A Clinical trial to evaluate the safety and efficacy of dutogliptin in patients with type 2 diabetes mellitus (T2DM) who are receiving background therapy with pioglitazone
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF DUTOGLIPTIN IN PATIENTS WITH TYPE 2 DIABETES MELLITUS ON BACKGROUND TREATMENT WITH PIOGLITAZONE
Inclusion and exclusion criteria for participant selection, including age and sex.
Age 18 to 85
To be eligible to participate in the study, patients must meet the following criteria:
At the Screening Visit (Visit 1):
1. Be able to understand and provide written informed consent before participating in any study-related procedures
2. Be male or female outpatients 18 to 85 years of age, inclusive
3. Be willing to return for all clinic visits and complete all study-related procedures, including self-monitoring of blood glucose
4. Have a body mass index of 20 to 48 kg/m2
5. Have stable weight, with no more than a 7% gain or loss in the previous 3 months
6. Be diagnosed with T2DM at least 3 months before the screening visit ( visit1).Verification of diagnosis should be made by obtaining documentation or written confirmation from the physician treating the patients?s diabetes.
7. If taking a medication(s) for hypertension (including a diuretic), be taking a stable dose for at least 4 weeks before study start
8. If taking a medication(s) other than an antidiabetic that might affect blood glucose level, be taking a stable dose for at least 4 weeks before study start
9. Have a thyroid-stimulating hormone level on laboratory testing at screening that is within the reference range provided by the central laboratory. If the patient is taking thyroid hormone, the dose must have been stable for at least 6 weeks before study start
10. Be willing to discontinue, for the duration of the study, all herbal medication taken for the treatment of diabetes
11. Have a fasting serum C-peptide > 0.26 nmol/L (> 0.8 ng/mL; > 260 pmol/L) on laboratory testing at screening
12. Female patients must not be pregnant, not planning to become pregnant during the course of the study, and not lactating. Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test on laboratory testing at screening
13. 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 methods include, but are not limited to, oral contraceptives (stable use for 2 or more cycles before screening); intrauterine devices; Depo Provera; Norplant System implants; bilateral tubal ligation; vasectomy; condom or diaphragm plus either contraceptive sponge, foam, or jelly; and abstinence.
14. Have an HbA1c level ≥ 7.0% and ≤ 10.0%
15. Be drug-treatment naïve, or treated with a stable dose of pioglitazone or rosiglitazone, or treated with a stable dose of any other oral hypoglycemic agent (OHA) as monotherapy at the time of the Screening Visit (Visit 1):
○ Drug-treatment naïve means never having received an OHA or parenteral medication (insulin or GLP-1 analogue) or, if having received an OHA or parenteral medication, been off said OHA or parenteral medication for a minimum of 6 weeks (12 weeks for pioglitazone or rosiglitazone) before Visit 1
â—‹ Stable dose of pioglitazone or rosiglitazone means a minimum of 12 weeks
â—‹ Stable dose of any other OHA as monotherapy means a minimum of 6 weeks
16. Be willing to refrain from donating blood during the study and up to 1 month after completing the study
Between Visits 1 and 2:
17. Patients who switch to pioglitazone or whose dosage of pioglitazone is increased during the screening period must have an FPG level ≤ 270 mg/dL (15 mmol/L) before Visit 2 (see Appendix I for information on switch algorithm and dose adjustment during the screening period)
At Visit 2:
18. Have been on a stable dosage of pioglitazone, 30 to 45 mg/d, as monotherapy for 8 or 12 weeks, depending on OHA therapy leading up to Visit 1 (Screening) (see Appendix I for information on switch algorithm and dose adjustment during the screening period)
At the Randomization Visit (Visit 4):
19. Have an HbA1c level ≥ 7.0% and ≤ 10.0% (measured at Visit 3)
20. Have an FPG level ≤ 270 mg/dL (15 mmol/L) (measured at Visit 3). The test can be repeated once if the initial result is felt to be inaccurate or not representative of the patient?s usual value
ExclusionCriteria
Details
Patients who meet any of the following criteria will not be eligible to participate in the study:
1. Currently taking more than one OHA
2. Have been treated as an outpatient with insulin or a GLP-1 analogue,or a DPP4 inhibitor within 6 weeks of the Screening Visit (Visit 1)3. Have type 1 diabetes mellitus, maturity-onset diabetes of the young, insulin requiring T2DM, other unusual or rare forms of diabetes mellitus, or history of diabetic ketoacidosis
4. Have elevated blood glucose levels owing to medical treatment or to a concurrent medical condition other than T2DM (eg, hyperadrenocorticalism due to Cushing syndrome [or Cushing disease], pheochromocytoma, acromegaly, hyperthyroidism, other endocrine disorder that can raise blood glucose)
5. Have skin lesions (eg, discoloration, swelling, atrophy, ulceration), edema states, or diabetic foot ulcers considered medically important by the Investigator
6. Have a history of epilepsy, not including childhood febrile seizures
7. Have a history of hypoglycemic episode requiring glucose, glucagon, orange juice, etc administered by a second person during the 6 months before the Screening Visit (Visit 1)
8. Have a history of hyperosmolar, hyperglycemic, or nonketotic syndrome during the 6 months before the Screening Visit (Visit 1)
9. Have had a stroke, myocardial infarction, symptomatic coronary artery disease, angina, or arrhythmia within 4 weeks before the Screening Visit (Visit 1) or a history of class III or class IV congestive heart failure (according to the New York Heart Association functional classification system)
10. Have a history of or risk factors for acute pancreatitis (eg, alcohol abuse, extreme hypertriglyceridemia [> 1000 mg/dL], multiple small gallstones) or exacerbation of chronic pancreatitis
11. Have a systolic blood pressure (SBP) ≥ 160 mm Hg or < 90 mm Hg and/or diastolic blood pressure (DBP) ≥ 100 mm Hg or < 50 mm Hg at the Screening Visit (Visit 1). The measurement at the Screening Visit (Visit 1) can be repeated if the initial reading is felt to be inaccurate or unrepresentative of the patient?s usual blood pressure value
12. Have had gastrointestinal surgery for obesity (including bypass, gastroplasty, and banding procedures) within 1 year before the Screening Visit (Visit 1) or have plans to have such surgery or procedures for the removal of excess fatty tissue (eg, liposuction, breast reduction) during the course of the study
13. Have started a weight-loss regimen within 4 weeks of the Screening Visit (Visit 1), either on one?s own or by participating in a commercial behavior modification/diet program (eg, Jenny Craig, Weight Watchers) or by taking a medication for weight reduction (eg, phentermine, sibutramine, Xenical/Alli [orlistat])
14. Currently taking an antipsychotic medication (except prochlorperazine as needed for nausea), have taken systemic glucocorticoids at a dose > 5 mg of prednisone or equivalent daily within the 2 weeks before the Screening Visit (Visit 1), or currently taking products intended to stimulate appetite (eg, megestrol acetate [Megace]). (See the Study Reference Manual for prednisone equivalence of other glucocorticoids)
15. Have a history of cancer other than treated basal-cell or squamous-cell carcinoma of the skin. (Note: Patients with a history of cancer are allowed to participate provided that the malignancy has been in complete remission for at least 5 years before the Screening Visit [Visit 1]. Complete remission is defined as the disappearance of all signs of cancer in response to treatment)
16. Have been infected with or have serologic evidence of previous infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus (as determined by the central laboratory)
17. Have a history of alcohol or substance abuse in the prior 2 years or an eating disorder diagnosed in the prior 5 years
18. Have total bilirubin concentration above the upper limit of normal (ULN) (unless associated with an elevated indirect bilirubin concentration typical of Gilbert syndrome), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times the ULN, or alkaline phosphatase > 1.5 times the ULN from the Screening Visit (Visit 1) clinical laboratory results
19. Have hemoglobin level < 11 g/dL (< 110 g/L) from the Screening Visit (Visit 1) clinical laboratory results
20. Have an estimated gomerular filteration rate (GFR) <50mL/min/1.73m2 per the Modification of Diet in Renal Disease(MDRD) equation at screening visit ( Visit1),as provided by the central laboratory.
21. Have received treatment with any investigational product or participated in any investigational study within 30 days or 5 half-lives of the investigational product, whichever is longer, before the Screening Visit (Visit 1)
22. Have been randomized in a previous investigational study of dutogliptin
23. Be an employee or a relative of an employee of the study center
24. Have a history of hypersensitivity reaction to pioglitazone, rosiglitazone, glimepiride, or DPP4 inhibitors
25. Have any condition, disease, disorder, or clinically significant 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
Approximately 152 patients will be randomized from 19 sites from India. One site is yet to be selected. The anticipated first patient enrollment from India is 15 Feb 2010 This will be a randomized, double-blind, placebo-controlled, multicenter, parallel-group study with a screening period of up to 12-weeks, a 4-week single-blind placebo run-in period, and a 26-week double-blind treatment period. Patients will be screened, complete the 4-week single-blind placebo run-in period, and then be randomized to receive either dutogliptin 400 mg once daily or placebo (1:1 ratio). During the study, all patients will be receiving background therapy with pioglitazone. Dutogliptin 400 mg or placebo will be administered orally once daily with or without food. Dietary and exercise advice will be provided to the patients. Glucose monitoring at home will be required; results will be used for safety monitoring but not for assessing efficacy. Efficacy analyses will be performed based on the Intent-to-Treat Population. The primary efficacy parameter is the change from baseline in HbA1c at Visit 8 (last observation carried forward [LOCF]). Between?treatment group differences for this parameter will be analyzed using an analysis-of-covariance (ANCOVA) model with treatment group and country as factors and baseline HbA1c as a covariate.