| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Type 2 Diabetes Mellitus (T2DM) |
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| 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 |
| The primary objective of this dose-ranging study is to evaluate the effects of JNJ-28431754 as compared with placebo on the change in hemoglobin A1c (A1C) from baseline to Week 12 in subjects with T2DM. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to compare the effects of JNJ-28431754 relative to placebo on:
- change in FPG from baseline through Week 12
- proportion of subjects with A1C <6.5% and <7.0% at Week 12
- change in 7-point self monitored blood glucose (SMBG) profiles from baseline through Week 12
- proportion of subjects with symptomatic hypoglycemia and the rate of symptomatic hypoglycemia throughout the study
- PK exposure, to explore exposure-response relationships, and to develop a population PK model
- safety and tolerability compared with placebo
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria:
1. Man or woman between 18 and 65 years of age, inclusive
2. Diagnosis of T2DM for at least 3 months before Week -3
3. Hemoglobib A1C levels must be greater than or equal to 7% and less than or equal to 10.5% eitherat the optional prescreening visit or at the screening visit
4. Subjects must be on a stable daily metformin dose (equal to of greater than 1,500mg/day) for the 3 months immediately before Week -3
5. Body mass index (BMI) 25to 45 kg/m2, except those of Asian descent who must have a BMI 24 to 45 kg/m2, at Week -3
6. Must have a stable weight, i.e., increasing or decreasing not more than 5% in the 3 months before week -3
7. Serum creatinine less than or equal to 1.5 mg/dL for men and less than or equal to 1.4 mg/dL for women at Week -3
8. ALT and AST levels within 2 times the upper limit of normal and bilirubin within the upper limit of normal range at Week -3 unless in the opinion of the investigator and agreed upon by the medical monitor that the findings are consistent with Gilbert's disease
9. Fasting plasma glucose should be less than 270 mg/dL (14,9 mmol/L) at Week -3. In cases where there is doubt concerning fasting conditions, a one-time repeat of the fasting plasma glucose is allowed (fasting is defined as no caloric intake for at least 8 hours before the test)
10. Healthy on the basis of clinical laboratory tests performed at screening other than those clinical tests with specific limits indicated in the exclusion criteria. If the results of the serum chemistry panel including liver enzymes, other specific tests, hematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal would not preclude the subject's safe participation in the study. This determination must be recorded in the subject's source documents and initialed by the investigator.
11. Women must be:
– postmenopausal as defined as amenorrhea for at least 6 months before screening and a serum follicle stimulating hormone (FSH) level consistent with postmenopausal status as per the central reference laboratory at Week -3, or
– surgically sterile, (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy)
– abstinent (at the discretion of the investigator),
– or if sexually active, be practicing an effective method of birth control such as hormonal prescription oral contraceptives containing no more than 25 micro gram ethynylestradiol, progesterone implants or injections, intrauterine device (IUD), or male partner with a vasectomy. A double-barrier method such as condoms, diaphragms, or cervical caps with spermicidal foam, cream, or gel may be used as a method of birth control where country-specific regulations permit. Women of the childbearing potential must have a negative serum beta human chrionic gonsdotropin pregnancy test at Week - 3 and a negative urine pregnancy test at baseline before the first dose of study drug is received.
12. It is recommended that men, who have female partners of childbearing potential, use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug.
13. Willing to adhere to the prohibitions and restrictions specified in this protocol
14. Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
15. To participate in the optional pharmacogenomic component of this study, subjects (or their legally acceptable representative) must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit). Refusal to consent for this component does not exclude a subject from participation in the clinical study.
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| E.4 | Principal exclusion criteria |
Subjects must not meet the following criteria:
1. Prior exposure or known contraindication or known hypersensitivity to JNJ 28431754 or its excipients
2. Known contraindication or suspected hypersensitivity to sitagliptin or metformin
3. History of diabetic ketoacidosis, type 1 diabetes mellitus, pancreas or b cell transplantation
4. Active proliferative diabetic retinopathy, as defined by the application of focal or panretinal photocoagulation or vitrectomy, in the 6 months before Week -3, or any other unstable (rapidly progressing) retinopathy that may require surgical treatment (including laser photocoagulation) during the study
5. A history of hereditary glucose-galactose malabsorption or primary renal glucosuria
6. Fasting triglyceride >6.77 mmol/L (600 mg/dL) at Week -3. A one-time repeat of the fasting triglyceride is allowed (fasting is defined as no caloric intake for at least 8 hours before the test)
7. History of human immunodeficiency virus (HIV)
8. History of clinically-relevant liver disease including hepatitis B or hepatitis C
9. History of significant cardiovascular disease within 6 months before Week -3, including a history of myocardial infarction, cerebrovascular accident, or unstable angina, or percutaneous coronary intervention (PCI) within 3 months Week - 3
10. History or evidence of a clinically-significant cardiac conduction abnormality that in the opinion of the investigator would preclude safe participation in this study
11.History of cardiovascular disability (functional Class III or IV) according to the New York Heart Association Classification of Cardiac Disease
12. An average from 3 seated blood pressure readings of diastolic blood pressure greater than or equal to 100 mg/Hg or systolic blood pressure greater than or equal to 160 mm/Hg at Week -3
13. Thyroid stimulating hormone (TSH) >10 mIU/L at screening. Subjects on medication for hypothyroidism must be on a stable dose for at least 3 months before Week -3 with no changes anticipated for the duration of the study
14. Active duodenal or gastric ulcer within the past year before Week -3 requiring medical therapy or a history of complicated gastric or duodenal ulcer (perforation, obstruction, or bleed)
15. History of inflammatory bowel disease, gluten or nongluten induced enteropathy, or other significant malabsorptive syndromes
16. Malignancy or a history of a malignancy within 5 years before the start of the screening period, other than basal cell carcinomas of the skin or in situ cervical carcinoma
17. Pregnant or lactating, or women who plan to become pregnant during the study
18. History of seizures or significant psychiatric disorders including schizophrenia
19. History of cutaneous hypersensitivity to sunlight or artificial source of intense light, especially ultraviolet light
20. History of nephrolithiasis
21. History of UTI, or VVC within 3 months before Week -3
22. History of chronic suppressive treatment for VVC within the last 12 months before Week -3
23. Current or ongoing use of pads/pantyliners for urinary incontinence
24. History of clinically-significant eating disorders (anorexia nervosa, bulimia, or binge-eating disorder)
25. A significant change in smoking habits within 3 months before Week -3
26. History of drug or alcohol abuse within the previous 2 years before Week - 3
27. Alcohol consumption exceeding 4 units per day for men or 3 units per day for women, 1 unit is defined as 330 mL beer or 100 mL wine or 30 mL spirits or equivalent
28. Treatment with prescription weight loss medications or over the counter orlistat within 3 months of Week -3
29. Use of cannabinoids in 3 months before Week -3
30. Use of antiepileptic drugs, systemic corticosteroids, antipychotic drugs, antidiabetic agents within 3 months before Week -3
31. Received an experimental drug or used an experimental medical device within 3 months before Week -3
32. Any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pharmacokinetics, Pharmacodynamics and safety evaluations. |
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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 | Yes |
| 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 |
| Dose-ranging, Tolerability |
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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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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.8.3 |
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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 | Information not present in EudraCT |
| 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 |
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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 | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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