will be directed to bring any used and unused bottles to each visit.  The Investigator
must maintain a complete and current accountability record for the investigational product.
Compliance 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 by taking the subject’s report. 
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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.
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. Such prohibited medications include use of 
any other anti-hyperglycemic therapy with the exception of the protocol-approved agents as 
well as pharmacological doses of corticosteroids as described 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 the exclusion criterion. Subjects who are not on a stable 
dose of thyroid replacement at S1 can be scheduled appropriately for S3 and Day 1 to ensure 
they have a stable dose for at least 6 weeks prior to randomization per exclusion criterion 20.
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.  
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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 required. 
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.
The use of herbal supplements and other natural products (including Traditional Chinese 
Medicine) should be discouraged.  Subjects who do not discontinue the use of such 
supplements or natural products prior to the S3 visit/Week -2 or combined visit S2/S3 should 
be instructed not to change the use or dose of the product during the trial.  Subjects should be 
instructed not to initiate new supplements during the trial.  Any use of herbal supplements or 
Traditional Chinese Medicine will be captured in the eCRF.
5.6. Glycemic Rescue Therapy
Subjects will be prescribed open-label glycemic rescue therapy with glimepiride with initial 
dose and titration managed according to physician judgment, if they meet specific, 
progressively more stringent, glycemic thresholds based on a repeated, confirmed FPG 
measured by the central lab according to the directions below:
Table 4.
Glycemic Thresholds
After Randomization (Day 1) 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)
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).
Glycemic rescue therapy with glimepiride 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. 
The investigator will determine initial dose and manage glimepiride titration as clinically 
appropriate and consistent with 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 6.5.
Subjects requiring glycemic rescue therapy are to remain in the trial (unless they meet 
discontinuation criteria) up to their trial completion by Week 26 (or Early Termination), and 
will continue to receive background metformin (same dose and regimen) and blinded 
investigational product (ertugliflozin/placebo). 
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5.6.1. Drug Supplies for Glycemic Rescue Therapy
Open-label glimepiride will be supplied 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 performed before or after blood 
specimen collection.

Visit windows for this trial are recommended, not required.

On scheduled visits to the site, subjects must be instructed to arrive without having 
taken the dose of investigational product, open-label metformin, or rescue therapy (if 
applicable).  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.
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 up to Week 26 visit (or early termination) 
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.
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
Instructions for home glucose monitoring:

Recommended frequency for routine home glucose monitoring will be 
determined for each subject by the Investigator with a minimum of 2 
determinations per week. 

Home glucose monitoring should be undertaken in the event subjects 
experience symptoms of hyperglycemia or hypoglycemia.

During the run-in period, subjects should be counseled to contact the trial site 
if fingerstick glucose levels are above 260 mg/dL (14.4 mmol/L) ≥2 times per 
week. Subjects will be instructed to contact the site if their fingerstick glucose 
values are ≤70 mg/dL (≤3.9 mmol/L). Furthermore, in order to assess the 
need for rescue and/or discontinuation from blinded investigational product, 
subjects should be instructed to contact the site for fingerstick glucose values 
that are >270 mg/dL (15.0 mmol/L) after Visit 4/Randomization (Day 1)
through Visit 5 (Week 6), or >240 mg/dL (13.3 mmol/L) after Visit 5/Week 6 
through Visit6/Week 12, or >200 mg/dL (11.1 mmol/L) after Visit 6/Week 
12.
6.1.1. Dispense Hypoglycemia Assessment Log and Instruct on Hypoglycemia 
Symptoms and Management
At S2 or combined S2/S3, 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 
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 
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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 or combined S2/S3 visit only; monitoring at other visits may be 
done by other appropriate site personnel evaluating the subject.
At S2 or combined S2/S3, the subject will receive counseling on a diet that is 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.  Subjects must 
not engage in physically strenuous exercise (for example: heavy lifting, weight training, 
calisthenics, and aerobics) within 48 hours before clinic visits in which blood samples will be 
collected. 
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).  

