| 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 |
Objective: To demonstrate the non-inferiority of ertugliflozin compared with placebo on the time of first occurrence of the composite endpoint of
MACE: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.
Hypothesis: The time to first occurrence of the composite endpoint of MACE in subjects treated with ertugliflozin is non-inferior compared to that in subjects treated with placebo. |
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| E.2.2 | Secondary objectives of the trial |
Objective: To demonstrate the superiority of ertugliflozin compared with placebo on the time to first occurrence of the composite endpoint of cardiovascular death or hospitalization for heart failure.
Objective: To demonstrate the superiority of ertugliflozin compared with placebo on the time to cardiovascular death.
Objective: To demonstrate the superiority of ertugliflozin compared with placebo on the time to first occurrence of the composite endpoint of renal death, renal dialysis/transplant, or >=2x increase in baseline serum creatinine.
Objective: To assess the effect of ertugliflozin as compared with placebo
on the time to first occurrence of:
- MACE plus;
- Fatal or non-fatal myocardial infarction;
- Fatal or non-fatal stroke;
- Hospitalization for heart failure;
- Individual components of MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Insulin with or without Metformin Add-on Glycemic Sub-Study This trial includes an 18-week sub-study to generate safety and efficacy data in T2DM subjects using insulin therapy alone or insulin with metformin as the only background anti-hyperglycemic treatment. The insulin with or without metformin sub-study has different requirements with respect to allowable background AHA than the main cardiovascular study.
SU Monotherapy Add-on Glycemic Sub-Study
This trial includes an 18-week sub-study to generate safety and efficacy data in subjects using a SU as monotherapy at the pre-specified doses.
The SU monotherapy sub study has different requirements with respect to allowable background AHA than the main cardiovascular study.
Metformin with SU Add-on Glycemic Sub-Study This trial includes an 18-week sub-study to generate safety and efficacy data in T2DM subjects using metformin with a SU as the only background anti-hyperglycemic treatment. The metformin with SU sub-study has different requirements with respect to allowable background AHA than the main cardiovascular study. |
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| E.3 | Principal inclusion criteria |
1. Subjects ≥ 40 years of age at the time of the initial Screening visit (V1) with a diagnosis of T2DM in accordance with American Diabetes Association (ADA) guidelines.13
2. HbA1c at the Screening visit (V1) of 7.0 10.5% (53 91 mmol/mol) on stable allowable AHA(s) or on no background AHA for at least 8 weeks prior to the Screening visit (V1).
3. Body Mass Index (BMI) ≥18.0 kg/m2.
4. Subjects must have evidence or a history of atherosclerosis involving the coronary, cerebral or peripheral vascular systems as follows (must have at least one of the following a-d):
a. Coronary artery disease as indicated by a history of presumed spontaneous myocardial infarction (hospitalized with final diagnosis of myocardial infarction, excluding peri-procedural or definite secondary myocardial infarction [eg, due to profound anemia or hypertensive emergency, troponin increase in sepsis] in which the most recent event occurred at least 3 months (90 days) prior to the Screening visit (V1); OR
b. Coronary artery disease as indicated by a history of coronary revascularization through either a Percutaneous Coronary Intervention (PCI) at least 3 months (90 days) prior to the Screening visit (V1) or Coronary Artery Bypass Graft (CABG) at least 3 months (90 days) prior to the Screening visit (V1); OR
c. Ischemic (presumed thrombotic) cerebrovascular disease as indicated by a history of ischemic stroke (hospitalized with a final diagnosis of non hemorrhagic stroke [includes completion of a standard evaluation for stroke in an acute care facility or stroke clinic without hospital admission] with the most recent event occurring at least 3 months (90 days) prior to the Screening visit (V1) or a history of carotid revascularization at least 3 months (90 days) prior to the Screening visit (V1); OR
d. Peripheral arterial disease as indicated by:
1. Angiographically documented peripheral vascular disease; or
2. Resting ankle/brachial index (ABI) of <0.85 (measured by a certified vascular laboratory) plus symptoms of claudication; or
3. Amputation, peripheral bypass, or peripheral angioplasty of the extremities secondary to ischemia occurring at least 3 months (90 days) prior to the Screening visit (V1).
5. There is adequate documentation of the objective evidence that the subject has established vascular disease such as investigational site's medical records, copies of such records from other institutions, or a letter from a referring physician that specifically states the diagnosis and date of the most recent occurrence of the qualifying event(s) or procedure(s).
