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

PHRR160502-001211

MK-8835-012 / B1521045

2015-CT0323

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

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

Ongoing

Type 2 Diabetes mellitus

Change in HbA1c from Baseline to Week 26.

 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.

Completed

Clinical Trial

20151009104055

2016-04-18

0000-00-00

34

23

Not yet started

2016-06-20

Inclusion criteria:
Asian subject greater than or equal to 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 greater than or equal to 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.
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
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
 Vasectomy with one of the following: diaphragm with spermicide;
cervical cap; contraceptive sponge; condom; IUD; or hormonal
contraception

Exclusion Criteria:
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.
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.
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 thyroidstimulating 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 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 protocolapproved
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.
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.

Interventional

Ertugliflozin

Metformin monotherapy;Combination therapy with metformin and one of the following allowable oral AHAs:sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, meglitinide, or alphaglucosidase inhibitor.

Randomized

Double Blind

Unspecified

Parallel

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

Phase III