| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1) Objective: After 24 weeks, to assess the effect of the addition of sitagliptin compared with the addition of dapagliflozin on A1C.
2) Objective: Over 24 weeks, to assess the overall safety and tolerability of sitagliptin in comparison to that of dapagliflozin.
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| E.2.2 | Secondary objectives of the trial |
| After 24 weeks, to assess the effect of the addition of sitagliptin compared with the addition of dapagliflozin on change from baseline in 2-hr incremental post-prandial glucose excursion and change from baseline in 2-hr post-prandial glucose. To assess, in a subset of subjects, the effect of the addition of sitagliptin compared with that of dapagliflozin on change from baseline in post-prandial insulin AUC, glucagon AUC, and insulin AUC: glucagon AUC ratio. To assess the effect of the addition of sitagliptin compared with that of dapagliflozin on the proportion of subjects at the A1C goal of <7%. To describe the effect of the addition of sitagliptin compared with that of dapagliflozin on change in fasting plasma glucose (FPG) from baseline. |
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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 |
| Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
1.Have T2DM in accordance with ADA guidelines and be ≥25 years of age on the day of signing the ICF.
2.Have an eGFR ≥60 mL/min/1.73 m2 and <90 mL/min/1.73 m2, as calculated by the CKD-epi equation.
3. Be on metformin ≥1500 mg/day alone or in combination with an SU agent (at a dose of ≥ 50% maximum labeled dose in the country of the investigational site) for ≥8 weeks with a Visit 1/Screening A1C ≥7.0% and ≤9.5% (≥53 mmol/mol and ≤80 mmol/mol).
4.Have a body mass index (BMI) ≥18.0 kg/m2.
5.Have personally signed and dated the ICF indicating that he/she 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.Be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
7.Meet one of the following criteria:
a. Subject is a male.
b. Subject 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 Visit 1/Screening.
c. Subject 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 her partner use) acceptable contraception to prevent pregnancy while receiving blinded study drug and for 14 days after the last dose of blinded study drug. 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 and 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).
At Visit 2/Week -2
8. Have an eGFR ≥60 mL/min/1.73 m2 and <90 mL/min/1.73 m2, as calculated by the CKD-epi equation and ≤ 20 mL/min/1.73 m2 different from the qualifying Visit 1/Screening value.
At Visit 3/Randomization/Day 1
9. Be ≥80% compliant with placebo run-in medication (as determined by site-performed pill count).
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| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject:
1.Has a history of type 1 diabetes mellitus or a history of ketoacidosis or subject assessed by the investigator as possibly having type 1 diabetes mellitus confirmed with a C-peptide <0.7 ng/mL (0.23 nmol/L).
2.Has a history of secondary causes of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies).
3.Has a known hypersensitivity or intolerance to any DPP-4 inhibitor or SGLT2 inhibitor.
4.Has been treated with any of the following agents within 12 weeks of Visit 1:
Insulin of any type (except for short-term use [i.e., ≤7 days] during concomitant illness or other stress), DPP-4 inhibitors, Pioglitazone or rosiglitazone, GLP-1 agonists, SGLT2 inhibitors, Alpha glucosidase inhibitors, Meglitinides, Bromocriptine, Colesevelam, Any other AHA with the exception of metformin and for subjects on dual combination therapy, a sulfonylurea
5.Subject intends to initiate weight loss medication during the study period.
6.Subject has undergone bariatric surgery within 12 months of Visit 1.
7.Subject is not weight stable.
8. Subject has started a weight loss medication or a medication associated with weight changes within the prior 12 weeks.
9. Has a history of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or NYHA functional class III-IV heart failure within 3 months of Visit 1.
10. Is at high risk for volume depletion, hypotension and/or electrolyte imbalances, in the opinion of the investigator.
11. Has a history of malignancy ≤5 years prior to signing the ICF, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer:
12. Has human immunodeficiency virus (HIV) as assessed by medical history.
13. Has blood dyscrasias or any disorders causing hemolysis or unstable red blood cells, or clinically important hematological disorder.
14. Has a medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or symptomatic gallbladder disease.
15. Has any clinically significant malabsorption condition.
16. Is currently being treated for hyperthyroidism.
17. Is on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks prior to Visit 1.
18. Is on or likely to require treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids.
19. Is on or likely to require treatment for ≥7 consecutive days with non-steroidal anti-inflammatory drugs.
20. Has undergone a surgical procedure within 12 weeks prior to signing the ICF or has major surgery planned during the trial.
21. Has a mean value for duplicate sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg and blood pressure is considered unlikely to be below these limits by Visit 3 (Day 1) with initiation or adjustment of antihypertensive medication.
22. Has other medical condition, psychiatric condition or laboratory abnormality that may increase the risk associated with study participation 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.
23. Has an exclusionary laboratory value as listed in Table 1 of protocol
24. Has participated in other studies involving investigational drug(s) (Phase I-IV) within 30 days prior to Visit 1 or during the pre-randomization period.
25. Has a positive urine pregnancy test.
26. Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of blinded study drug.
27. Is planning to undergo hormonal therapy in preparation to donate eggs during the trial, including 14 days following the last dose of blinded study drug.
28. Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week or engages in binge drinking.
29. Has donated blood or blood products within 6 weeks of Visit 1 or who plans to donate blood or blood products at any time during the trial.
At Visit 2/Week -2:
31. Has a clinically significant ECG abnormality that requires further diagnostic evaluation or intervention.
32. Has a FPG consistently >260 mg/dL (14.4 mmol/L).
34. Has a fasting TG level >600 mg/dL (6.8 mmol/L).
At Visit 3 (Day 1)
35. Has a site fasting fingerstick glucose (FFSG) <110 mg/dL (6.1 mmol/L) or >260 mg/dL (14.4 mmol/L).
37. Is on lipid-lowering medication or blood pressure medication, and has not been on a stable regimen for the 4 weeks ) prior to Visit 3 (Day 1).
38. Has a mean value for duplicate sitting systolic blood pressure of >160 mm Hg and/or diastolic blood pressure of >90 mm Hg.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in A1C |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
| (1) Change from baseline in 2-hr incremental post-prandial glucose excursion; (2) change from baseline in 2-hr post-prandial glucose (PPG); (3) change from baseline in post-prandial insulin AUC, glucagon AUC, and insulin AUC:glucagon AUC ratio; (4) proportion of subjects at the A1C goal of <7.0% (<53 mmol/mol); (5) change in fasting plasma glucose (FPG) from baseline. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Colombia |
| Estonia |
| Finland |
| Germany |
| Hungary |
| Ireland |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Mexico |
| New Zealand |
| Norway |
| Peru |
| Puerto Rico |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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