| 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. To assess the effect of MK-0431D compared to sitagliptin alone on A1C. 2. To assess the safety and tolerability of MK-0431D. |
|
| E.2.2 | Secondary objectives of the trial |
After 16 weeks:
1. To assess the effect of MK-0431D compared to simvastatin alone on A1C.
2.To assess the effect of MK-0431D compared to sitagliptin alone on LDL-C.
3.To assess the effect of MK-0431D compared to simvastatin alone on LDL-C.
4. To assess the effect of MK-0431D compared to sitagliptin alone on FPG.
5. To assess the effect of MK-0431D compared to simvastatin alone on FPG.
6. To assess the effect of MK-0431D compared to sitagliptin alone on the proportion of patients achieving glycemic goals (A1C <7.0%) after 16 weeks of treatment.
7. To assess the effect of MK-0431D compared to sitagliptin alone on total cholesterol (TC), apolipoprotein B (Apo B), non-HDL-C, triglycerides (TG), very low-density lipoprotein cholesterol (VLDL-C), and high-density lipoprotein cholesterol (HDL-C).
8. To assess the effect of MK-0431D compared to simvastatin alone on A1C among patients with baseline A1C > or ≤ median. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At Visit 1/Screening Visit
1. Patient has T2DM and must be ≥18 and ≤79 years of age on the day of signing informed consent.
2. Patient is a male, or a female who is highly unlikely to conceive as indicated by meeting at least one of the following criteria:
a) Patient is not of reproductive potential. A female patient who is not of reproductive potential is defined as one who has either (1) reached natural menopause (defined as ≥12 months of spontaneous amenorrhea in women >45 years of age, or ≥6 months of spontaneous amenorrhea with serum FSH levels in the postmenopausal range as determined by the laboratory), or (2) had bilateral oophorectomy and/or hysterectomy, or had bilateral tubal ligation at least 6 weeks prior to screening.
b) Patient is of reproductive potential and agrees to remain abstinent or use (or have their partner use) two acceptable method of birth control within the projected duration of the study and for 14 days after the last dose of study medication.
Acceptable methods of birth control are: hormonal contraception, intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, vasectomy.
3. Patient understands the study procedures, alternative treatments available and risks involved with the study, and voluntarily agrees to participate by giving informed
written consent.
4. Provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
Metabolic Entry Criteria
5. Patient is currently on monotherapy with metformin at a dose of ≥1500 mg/day for at least 10 weeks and has a Visit 1/Screening Visit A1C ≥7% and ≤10%.
6. Patient is not on lipid-lowering agents for at least 6 weeks and has a Visit 1/Screening Visit LDL-C ≥70 mg/dL (1.81 mmol/L) and ≤130 mg/dL (3.37 mmol/L).
NOTE: Patients on other lipid-lowering agents (e.g. fibrates or fenofibrates) are excluded. The list of excluded lipid-modifying medications are in Appendix 6.1.
At Visit 3/Day 1/Randomization
7. Patient has ≥85% compliance (as measured by tablet count) with placebo treatment during run-in. |
|
| E.4 | Principal exclusion criteria |
At Visit 1/Screening Visit
Glucose Metabolism and Therapy Criteria
1. Patient has a history of type 1 diabetes mellitus, or a history of ketoacidosis or patient is assessed by the investigator as possibly having type 1 diabetes confirmed with a C-peptide <0.7 ng/mL (0.23 nmol/L).
Patients Requiring Specific Treatments
2. Patient has been on a thiazolidinedione (TZD) within the prior 16 weeks.
3. Patient has been treated with a statin or other lipid-lowering agents, including over the counter (OTC) supplements of fish oils containing >100 mg/day of EPA+DHA, red yeast rice extract, Cholestin, fibrates, niacin (>100 mg/day), or other lipidmodifying
agents not listed above within 6 weeks prior to Visit 1/Screening Visit (see Appendix 6.1 for the list of excluded medications).
4. Patient is currently participating in or has participated in another study in which the patient received an investigational compound or used an investigational device within the prior 12 weeks of signing the informed consent or is not willing to refrain from participating in any other study.
5. Patient is currently on or likely to require treatment with a prohibited medication (see Appendix 6.1 for a list of excluded medications).
6. Patient intends to consume >1.2 liters of grapefruit juice per day during the course of the study.
7. Patient is on or likely to require treatment for ≥2 consecutive weeks or repeated courses of pharmacologic doses of corticosteroids.
8. Patient has a history of intolerance or hypersensitivity or any contraindication to sitagliptin, simvastatin, metformin or glimepiride based upon the labels of the country of the investigational site.
9. Patient is on a weight loss program and not in the maintenance phase or has started a weight loss medication or has undergone bariatric surgery within 12 months prior to signing the informed consent.
10. Patient has undergone a surgical procedure within 4 weeks prior to signing informed consent or has planned major surgery during the study.
Concomitant Disease of Organs and Systems
11. Patient has symptomatic hyperglycemia that, in the investigator’s opinion, requires immediate initiation, adjustment, or addition of antihyperglycemic therapy.
12. Patient has a history of myopathy or rhabdomyolysis with any statin.
13. Patient has cardiovascular disease as indicated by a history of one of the following:
acute coronary syndrome (e.g., myocardial infarction or unstable angina), stable
angina, coronary artery procedures (angioplasty or bypass surgery), evidence of
clinically significant myocardial ischemia, peripheral arterial disease, and carotid
artery disease (transient ischemic attacks or stroke of carotid origin or >50%
obstruction of a carotid artery).
14. Patient has a diagnosis of congestive heart failure with New York Heart Association
(NYHA) Class III or IV cardiac status (refer to Appendix 6.3).
15. Patient has a systolic blood pressure ≥160 mm Hg or a diastolic blood pressure
≥90 mm Hg and blood pressure is unlikely to be within these limits at Visit 3/Day 1 with an adjustment in anti-hypertensive medication.
16. Patient 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.
17. Patient has chronic progressive neuromuscular disorder (such as multiple sclerosis or polymyositis).
18. Patient has human immunodeficiency virus (HIV) as assessed by medical history.
19. Patient has a clinically important hematological disorder (such as aplastic anemia, a myeloproliferative or myelodysplastic syndromes, thrombocytopenia).
20. Patient has uncontrolled endocrine or metabolic disease known to influence glycemic control or serum lipids/lipoproteins (i.e., secondary causes of hyperlipidemia).
21. Patient is currently being treated for hyperthyroidism or patient is on thyroid hormone therapy and has not been on stable dose for at least 6 weeks.
22. Patient has a history of malignancy ≤5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
23. Patient has donated or received blood products or has had phlebotomy of >300 mL within 8 weeks of signing informed consent, or intends to donate blood products within the projected duration of the study.
Exclusion Based on Laboratory Abnormalities
24. Patient has exclusionary laboratory values as listed in Table 2-1 below. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in A1C at Week 16 is the primary efficacy endpoint. Safety and tolerability will be assessed by a review of all safety parameters including adverse experiences, laboratory safety parameters, body weight, and vital signs. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Change from baseline in FPG at Week 16, percent change from baseline in LDL-C, total cholesterol, Apo B, non-HDL-C, TG, VLDL-C, and HDL-C at Week 16 are the key secondary
efficacy endpoints. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 127 |
| 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 |
| Chile |
| Colombia |
| India |
| Indonesia |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Peru |
| Philippines |
| Russian Federation |
| Taiwan |
| Thailand |
| Ukraine |
| United States |
| Croatia |
|
| 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
|
Last Patient Post-study Telephone Follow-up
(Fourteen days after the last dose of study medication - Week 16 - Visit 5). |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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