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 | 20.0 |
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 |
The primary objectives and hypotheses of the trial are:
1. Objective: At Week 26, to assess the effect on HbA1c of 15 mg ertugliflozin as compared with placebo.
Hypothesis: At Week 26, the mean reduction from baseline in HbA1c for 15 mg ertugliflozin is greater than that for placebo.
2. Objective: At Week 26, to assess the effect on HbA1c of 5 mg ertugliflozin as compared with placebo.
Hypothesis: At Week 26, the mean reduction from baseline in HbA1c for 5 mg ertugliflozin is greater than that for placebo.
3.Objective: To assess the safety and tolerability of ertugliflozin. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the trial are:
1. Objective: At Week 26, to assess the effect on fasting plasma glucose (FPG) of 15 mg ertugliflozin as compared with placebo.
2. Objective: At Week 26, to assess the effect on FPG of 5 mg ertugliflozin as compared with placebo.
3. Objective: At Week 26, to assess the effect on body weight of 15 mg ertugliflozin as compared with placebo.
4. Objective: At Week 26, to assess the effect on body weight of 5 mg ertugliflozin as compared with placebo.
5. Objective: At Week 26, to assess the proportion of subjects with an HbA1c <7% (53 mmol/mol) treated with 15 mg ertugliflozin as compared with placebo.
6. Objective: At Week 26, to assess the proportion of subjects with an HbA1c <7% (53 mmol/mol) treated with 5 mg ertugliflozin as compared with placebo.
7. Objective: At Week 26, to assess the effect on systolic blood pressure of 15 mg ertugliflozin as compared with placebo. |
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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 American Diabetes Association (ADA) guidelines.
2. Receiving one of the following diabetes therapy regimens at the time of Screening Visit 1 (S1) and with an HbA1c within the following range:
Diabetes Medication at Screening Visit (S1) HbA1c Inclusion Criterion at S1
Metformin monotherapy, ≥1500 mg/day 7.0%–10.5%, ( 53-91 mmol/mol) inclusive
Metformin monotherapy, <1500 mg/day 7.5% - 11.0% (58-97 mmol/mol inclusive
Dual combination therapy with metformin + sulfonylurea, DPP-4 inhibitor, meglitinide, or alpha glucosidase inhibitor 6.5%–9.5% (48-80 mmol/mol),
Inclusive
3. Subjects taking metformin monotherapy for less than 8 weeks at S1 or who require a change to their diabetes regimen at the S2 visit to remain eligible to participate (including subjects discontinuing AHA therapy at S2) must have an HbA1c of 7.0 10.5% (53 91 mmol/mol) at S3 after at least 8 weeks on a regimen of metformin in monotherapy.
4. Body Mass Index (BMI) 18.0 40.0 kg/m2.
5. Evidence of a personally signed and dated informed consent document indicating that the subject (or legal representative) has been informed of all pertinent aspects of the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
6. Subjects who, in the opinion of the Investigator, are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
7. Subject meets one of the following criteria:
a. Is a male.
b. Is a female not of reproductive potential defined as one who (See Sections 4.4.4.1 and 4.4.4.2 for reference on childbearing potential):
1. Is postmenopausal defined as at least 12 months with no menses in women ≥45 years of age, or
2. Has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to Screening Visit 1 (S1).
c. Is a female of reproductive potential and:
1. Agrees to remain abstinent from heterosexual activity (if this form of birth control is accepted by local regulatory agencies and ethics review committees as the sole method of birth control for subjects participating in clinical trials), or
2. Agrees to use (or have their partner use) acceptable contraception to prevent pregnancy within the projected duration of the trial and for 14 days after the last dose of investigational product. Two methods of contraception will be used to avoid pregnancy. Acceptable combinations of methods include:
• Use of one of the following double barrier methods: diaphragm with spermicide and a condom; cervical cap and a condom; or a contraceptive sponge and condom.
• Use of hormonal contraception (any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent [including oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous patch]) with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; vasectomy; or intra-uterine device (IUD). As an exception, medroxyprogesterone acetate (Depo Provera) is not permitted.
• Use of an IUD with one of the following: condom; diaphragm with spermicide; contraceptive sponge; vasectomy; or hormonal contraception (see above).
• Vasectomy with one of the following: diaphragm with spermicide; cervical cap; contraceptive sponge; condom; IUD; or hormonal contraception (see above).
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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 1 (S1).
2. History of secondary types of diabetes (eg, genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical induced, and post organ transplant).
3. Subjects who are <80% compliant based on pill count with the Placebo Run in medication.
4. History of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or New York Heart Association (NYHA) functional class III-IV heart failure within 3 months of Screening Visit 1 (S1).
5. Mean value for triplicate screening sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg after at least a 5 minute seated rest at Screening Visit 1 (S1), confirmed via 1 repeat triplicate set at Screening Visit 1 (S1) if deemed necessary. For subjects with a confirmed mean triplicate value of sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg at the S1 visit, the Investigator and/or treating physician is allowed to adjust background blood pressure medication(s) to improve blood pressure control in order for the subject to be re assessed for eligibility.