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 [refer to Section 7.4.1]
of:

Hematology, chemistry;

HbA1c, fasting plasma glucose (FPG), fasting triglycerides, TSH;

Urine pregnancy test for women of childbearing potential.

Review of eligibility criteria.
Subjects must be instructed to continue their background oral AHA(s); no changes to 
background oral AHA (metformin or non-metformin plus single allowable AHA if 
applicable) will be made until the S2 Visit.  Allowable AHA are: sulfonylurea, DPP-4 
inhibitor, meglitinide, or alpha-glucosidase inhibitor.
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 at S2 
(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 at a stable dose of 
1500 mg/day for 8 weeks or more at S1 can proceed to a combined S2/S3 Visit. For 
combined visits, all procedures from each individual visit must be performed at the one 
combined visit.
Subjects on a stable dose of metformin monotherapy 1500 mg/day <8 weeks at S1 will 
enter a dose stable period, so that they will have received at least 8 weeks of a stable dose of 
metformin monotherapy prior to S3 and entering the placebo run-in period.  For subjects 
receiving metformin monotherapy <1500 mg/day, the metformin dose must be titrated to 
1500 mg/day and maintained at a stable dose for at least 8 weeks before the placebo run-in 
visit at S3. Subjects receiving metformin in combination with another single allowable AHA 
must discontinue this non-metformin AHA beginning at the S2 visit and remain off this other 
AHA for the duration of this trial, and if applicable, the metformin dose must be titrated to 
1500 mg/day and maintained at a stable dose for at least 8 weeks before S3.   
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 urine sample for urinalysis [refer to Section 7.4.1].

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.
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
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 severe hyperglycemia symptoms 
occur/or if fingerstick glucose levels are above 260 mg/dL (14.4 mmol/L) ≥2 times 
per week [refer to Section 6.1].

Subjects will be educated on the symptoms of hypoglycemia and instructed to call the 
site should severe hypoglycemia occur or an episode of fingerstick glucose 
70 mg/dL (3.9 mmol/L) before next visit (ie, S3) [refer to Section 6.1.1].  Subjects 
will be provided with a hypoglycemia assessment log that they must use to track the 
incidence of hypoglycemia..

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.
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 at a stable dose of 
1500 mg/day for 8 weeks or more at S1 can proceed with a combined S2/S3 Visit. If the 
S2 and S3 are combined as 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.

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?”

Perform complete physical examination [refer to Section 7.3].

Obtain supine, single, standard, 12-lead ECG [refer to Section 7.4.4].

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].
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
Perform a fasting finger stick blood glucose assessment.

Measure HbA1c to assess eligibility for subjects taking metformin monotherapy for 
less than 8 weeks at the S1 visit and for those that required a change to their diabetes 
regimen at the S2 visit (including subjects receiving <1500 mg/day of metformin at 
S1 and for subjects who have discontinued the non-metformin AHA therapy at the 
S2 visit).

Urine pregnancy test for women of childbearing potential.

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. 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 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 duplicate orthostatic blood pressure and pulse rate measurement (supine 
standing) [refer to Section 7.4.3].
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
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].

Perform a fasting finger stick blood glucose assessment (FFSG) at the clinic. If the 
FFSG <120 mg/dL (6.7 mmol/L) or >270 mg/dL (15.0 mmol/L) AND the
investigator believes that the value is not consistent with the subject’s current self-
monitoring blood glucose (SMBG) values, the subject should not be excluded at this 
time. This visit should be changed to an Unscheduled Visit and the subject should be 
rescheduled for Visit 4/Day 1 within 7 days. Additional single-blind placebo run-in 
medication should be dispensed if needed.

For subject who had Visit 4 rescheduled due to FFSG <120 mg/dL (6.7 mmol/L) or 
>270 mg/dL (15.0 mmol/L) in the previous visit, FFSG needs to be re-tested at this 
visit and only those whose re-test FFSG is eligible can proceed into the study.  In 
such cases, the sites will need to repeat all Visit 4/Day 1 procedures.