6. 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 Section 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 the Screening visit (V1).
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); or
2. Agrees to use (or have their 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 intrauterine 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).
7. Evidence of a personally signed and dated informed consent document (ICD) 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.
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| E.4 | Principal exclusion criteria |
1. Subjects who had been previously randomized into this trial.
2. Subjects experiencing a cardiovascular event (eg, myocardial infarction or stroke) or undergoing coronary angioplasty or peripheral intervention procedure between the Screening visit (V1) and
randomization.
3. Subjects undergoing any cardiovascular surgery (eg, valvular surgery) within 3 months (90 days) of the Screening visit (V1).
4. Subjects with any planned coronary revascularization or peripheral intervention procedure or other cardiovascular surgery.
5. Subjects with New York Heart Association (NYHA) Class IV heart failure at the Screening visit (V1).
6. 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 the Screening visit (V1), confirmed via 1 repeat triplicate set at the Screening visit (V1) if deemed necessary. For subjects with a mean triplicate value of sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg after at least a
5 minute seated rest at the Screening visit (V1) the investigator or the treating physician is allowed to adjust background blood pressure medication(s) to lower blood pressure values in order for the subject to
be re-assessed for enrollment eligibility.
7. Subject has a clinically significant ECG abnormality at Screening visit (V1) that requires further diagnostic evaluation or intervention.
8. History of type 1 diabetes mellitus or a history of ketoacidosis.
9. History of other specific types of diabetes (eg, genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drugor chemical induced, and post organ transplant).
10. Subject has active, obstructive uropathy or indwelling urinary catheter.
11. 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.
12. 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.
13. Any clinically significant malabsorption condition.
14. Subjects with a known hypersensitivity or intolerance to any SGLT2 inhibitor.
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.
16. History of one or more severe hypoglycemic episodes within 6 months of Screening (V1) or a severe hypoglycemic episode occurring during the interval between the Screening visit (V1) and randomization.
17. Fasting triglycerides >600 mg/dL (6.78 mmol/L) at Screening (V1), confirmed by a single repeat if deemed necessary. For subjects with fasting triglycerides >600 mg/dL the investigator or treating physician is allowed to adjust background lipid altering medication(s) to lower fasting triglycerides in order for the subject to be re-assessed for enrollment eligibility.
18. 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. Subjects who require a change in blood pressure and/or lipid altering medications to meet the entry criteria related to blood pressure and/or triglycerides must be on a stable dose of such therapy for at least 4 weeks prior to randomization.
19. Subjects who meet any of the following categories:
• 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.
• Subject has undergone bariatric surgery >12 months prior to Visit 1/Screening and is not weight-stable.
• Subject has undergone bariatric surgery within 12 months of Screening visit (visit 1).
Note: Weight-stable is defined as <5% change in body weight in the last 6 months.
20. 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 the Screening visit (V1) and/or subjects who have
a thyroid TSH outside of the laboratory reference range at the Screening visit (V1). Subjects excluded due to TSH criterion may be re-tested after being on a stable thyroid replacement regimen for at least 6 weeks. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary cardiovascular endpoint is time to first occurrence of the
composite endpoint of MACE.
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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) |
•Time to first occurrence of:
- Cardiovascular death or hospitalization for heart failure;
- Cardiovascular death;
- MACE plus;
- Fatal or non-fatal myocardial infarction;
- Fatal or non-fatal stroke;
- Hospitalization for heart failure;
- Individual components of MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke).
• All-cause mortality
• All MACE events (ie, not censored at the time of the first event).
• All cardiovascular death or hospitalizations for heart failure (ie, not censored at the time of the first event).
• Time to first occurrence of the composite of renal death, renal dialysis/transplant, or >=2x increase in baseline serum creatinine. |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
To demonstrate the non-inferiority of ertugliflozin compared with placebo on the time to first occurrence of the composite endpoint of MACE:
cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. |
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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) | No |
| 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 | 29 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 189 |
| 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 |
| Argentina |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Croatia |
| Czech Republic |
| Denmark |
| Finland |
| Georgia |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Malaysia |
| Mexico |
| Netherlands |
| Peru |
| Philippines |
| Poland |
| Romania |
| Serbia |
| South Africa |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
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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
|
End of Trial in all other participating countries is defined as Database Lock.
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 study as stated in the regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the
Member State. |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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