| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
(1) Objective: At Week 26, to assess the effect on HbA1c of 15 mg ertugliflozin as compared with placebo. Hypothesis: At Week 26, the mean reduction from baseline in HbA1c for 15 mg ertugliflozin is greater than that for placebo.
(2) Objective: At Week 26, to assess the effect on HbA1c of 5 mg ertugliflozin as compared with placebo. Hypothesis: At Week 26, the mean reduction from baseline in HbA1c for 5 mg ertugliflozin is greater than that for placebo.
(3) Objective: To assess the safety and tolerability of ertugliflozin.
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| E.2.2 | Secondary objectives of the trial |
(1) Objective: At Week 26, to assess the effect on fasting plasma glucose (FPG) of 15 mg ertugliflozin as compared with placebo. Hypothesis: At Week 26, the mean reduction from baseline in FPG for 15 mg ertugliflozin is greater than that for placebo.
(2) Objective: At Week 26, to assess the effect on FPG of 5 mg ertugliflozin as compared with placebo. Hypothesis: At Week 26, the mean reduction from baseline in FPG for 5 mg ertugliflozin is greater than that for placebo.
(3) Objective: At Week 26, to assess the effect on body weight of 15 mg ertugliflozin as compared with placebo. Hypothesis: At Week 26, the mean reduction from baseline in body weight for 15 mg ertugliflozin is greater than that for placebo.
(4) Objective: At Week 26, to assess the effect on body weight of 5 mg ertugliflozin as compared with placebo. Hypothesis: At Week 26, the mean reduction from baseline in body weight for 5 mg ertugliflozin is greater than that for placebo.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects ≥18 years of age at the time of the initial Screening Visit (S1) with a diagnosis of T2DM in accordance with ADA guidelines.
2. Subjects with no prior allowable oral AHA for ≥8 weeks prior to S1 with an HbA1c 7.0 - 10.5% (53-91 mmol/mol) at the initial Screening Visit (S1) or subjects on monotherapy with a single allowable oral AHA with an HbA1c 6.5-9.5% (48-80 mmol/mol) at the initial Screening Visit (S1). Subjects discontinuing an oral AHA at Screening Visit (S2) should remain off the oral AHA for ≥8 weeks prior to Screening Visit (S3) and will require an HbA1c of 7.0-10.5% (53-91 mmol/mol) at Screening Visit (S3) in order to be randomized.
3. Subjects on a single allowable oral AHA must be willing to discontinue this medication starting at Screening Visit (S2) and remain off this medication for the duration of the trial. Allowable oral AHAs for discontinuation are metformin, sulfonylureas, DPP-4 inhibitors, glinides or alpha-glucosidase inhibitors.
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 a legal representative) has been informed of all pertinent aspects of the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
6. In the investigator’s opinion, subjects are willing and likely able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
7. Subject meets one of the following criteria (a, b or c):
a. is a male.
b. is a female not of reproductive potential defined as one who (See Section 4.4.4.1 and 4.4.4.2 for reference on childbearing potential):
1. is postmenopausal defined as at least 12 months with no menses in women ≥45 years of age, or
2. has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to Screening Visit (S1).
c. is a female of reproductive potential and:
3. agrees to remain abstinent from heterosexual activity (if this form of birth control is accepted by local regulatory agencies and ethics review committees as the sole method of birth control), or
4. agrees to use (or have her partner use) acceptable contraception to prevent pregnancy while the subject is receiving investigational product and for 14 days after the last dose of investigational product. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:
• Use of one of the following double-barrier methods: diaphragm with spermicide and a condom; cervical cap and a condom; or a contraceptive sponge and condom.
• Use of hormonal contraception (any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or 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).
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| E.4 | Principal exclusion criteria |
1. History of type 1 diabetes mellitus or a history of ketoacidosis or subject assessed by the investigator as possibly having type 1 diabetes confirmed with a C-peptide <0.7 ng/mL (0.23 nmol/L). Note: Only subjects assessed by the investigator as possibly having type 1 diabetes should have C-peptide measured at Screening Visit (S1).