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] 
of:

Hematology, chemistry, urinalysis; 

HbA1c, lipid panel, FPG;

Urinary albumin/creatinine ratio, urine pregnancy test (for women of childbearing 
potential) [refer to Section 7.1].
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]. 
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6.3.2. Week 6 (Visit 5)
At Week 6 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:

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 7.6].

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]
of:

Chemistry, urine pregnancy test (for women of childbearing potential) [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 glimepiride glycemic rescue therapy, if applicable.

Dispense investigational product.
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6.3.3. Week 12 (Visit 6)
At Week 12 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 7.6].

Review self-monitoring blood glucose and Hypoglycemia Assessment Logs 
completed by the subject [refer to Section 7.4.6].

Diet and exercise monitoring [refer to 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 (for women of childbearing potential) [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.

The dose of double-blind investigational product should be administered and 
witnessed in clinic [refer to Section 5.3.4], time of administration should be 
collected.
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 glimepiride glycemic rescue therapy, if applicable.

Dispense investigational product.
6.3.4. Week 18 (Visit 7)
At Week 18 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 7.6].

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]
of:

Chemistry, urine pregnancy test (for women of childbearing potential) [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.

The dose of double-blind investigational product should be administered and 
witnessed in clinic [refer to Section 5.3.4], time of administration should be 
collected.
Following completion of the above procedures:

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.
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
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.

Dispense glimepiride glycemic rescue therapy, if applicable.

Dispense investigational product.
6.3.5. Week 26 (Visit 8) – Final Study Visit / Early Termination Visit
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.  At this visit (or early termination visit), the following 
procedures will be completed:

Contact IVRS.

Assess treatment compliance with investigational product.

Review and 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].

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 and extremities.

Obtain duplicate orthostatic blood pressure and pulse rate measurement (supine 
standing [refer to 7.4.3].

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 7.6].

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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
Obtain blood and urine specimens for clinical laboratory tests [refer to Section 7.4.1]
of:

Hematology, chemistry, urinalysis, urinary albumin/creatinine ratio, urine 
pregnancy test (for women of childbearing potential) [refer to Section 7.1], lipid 
panel, HbA1c, 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.
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 26 visit unless they withdraw consent per Section 6.6.
6.4. Follow-up Phone Call
Each randomized subject should have a follow-up phone call 14 days after the last dose of
investigational product to assess for AEs, SAEs and collect information on clinical events per 
Section 7.6, if applicable.  The phone call should be completed within a 3 day window. 
6.5. 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. The following 
procedures are to be completed at a rescue visit:

Review and update concomitant medications since last visit,

Assess treatment compliance with investigational product and counsel subjects who 
have been <80% compliant [refer to Section 5.3.5]. 

Measure body weight in duplicate [refer to Section 0].

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].

Conduct brief physical examination which includes assessment of heart, lungs, 
abdomen and extremities.

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) and FPG. 
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
Conduct inquiry about any spontaneously reported AEs by asking the subject to 
respond to a non-leading question such as “how do you feel?”  Assess potential 
clinical events for adjudication [refer to Section 7.6].

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 with glimepiride.  Dosing of open-label 
glimepiride is at the Investigator’s discretion.

Provide subject with glucose meter supplies and additional self-monitoring blood 
glucose or hypoglycemia assessment logs, as needed.
6.6. 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. 
Subjects who discontinue treatment with blinded investigational product for reasons other 
than withdrawn consent should attend the clinic for a visit where all early termination 
procedures are performed followed by a post-treatment telephone call 14 days after the last 
dose of blinded investigational product. Thereafter, subjects will be followed by telephone 
contacts according to the study visit schedule until the end of the trial (Week 26), but will not 
have other procedures performed that are outlined in the study schedule of activities. The 
purpose of the telephone contacts, as well as the 14-day post-treatment telephone call, is to 
collect information about subjects’ health status (ie, evaluate if the subject experienced any 
SAEs or events eligible for adjudication [see Section 7.6]).
If a subject indicates his or her intention to stop active participation in the trial (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), or if the 
Investigator has recommended stopping the investigational product, the Investigator must 
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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 7.6]).  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 investigational product
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 
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. The 
Investigator should inquire about the reason for withdrawal, requests the subject to return all 
unused investigational product(s), requests the subject to return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved AEs.
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 (for those rescued) until Week 
26.  The Investigator should ensure that the subject has enough open-label rescue medication 
until the next scheduled in clinic visit (if applicable).  Procurement of any other AHAs is the 
responsibility of the subject. 
6.6.1. 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).