6. Subject has a clinically significant electrocardiogram (ECG) abnormality at Screening Visit (S1) that requires further diagnostic evaluation or intervention (eg, new, clinically significant arrhythmia or a conduction disturbance).
7. Subject has active, obstructive uropathy or indwelling urinary catheter.
8. Subject has a history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
Note (1): A subject with a history of malignancy >5 years prior to signing informed consent should have no evidence of residual or recurrent disease.
Note (2): A subject with any history of melanoma, leukemia, lymphoma, or renal cell carcinoma is excluded.
9. Subject routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking.
Note (1): One alcoholic drink is defined as 5 oz (150 mL) of wine, or 12 oz (350 mL) of beer, or 1.5 oz (50 mL) of 80 proof liquor.
Note (2): Binge drinking is defined as a pattern of 5 or more alcoholic drinks (male), or 4 or more alcoholic drinks (female) in about 2 hours.
10. Any clinically significant malabsorption condition.
11. Meets any of the following criteria:
• Subject is on a weight loss program and is not weight stable.
• Subject is on a weight loss medication (eg, orlistat, phentermine/topiramate, lorcaserin) and is not weight stable.
• Subject is on other medications associated with weight changes (eg, anti psychotic agents) and is not weight stable.
Note: Weight stable is defined as <5% change in body weight in the last 6 months.
12. Subject who had bariatric surgery at any time in the past.
13. Subjects with a gender specific BMD T score of <-2.5 at any site assessed at Screening Visit 3.
14. Subjects with a documented history of osteoporosis (prior documented BMD T score of <-2.5).
15. Subjects with rheumatoid arthritis.
16. Subjects with any other illness that could impact BMD assessment such as inherited bone disorders, metabolic bone disease or autoimmune endocrinopathies.
17. Subjects with bilateral hip prosthesis or subjects who have fewer than 3 vertebrae which are evaluable by DXA at Screening Visit 3 (S3).
18. Subjects with hyperparathyroidism defined as a parathyroid hormone (PTH) value at Screening Visit 1 that exceeds the upper limit of the reference range of the central laboratory.
19. Subjects with previously diagnosed atraumatic vertebral fracture or high and low impact fracture of the hip or wrist.
20. Subjects with a known hypersensitivity or intolerance to any SGLT2 inhibitor.
21. Subjects who have previously been randomized in a trial with ertugliflozin.
22. Subjects with a known hypersensitivity or intolerance to glimepiride.
23. Screening fasting plasma or finger-stick glucose >270 mg/dL (15 mmol/L), confirmed by a single repeat following counseling on exercise and diet. This will be assessed at each of the screening visits (as applicable).
24. Fasting serum triglyceride >600 mg/dL (6.8 mmol/L) at Screening Visit 1 (S1), confirmed by a single repeat if deemed necessary. For subjects with confirmed fasting triglycerides >600 mg/dL, the Investigator and/or treating physician is allowed to adjust the background lipid altering medication(s) to lower fasting triglycerides in order for the subject to be re assessed for eligibility. |
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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 in FPG from Baseline to Week 26.
• Change in body weight from Baseline to Week 26.
• Incidence of HbA1c of <7% (53 mmol/mol) at Week 26.
• Change in systolic and diastolic blood pressure from Baseline to Week 26.
• Change in HbA1c, FPG, and body weight from Baseline to Weeks 52 and 104.
• Incidence of HbA1c <7% (53 mmol/mol) at Weeks 52 and 104.
• Incidence of HbA1c ≤6.5% (48 mmol/mol) at Weeks 26, 52 and 104.
• Change in systolic and diastolic blood pressure from Baseline to Weeks 52 and 104.
• Proportion of subjects requiring glycemic rescue therapy up to Weeks 26, 52 and 104.
• Time to glycemic rescue therapy up to Weeks 26, 52 and 104.
• Endpoints related to pharmacokinetics of ertugliflozin.
Secondary endpoints related to bone safety are:
• Change in BMD as measured by DXA at the lumbar spine (L1 L4), femoral neck, total hip and distal forearm from Baseline to Week 26.
• Change in BMD as measured by DXA at the lumbar spine (L1 L4), femoral neck, total hip and distal forearm from Baseline to Weeks 52 and 104.
• Change from baseline in bone biomarkers at Weeks 26, 52 and 104. |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
This study will assess changes in bone mineral density (BMD) by dual energy X ray absorptiometry (DXA), and so provide important information on the bone safety of ertugliflozin. |
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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 | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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 |
Australia |
Czech Republic |
Hong Kong |
Hungary |
Israel |
Mexico |
Peru |
Poland |
Romania |
Russian Federation |
Slovakia |
South Africa |
Taiwan |
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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End of Trial in a Member State of the European Union is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the trial as stated in the regulatory application (ie, CTA) and ethics application in the Member State.
End of Trial in all other participating countries is defined as last subject last visit.
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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 | 4 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |