| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 diabetes mellitus (T2DM) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
|
| 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 objective of this study is to obtain safety information regarding patients with T2DM who are at high risk for MACEs while they are receiving treatment with dutogliptin or placebo in addition to a background of antidiabetic therapy. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to understand and provide written informed consent before the initiation of any study-related procedures
2. Male or female outpatients aged 40 to 85 years, inclusive
3. Diagnosis of T2DM for at least 3 months
4. Treatment naive or receiving stable treatment for T2DM (see also exclusion criterion #1)
○ Treatment naive is defined as no treatment with oral hypoglycemic agents, insulin, or other diabetes medication for a minimum of 4 weeks
○ Stable treatment for oral hypoglycemic agents is defined as the same dosage for at least 4 weeks, except for pioglitazone, for which stable dose means the same dose for at least 12 weeks
○ Stable treatment for insulin means that the total number of units of insulin (short, intermediate, and long-acting) has not changed by more than 15% in the 4 weeks preceding Visit 1
5. HbA1c value of 6.5% to 10%, inclusive
6. Fasting Plasma Glucose (FPG) value ≤ 270 mg/dL (15 mmol/L)
7. Stable weight, with no more than a 7% weight gain or loss in the last 3 months (by history)
8. Body mass index (BMI) of 20 to 48 kg/m2, inclusive
9. Having (A) a history of previously demonstrated CV disease OR (B) the presence of multiple risk factors for CV disease
A. History of previously demonstrated CV disease includes any of the following:
1) Any previous clinical CV events: myocardial infarction, unstable angina pectoris with diagnostic ischemic ST-T wave changes on electrocardiogram (ECG), or stroke but not within 2 months of Visit 1 for these clinical events),
OR
2) Positive diagnostic tests: ankle-brachial index < 0.7 or clear myocardial ischemia on exercise stress testing with nuclear perfusion or echocardiographic imaging. (Patients should be enrolled only if no revascularization procedure is being planned in response to the diagnostic test result.),
OR
3) Revascularization procedures: surgical or percutaneous revascularization procedures on one or more sites of coronary, carotid, or peripheral arteries, eg, coronary artery bypass grafting, angioplasty, stent placement; carotid endarterectomy; ilio-femoral or femoral-popliteal bypass grafting, renal artery angioplasty or stenting (if performed due to renal arterial atherosclerotic
disease only). Procedures should not have occurred within 4 weeks of Visit 1 if revascularization was performed electively and not within 2 months if revascularization was performed at the time of presentation with an acute coronary syndrome
B. Presence of multiple risk factors indicative of increased risk for CV disease is defined as follows:
1) Patient’s age ≥ 60 years for males or ≥ 65 years for females, AND
2) Patient has 3 or more of the following risk factors:
- Current treatment with 2 or more antihypertensive medications
(Antihypertensive treatment with a fixed-dose combination product will count as treatment with 2 medications; however, a combination product of 2 diuretics will only count as 1 antihypertensive [eg, hydrochlorothiazide/triamterene])
- eGFR ≥ 35 to < 60 mL/min/1.73 m2 as assessed by the MDRD study equation
- Echocardiographic evidence of left ventricular hypertrophy
- Low-density lipoprotein cholesterol level ≥ 160 mg/dL (4.1 mmol/L), whether or not the patient is receiving treatment with a dyslipidemia medication
- Albuminuria or persistent microalbuminuria (urine albumin-to-creatinine ratio [ACR] > 30 μg/mg) on two or more occasions including on the Visit 1 assessment
- Current cigarette smoking or having quit within the 3 months before screening
Note: If patients have a both (A) a history of previously demonstrated cardiovascular
CV disease and (B) the presence of multiple risk factors, they will be qualified for the
study under the history of previous CV disease group criterion (A); all qualification
criteria, however, will be recorded.