Death.
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Discontinuation of Investigational Product
1. Subject meets protocol-specified hyperglycemia criteria as specified below:
Subject has been rescued with glimepiride and is on the maximum labeled or maximum-
tolerated dose (if lower than the maximum labeled dose) for at least 4 weeks, and 
continues to meet glycemic thresholds specified in Table 4 for the relevant time point in 
the trial, without a reasonable explanation (eg, intercurrent illness or medication 
omission).
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) or with a reasonable 
explanation and likely to reoccur.
Note: For subjects rescued with glimepiride, the protocol-specified discontinuation 
criteria for hypoglycemia only apply after the subject has interrupted glycemic rescue 
medication.  
3. Abnormal liver function tests meeting discontinuation 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 (within 7 days).  If this repeat continues to 
meet the discontinuation criteria, the subject must be discontinued from investigational 
product.  See Section 6.6.1.1 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 5. Subjects 
temporarily placed on a prohibited medication by a non-study physician that has been 
stopped and which is not clinically necessary may continue in the study.
6. For subjects who are on glycemic rescue medication, and found to be hypersensitive to 
or intolerant to glimepiride or if such a subject develops any condition for which 
glimepiride is contraindicated in accordance with the local drug label of the country 
where the subject is participating.
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7. Pregnancy.
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 
8.3 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).
11. Subject’s decision: Subject no longer agrees to actively participate in the study (ie, take 
blinded investigational product or other required concomitant study medication, attend 
study visits, or otherwise comply with study procedures) but agrees to be contacted at 
times of regular study visits to collect health status (ie, SAEs and adjudicated events).
If a subject discontinues investigational product, he/she should complete all Early 
Termination Visit procedures as described in Section 6.3.5 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 26.  Such subjects may initiate other AHA therapy as indicated (prohibited 
medications described in Section 5.5 will not apply to these subjects.)
6.6.1.1. Follow-up for Subjects who Discontinue Due to Decreased Renal Function
Subjects who discontinue blinded investigational product for eGFR/creatinine 
discontinuation criteria (see Section 6.6.1) or renal-related adverse events should have a 
repeat eGFR/creatinine performed approximately 1 week after the last dose of Investigational 
Product.  This post-treatment visit may occur at the Early Termination visit (if the Early 
Termination 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 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 
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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.
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 a 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 26 visit.  Pregnancy
tests may also be repeated as per request of IRB (institutional review board)/IEC
(independent ethics committee)s 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. 
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
Subjects should be instructed to step gently onto the scale, place both feet together in 
the center of the scale and stand straight with eyes directed ahead.  Subjects should be 
instructed to stand still and not sway.  Measurement will be recorded after the weight 
has stabilized.

