TYPE 2 DIABETES

Objective: To assess the effect on HbA1c of 15 mg ertugliflozin relative to placebo. To assess the effect on HbA1c of 5 mg ertugliflozin relative to placebo. To assess the safety and tolerability of ertugliflozin. To assess the effect on fasting plasma glucose (FPG) of 15 mg ertugliflozin relative to placebo. To assess the effect on FPG of 5 mg ertugliflozin relative to placebo. To assess the effect on body weight of 15 mg ertugliflozin relative to placebo. To assess the effect on body weight of 5 mg ertugliflozin relative to placebo. To assess the proportion of subjects with an HbA1c <7.0% (53 mmol/mol) treated with 15 mg ertugliflozin relative to placebo. To assess the proportion of subjects with an HbA1c <7.0% (53 mmol/mol) treated with 5 mg ertugliflozin relative to placebo. To assess the effect on systolic blood pressure of 15 mg ertugliflozin relative to placebo. To assess the effect on systolic blood pressure of 5 mg ertugliflozin relative to placebo. To assess the effect on diastolic blood pressure of 15 mg ertugliflozin relative to placebo. To assess the effect on diastolic blood pressure of 5 mg ertugliflozin relative to placebo. To assess the proportion of subjects with an HbA1c <6.5% treated with ertugliflozin (for each dose) relative to placebo. 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. To descriptively summarize pharmacokinetics of ertugliflozin and provide population PK [(pharmacokinetic(s)] analysis in this study.

Ertugliflozin (MK-8835/PF-04971729)

Ertugliflozin (MK-8835/PF-04971729)

F.C. Tablet

10mg
5mg

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.
 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.

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. In a country where the minimum age for consent and enrollment is>=21 years of age, this age
criterion should be followed.( In Taiwan enrollment is>=20 years of age)
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:
1. Is postmenopausal defined as at least 12 months with no menses in women>=45 years of age, or
2. Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to 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.
Accept able 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.

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 Run-in medication.
4. History of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or New York Heart
Asso ciation (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.
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 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 umol/L) or female subjects with a serum creatinine >=1.2 mg/dL (>=106umol/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.
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 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.
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.