10. If female, must not be pregnant, planning to become pregnant during the course of the study, or lactating. Women of childbearing potential must have a negative serum β-hCG pregnancy test at Visit 1
11. If of childbearing potential (or having partner[s] of childbearing potential), must be willing to use an adequate method of contraception and not become pregnant (or have partner[s] become pregnant) for the duration of the study. Adequate contraceptive measures include, but are not limited to, oral contraceptives (stable use for 2 or more cycles before screening); intrauterine device; Depo-Provera; Norplant; hormonal contraceptive implants; bilateral tubal ligation; vasectomy; condom or diaphragm plus contraceptive sponge, foam, or jelly; and abstinence
12. Willing to return for all clinic visits and complete all study-related procedures, including SMBG
13. Willing to refrain from donating blood during the study and for up to 1 month after completing treatment in the study
14. If receiving any medications for hypertension, including a diuretic, must be at a stable dosage for at least 6 weeks by the time of Visit 2 (randomization) |
|
| E.4 | Principal exclusion criteria |
1. Taken a GLP-1 agonist (eg, exenatide, liraglutide), rosiglitazone, or a DPP-4 inhibitor (eg, Januvia [sitagliptin], Galvus [vildagliptin], Onglyza [saxagliptin], alogliptin) in the past 3 months
2. Type 1 diabetes mellitus, maturity-onset diabetes of the young, or any unusual or rare form of diabetes mellitus
3. Elevated blood glucose resulting from medical treatment or from a concurrent medical condition other than T2DM, eg, hyperadrenocorticalism caused by Cushing syndrome (or Cushing disease), pheochromocytoma, acromegaly, and hyperthyroidism
4. Skin lesions (eg, discoloration, swelling, atrophy, ulceration) or edema states that are considered medically important by the Investigator
5. Current diabetic foot ulcer or a foot ulcer that healed within the month before screening
6. History of epilepsy, not including childhood febrile seizures
7. History of hypoglycemic episode requiring the assistance of a second person to
administer glucose, glucagon, orange juice, etc, during the 6 months before screening
8. History of diabetic ketoacidosis ever, or hyperosmolar, hyperglycemic, nonketotic
syndrome during the 6 months before screening
9. Congestive heart failure class III or IV (according to the New York Heart Association
functional classification system) at screening or during the month before screening
10. History of or risk factors for acute pancreatitis (eg, alcohol abuse, extreme
hypertriglyceridemia [> 1000 mg/dL], multiple small gallstones [unless cholecystectomy subsequently performed]), or risk factors for exacerbation of chronic
pancreatitis
11. Systolic blood pressure (SBP) ≥ 160 mm Hg or < 90 mm Hg and/or diastolic blood
pressure (DBP) ≥ 90 mm Hg or < 50 mm Hg. The measurement can be repeated once
if the initial reading is considered by the Investigator to be inaccurate or
unrepresentative of the patient’s usual blood pressure, and the second value used to meet this criterion
12. Taken systemic glucocorticoids at a dosage > 5 mg of prednisone or equivalent daily within the 2 weeks before screening. See study reference manual for prednisone equivalence of other glucocorticoids
13. History of cancer, other than treated basal cell or squamous cell carcinoma of the
skin, unless the malignancy has been in complete remission for at least 3 years.
(Complete remission is defined as the disappearance of all signs of cancer in response to treatment)
14. History of infection with or history of serologic evidence of previous infection with
human immunodeficiency virus, hepatitis B, or hepatitis C virus
15. History of alcohol or cocaine abuse in the past 2 years or current use of other illicit drugs that, in the judgment of the PI, would negatively affect the patient’s ability to participate in the study
16. Total bilirubin level above the upper limit of normal (ULN), unless associated with an elevated indirect total bilirubin typical of Gilbert syndrome; aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN; or alkaline
phosphatase > 1.5 × ULN
17. eGFR as assessed by the MDRD study equation < 35 mL/min/1.73 m2
18. Treatment with any IP or participation in any investigational study within 30 days or 5 half-lives of the IP before screening
19. Randomized in a previous investigational study of dutogliptin
20. Employee or relative of an employee of the investigational study center or of anyone associated with the conduct of the study
21. History of hypersensitivity reaction to dutogliptin or other DPP-4 inhibitors
22. Any condition, disease, disorder, or clinically relevant laboratory abnormality that, in the opinion of the PI, would jeopardize the patient’s appropriate participation in this study or obscure the effects of treatment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the incidence rate of major adverse cardiovascular events occurring while on IMP treatment or during the 30 days following the last dose of IMP. |
|
| 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 | Yes |
| 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) | 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 | 8 |
| 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 | 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 |
|
| 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
|
Last patient last visit:
End of study (EOS) will be after the required number of blinded, adjudicated MACEs have been accumulated. Patients still receiving IMP treatment will have a single visit for End of Treatment (EOT) and EOS. Patients who have previously reached EOT and still being followed will have a telephone check or visit for EOS. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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