Body weight should be reported with precision to one decimal place (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 approximately 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, and extremities 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):
-HbA1c
- FPG
-Urinary albumin/creatinine ratioe
- Pregnancy tests (where 
applicable)
- Lipid panel (ie, total cholesterol, 
HDL, LDL, non-HDL-C, 
triglycerides)
a.
Samples collected for urinalysis will be sent to the central laboratory for dipstick analysis (not including 
uninary glucose assessment) 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.
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
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. 
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 
not be obtained if the subject is menstruating, has vigorously exercised within 24 hours or 
had fever or an active infection within 2 days of the visit.
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7.4.2. 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, Week 26 (or ET) and Rescue Visit, 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 at these clinic visits (except for 
S3 visit).  Measurement of postural blood pressure and pulse rate will also occur at the 
glycemic Rescue Visit.
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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 ECGs performed at scheduled time points should be reviewed at the investigative site for 
subject eligibility confirmation and 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.  Unscheduled ECGs (if needed per investigator 
judgment) will follow the same procedure and will be reviewed at the investigative site and 
be transferred to the central vendor for reading and interpretation.
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 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.
A subject should be discontinued from the investigational product [refer to Section 6.6.1] 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) or with a reasonable explanation and likely to 
reoccur.
Any episode of hypoglycemia must be captured on the Hypoglycemic Adverse Assessment
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).
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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). 
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.
Relative Hypoglycemia: An event during which the person with diabetes reports any of the 
typical symptoms of hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, 
but with a measured plasma glucose concentration >70 mg/dL (3.9 mmol/L).  This classification 
reflects the fact that patients with chronically poor glycemic control can experience symptoms of 
hypoglycemia at plasma glucose levels >70 mg/dL (3.9 mmol/L) as plasma glucose 
concentrations decline toward that level.
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 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 (since a urinary glucose measurement may provide information 
suggestive of treatment group assignment).  If a urinalysis is clinically necessary, a 
microscopic urinalysis ONLY and not a dipstick urinalysis should be performed. If 
symptoms are reported outside of a routine scheduled study visit, clinical assessment and 
urine testing should be done promptly at an unscheduled visit. The investigator or treating 
physician should initiate antibiotic treatment as considered clinically appropriate; if possible, 
a locally obtained culture and sensitivity should be obtained. 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.
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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. 
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 26. 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.
7.6. Clinical Event Adjudication
7.6.1. Clinical Cardiovascular Events, Venous Thromboembolic Events and All Deaths
The identification of potential clinical cardiovascular events (specified below), venous
thromboembolic 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 US and European Union 
regulatory requirements for the assessment of cardiovascular safety of any new diabetic 
therapy, selected serious cardiovascular events (specified below) 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.  In 
addition, venous thromboembolic events, and hospitalization due to CHF will also be 
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adjudicated, to assure a comprehensive assessment of potentially significant cardiovascular 
events. 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 (ie, withdraws consent). 
Clinical cardiovascular events occurring between the Screening visit (the time of informed 
consent) and double-blind treatment randomization will not be adjudicated as that subject 
will be excluded from the trial as per Section 4.2.
The identification of a potential clinical cardiovascular event will be made by the trial site or 
by the Pfizer or designee. The site will communicate the event to Pfizer or designee within 
24 hours of awareness of the potential clinical cardiovascular event using the appropriate 
CRF module. Pfizer or designee will in turn provide a listing of specific documents needed to 
support adjudication by the EAC. Obtaining documentation will be the responsibility of 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.
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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.
7.6.2. Fractures
In the Phase 2 study (B152006), following 12 weeks of dosing with ertugliflozin, there was a 
suggestion of an increase 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 bone 
mineral density will be evaluated in a Phase 3 trial. In addition, in this trial and throughout 
the Phase 3 program, all clinical fractures will be adjudicated by an external independent 
panel of physicians (radiologists) experienced in assessing fractures. The radiologists will 
review the radiograph(s) (if available) and, where applicable the local radiologist report and 
other source documents and confirm the presence of the fracture, location of fracture, number 
of fractures, and type of fracture (ie, high-trauma, low-trauma, pathological fracture, stress 
fracture, and other fracture). The panel will be blinded to treatment assignment. A Fracture 
Adjudication Charter will describe the precise mandates and procedures to be used for the 
adjudication of clinical fractures.
7.6.3. 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.
7.6.4. Liver Injury
As hepatic safety is a significant issue in drug development, all events that meet pre-specified 
criteria for potentially important hepatotoxicity will be adjudicated by an external 
independent panel of physicians experienced in assessing liver injury. The panel will be 
blinded to treatment assignment and will assess causality. A Liver Injury Adjudication 
Charter will describe the precise mandates and procedures to be used for assessing liver 
injury and assigning causality.
7.6.5. 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), due to 
the effect on plasma volume (ie, a hemodynamic effect on eGFR). As part of the overall 
assessment of renal safety, events reported in this trial and throughout the Phase 3 program 
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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 
unfavorable 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.
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.
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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;

