| 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 |
Objective 1: To assess the effect of sitagliptin in combination with atorvastatin compared to atorvastatin alone on A1C after 16 weeks of treatment.
Objective 2: To assess the effect of atorvastatin in combination with sitagliptin compared to sitagliptin alone on LDL-C after 16 weeks of treatment.
Objective 3: To assess the safety and tolerability of the co-administration of sitagliptin and atorvastatin. |
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| E.2.2 | Secondary objectives of the trial |
After 16 weeks:
1: To assess the effect of sitagliptin in combination with atorvastatin compared to sitagliptin alone on A1C.
2: To assess the effect of atorvastatin in combination with sitagliptin compared to atorvastatin alone on LDL-C
3: To assess the effect of sitagliptin in combination with atorvastatin compared to atorvastatin alone on FPG.
4: To assess the effect of atorvastatin in combination with sitagliptin compared to sitagliptin alone on total cholesterol, apolipoprotein B, non-HDL-C, triglycerides, VLDL-C, and HDL-C.
5: To assess the effect of atorvastatin in combination with atorvastatin compared to atorvastatin alone in A1C among patients with baseline A1C > or <= median
After 54 weeks:
6: To assess the effect of sitagliptin in combination with atorvastatin on A1C and FPG.
7: To assess the effect of artovastatin in combination with sitagliptin on LDL-C, total cholesterol, Apo B, non-HDL-C, TG, VLDL-C, and HDL-C. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At Visit 1/Screening Visit
1. Patient has T2DM and is ≥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 at least one “yes” answer to the following questions:
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 ≥6 months of spontaneous amenorrhea with serum FSH levels in the postmenopausal range as determined by the laboratory, or ≥12 months of spontaneous amenorrhea in women >45 years of age), (2) undergone a bilateral oophorectomy and/or hysterectomy, or bilateral tubal ligation.
b) Patient is of reproductive potential and agrees to remain abstinent or use (or have their partner use) two acceptable methods 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 contraceptives, 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.
Metabolic Entry Criteria
4. Patient is currently on monotherapy with metformin at a dose of ≥1500 mg/day for at least 8 weeks and has a Visit 1/Screening Visit A1C ≥7% and ≤10%.
5. Patient is not on statin therapy or other 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).
At Visit 3/Day 1/Randomization
6. Patient has ≥85% compliance with both sitagliptin placebo and atorvastatin placebo during the single-blind run-in period (as determined by site-performed tablet count). |
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| E.4 | Principal exclusion criteria |
1.Patient has a history of type 1 diabetes mellitus, 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).
2.Patient has ever taken a DPP-4 inhibitor (such as sitagliptin, vildagliptin, alogliptin, or saxagliptin) or a GLP-1 mimetic (such as exenatide or liraglutide), or the patient has required insulin therapy within 12 weeks prior to signing informed consent.
3.Patient has been on a PPARĪ³ agonist (TZD) within the prior 12 weeks.
4.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, bile-acid sequestrants, fibrates, niacin (>100 mg/day), or other lipid-modifying agents not listed above within 6 weeks prior to Visit 1/Screening Visit.
5.Patient is currently participating in or has participated in another study with an investigational compound or device within the prior 12 weeks of signing the informed consent and does not agree to refrain from participating in any other study while participating in this study.
6.Patient is currently taking, or intends to take during the course of the study, any excluded medications as listed in Appendix 6.1. This includes, but is not limited to any potent inhibitor of CYP3A4 (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, protease inhibitors, or nefazodone), or medications that could increase the risk of myopathy (e.g., cyclosporine).
7.Patient intends to consume >1.2 liters of grapefruit juice per day during the course of the study.
8.Patient is on or is likely to require treatment with ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids.
9.Patient has a history of hypersensitivity or any contraindication to sitagliptin, atorvastatin, metformin or glimepiride based upon the labels of the country of the investigational site.
10.Patient is on a weight loss program and not in the maintenance phase or has started a weight loss medication (such as orlistat or sibutramine) within the prior 8 weeks.
11.Patient has undergone a surgical procedure within the prior 4 weeks.
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, abdominal aortic aneurysm, and carotid artery disease (transient ischemic attacks or stroke of carotid origin or >50% obstruction of a carotid artery).
14.Patient has New York Heart Association (NYHA) Class III or IV congestive heart failure .
15.Patient has inadequately controlled hypertension (i.e., systolic blood pressure >160 mm Hg or diastolic >95 mm Hg).
16.Patient has a medical history of active liver disease (other than fatty liver) including primary biliary cirrhosis, chronic active hepatitis B or C or patient reports symptomatic gallbladder disease
17.Patient has chronic progressive neuromuscular disorder (such as multiple sclerosis or polymyositis).
18.Patient is HIV positive
19.Patient has a clinically significant hematological disorder (such as aplastic anemia, thrombocytopenia, or a myeloproliferative or myelodysplastic syndrome).
20.Patient has uncontrolled endocrine or metabolic disease known to influence glycemic control or serum lipids/lipoproteins (i.e., secondary causes of hyperlipidemia), such as Cushing syndrome.
21.Patient has untreated hyperthyroidism or is currently under treatment for hyperthyroidism.
22.Patient has a history of malignancy within 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Patients with a history of malignancy >5 years prior to signing informed consent should have no evidence of disease. Patients with a diagnosis or a history of melanoma, leukemia, lymphoma and myeloproliferative disorders of any duration are excluded.
23.Patient has a positive urine pregnancy test.
24.Patient is pregnant or breastfeeding, or is intending to become pregnant or donate eggs within the projected duration of the study and post-study follow-up period.
25.Patient is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug abuse or increased alcohol consumption.
26.Patient has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance such that it is not in the best interest of the patient to participate, or that might confound the results of the study, or interfere with the patient’s participation for the full duration of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Change from baseline A1C at week 16
- percent change from baseline in LDL-C at week 16 |
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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 FPG at week 16
- Percent change from baseline Apo-B, non-HDL-C, VLDL-C, HDL-C, total cholesterol at week 16
- Percent change from baseline TG at week 16 |
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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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Colombia |
| Germany |
| Hong Kong |
| Hungary |
| India |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Turkey |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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