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 Screening Visit (S1).
5. Mean value for triplicate screening sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg after at least a 5-minute seated rest at Screening Visit (S1), confirmed via 1 repeat triplicate set at Screening Visit (S1) if deemed necessary. For subjects with a confirmed mean triplicate value of sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg at the S1 visit, the Investigator and/or treating physician is allowed to adjust background blood pressure medication(s) to improve blood pressure control in order for the subject to be re screened.
6. Subject has a clinically significant ECG abnormality at Screening Visit (S1) that requires further diagnostic evaluation or intervention (eg, new, clinically significant arrhythmia or a conduction disturbance).
7. Subject has active, obstructive uropathy or indwelling urinary catheter.
8. Subject has a history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
Note (1) A subject with a history of malignancy >5 years prior to signing informed consent should have no evidence of residual or recurrent disease.
Note (2) A subject with any history of melanoma, leukemia, lymphoma, or renal cell carcinoma is excluded.
9. Subject routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking.
Note (1): One alcoholic drink is defined as 5 oz (150 mL) of wine, or 12 oz (350 mL) of beer, or 1.5 oz (50 mL) of 80-proof liquor.
Note (2): Binge drinking is defined as a pattern of 5 or more alcoholic drinks (male), or 4 or more alcoholic drinks (female) in about 2 hours.
10. Any clinically significant malabsorption condition.
11. Meets any of the following categories:
12. Subject is on a weight-loss program and is not weight-stable.
13. Subject is on a weight-loss medication (eg, orlistat, phentermine/topiramate, lorcaserin) and is not weight-stable.
14. Subject is on other medications associated with weight changes (eg, anti-psychotic agents) and is not weight-stable.
15. Subject has undergone bariatric surgery >12 months prior to Visit 1/Screening and is not weight-stable.
16. Subject has undergone bariatric surgery within 12 months of Visit 1/Screening.
17. Note: Weight-stable is defined as <5% change in body weight in the last 6 months.
18. Subjects with a known hypersensitivity or intolerance to any SGLT2 inhibitor.
19. Subjects with a known hypersensitivity or intolerance to metformin (because of its use as glycemic rescue therapy in Phase A and potential use in Phase B in subjects originally assigned to placebo).
20. Screening fasting plasma or finger-stick glucose >270 mg/dL (15 mmol/L), confirmed by a single repeat following counseling on exercise and diet. This will be assessed at each of the screening visits (as applicable).
21. Fasting serum triglyceride >600 mg/dL (6.78 mmol/L) at Screening Visit (S1), confirmed by a single repeat if deemed necessary. For subjects with fasting triglycerides >600 mg/dL, the Investigator and/or treating physician is allowed to adjust the background lipid altering medication(s) to lower fasting triglycerides in order for the subject to be re screened.
22. Subjects currently taking blood pressure or lipid altering medications that have not been on a stable dose for at least 4 weeks prior to randomization.
23. Subjects currently being treated for hyperthyroidism, subjects on thyroid replacement therapy that have not been on a stable dose for at least 6 weeks prior to randomization and/or subjects who have a TSH outside of the laboratory reference range at Screening Visit (S1).
24. 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 MDRD equation.
25. Male subjects with a hemoglobin of <12 g/dL (120 g/L) or female subjects with a hemoglobin <11 g/dL (110 g/L).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change in HbA1c from Baseline to Week 26. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessment according to protocol |
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| E.5.2 | Secondary end point(s) |
• Change from Baseline in FPG at Week 26.
• Change from Baseline in body weight at Week 26.
• Incidence of HbA1c <7% (53 mmol/mol) at Week 26.
• Change from Baseline in 2-hour post-prandial plasma glucose at Week 26.
• Change from Baseline in systolic blood pressure at Week 26.
• Change from Baseline in diastolic blood pressure at Week 26.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assessment according to protocol |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Italy |
| Lithuania |
| Israel |
| Mexico |
| Romania |
| South Africa |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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