Is a congenital anomaly/birth defect;

Is a cancer;

Is associated with an overdose;

Is an other important medical event.
Refer to Table 6 for additional details regarding each of the above criteria.
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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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Table 6.
Evaluating Adverse Events
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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Table 6.
Evaluating Adverse Events
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 FDA (Food and Drug Administration)
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 product
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 product if a pre-specified criterion is met. 
The Investigator should select the appropriate set of instructions (either A, B, or C below) for 
managing a subject with elevated liver enzymes based upon the following factors: (1) the 
magnitude of a subject’s ALT or AST elevation, (2) the presence or absence of symptoms, 
(3) whether there is a corresponding increase in total bilirubin (TBL) 2X ULN. 
Investigator Instructions for Management of Subjects with ALT or AST 3X ULN
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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 product.  
In summary, subjects should be discontinued from investigational product 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 or longer.
Section II: Guidance for Assessment of Potential Etiology
Questions to Assess Etiology
Investigate potential causes for the subject’s elevated liver enzymes using the questions 
below.  Answers to the questions should be recorded in the subject’s source documents and 
appropriate eCRFs. 
1. Has the subject recently:

Had a change in his/her pattern of alcohol use?  Investigate historic pattern of 
alcohol use as well.

Administered an illegal drug(s) (including intravenous drugs)?

Been exposed to a chemical agent or other environmental toxin?

Consumed any unusual foods (eg, mushrooms), seasonal foods, or initiated 
treatment with new herbal/nutritional supplements?

Initiated a new diet regimen, started a rigorous exercise program, or experienced 
any form of severe physical exertion? 

Traveled to another country or region?
2. Does the subject have a relevant concomitant illness (eg, cholelithiasis, hepatitis, etc.) 
or has the subject had potential exposure to viral hepatitis (transfusion, tattoo, new 
sexual partner)?
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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 7.6.1 for details). 
The following potential cardiovascular SAEs will not be subject to expedited reporting by the 
Sponsor, even if reported as related to investigational product 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
All efficacy and safety analyses will be performed for the overall study population, as well as
for the China subpopulation using the analysis methods described in Sections 9.2 and 9.3.
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
The sample size determination is based on the primary endpoint, reduction in HbA1c from 
Baseline to Week 26, within the subjects enrolled from China. Assuming a standard 
deviation (SD) of 1.0%,11-18 a sample size of 105 subjects from China per group (total of 315 
subjects from China) provides approximately 95% power to detect a difference in HbA1c of 
0.5% between each ertugliflozin dose and placebo (and approximately 90% power for 
detecting this difference for both doses vs. placebo) using a two-sided 0.05 alpha level test.
To control the overall Type I error rate at 0.05 within each population (overall study 
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population and the China subpopulation) 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. Assuming a drop-out rate of 20% at Week 26 [(ie, either subjects 
who discontinue from the study, discontinue administration of IP (Investigational Product) or 
subjects who take rescue medication and are censored], approximately 396 subjects from
China (132 per group) will be randomized. Additionally, this study will have approximately 
99 subjects from at least two other Asian countries.
The total sample size for this study is approximately 495 randomized subjects.
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 the trial including baseline and 
post-baseline time points.  Post-glycemic rescue therapy data from subjects who receive
rescue therapy prior to Week 26, as well as post-bariatric surgery data will be censored from 
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:

Country (categorical) (Applicable only for the analyses of the overall study 
population)

Treatment (categorical), 

Visit (categorical), 

Treatment by visit interaction (categorical), 

AHA status at study entry (binary),

Baseline eGFR (continuous) Values above 120 mL/min per 1.73 m2 will be set to 120 
mL/min per 1.73 m2.
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.20  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 
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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. Methods to address the 
potential issue of large differences in  sample size from different countries will be described 
in the SAP.
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 country (categorical), treatment (categorical),
baseline HbA1c (continuous), AHA status at study entry (binary), baseline eGFR 
(continuous) (eGFR values above 120 mL/min per 1.73 m2 will be set to 120 mL/min per 
1.73 m2).  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. The models utilized for the China subpopulation will not include country as a 
term.
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 within each population (the overall 
study population, and China subpopulation) (see below for sequence of testing for the overall 
population and the China subpopulation). Within each of these two populations, 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 with an HbA1c <7.0% (53 mmol/mol) at Week 26 will be 
analyzed using a logistic regression model with terms for country (categorical) (applicable 
only for the analyses of the overall study population), treatment (categorical), baseline 
HbA1c (continuous), AHA status at study entry, and baseline eGFR (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.
For the overall study population, the secondary efficacy endpoints of FPG, proportion of 
subjects with an HbA1c <7.0%, 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.  For the China 
subpopulation, due to smaller sample size, which limits power for other secondary endpoints,
only FPG and body weight endpoints will be tested for each ertugliflozin dose versus placebo 
using a multiple testing procedure that strongly controls the Type I error rate at 0.05.  
Therefore, a step-down hierarchical, sequential testing approach will be used, as follows:
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Order (for 
Overall Study 
population)
Order (for 
China  
subpopulation)*
Endpoint (Change 
from Baseline to 
Week 26**)
Arm Comparison
1
1
HbA1c
15 mg ertugliflozin arm to 
placebo
2
2
HbA1c
5 mg ertugliflozin arm to 
placebo
3
3
FPG
15 mg ertugliflozin arm to 
placebo
4
4
FPG
5 mg ertugliflozin arm to 
placebo
5
5
Body Weight
15 mg ertugliflozin arm to 
placebo
6
6
Body Weight
5 mg ertugliflozin arm to 
placebo
7 
N/A
HbA1c <7.0% at Wk 
26
15 mg ertugliflozin arm to 
placebo
8 
N/A
HbA1c <7.0% at Wk 
26
5 mg ertugliflozin arm to 
placebo
9
N/A
Systolic BP
15 mg ertugliflozin arm to 
placebo
10
N/A
Systolic BP
5 mg ertugliflozin arm to 
placebo
11
N/A
Diastolic BP
15 mg ertugliflozin arm to 
placebo
12
N/A
Diastolic BP
5 mg ertugliflozin arm to 
placebo
* Hierarchical hypothesis testing for the China study population will only be performed for the HbA1c, FPG and 
body weight endpoints.
**Except for HbA1c <7.0% at Wk 26 endpoint.
Within each study population, starting with the first hypothesis, the test will be conducted at 
a 5% level of significance.  If the hypothesis test is significant, then the next hypothesis 
within that study population will be tested at a 5% level of significance.  Otherwise, testing 
ceases within this hierarchy within each study population.  The testing sequence as specified 
above will be applied for  the overall studypopulation and the China subpopulation.  The 
non-numbered items listed above will be assessed with 95% CIs and nominal p-values.
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9.2.3. 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 All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this trial. The ASaT population consists of all randomized subjects who received at least one 
dose of investigational product. Subjects will be included in the treatment group 
corresponding to the trial treatment they actually received for the analysis of safety data 
using the ASaT population.  All safety analyses and summaries will be produced for the 
overall study population as well as for the China subpopulation.
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 AEs consist of 
pre-specified adverse events and will include AEs or collections of AEs related to urinary 
tract infection, genital mycotic infection, symptomatic hypoglycemia and hypovolemia. 
Where available, standard MedDRA queries 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 determined prior to unblinding. For these events, the percentage of subjects with 
incident AE, the risk difference, its 95% confidence interval, and p-value will be provided.  
The confidence intervals and p-values are not adjusted for multiplicity and therefore must be 
considered accordingly.  Tier-2 AEs are those that are not Tier-1, but 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, 
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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. 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 
according to the 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.
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.
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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), 
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.
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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.
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.
12.4. 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. 
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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
End of Trial 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).
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
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).
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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