Effect of Januvia on Beta Cell Function in Patients With Diabetes Mellitus

Phase III Study on the Effect of Sitagliptin on Maximal Beta Cell Stimulation

The study is designed to investigate the effect of 18 weeks treatment with Sitagliptin 100 mg/day on the insulin secretion capacity of beta cells.

Patients who meet the study enrollment criteria will undergo 2 experiments (see description below); a graded hyperglycemic technique and a meal test, prior to randomization and after a 12-wk double-blind study period. The treatment effect will shed light on the magnitude of the beta cell capacity to increase its mass and function.

Study design and duration: This will be an Israeli three center study. Study drug: Sitagliptin 100 mg. The study will be a double blind, randomized two arms parallel group study. The duration of the study will be up to 18 weeks (with 8 visits) for each patient. This will include: a screening period of up to 4 weeks (Visit 1 to visit 2), a 2 week single blind, placebo run-in period (visit 2 to visit 4), and a 12 week placebo controlled, double blind treatment period (visit 4 to visit 8).

Patients with T2DM who have not been treated with an AHA, or who are on AHA monotherapy or low dose oral combination therapy (low dose defined as ≤50% of the maximum labeled dose of each agent), may participate if they meet all enrollment criteria. Patients eligible to be randomized will have a HbA1c ³6.5% and £10% .

Patients who meet the study enrollment criteria will undergo 2 experiments (see description below); a graded hyperglycemic technique and a meal test, prior to randomization (Visit 3 and 4). These experiments will be will be completed after a 12-hour overnight fast. The 2 experiments will be repeated at the conclusion of the 12-wk double-blind study period (Visits 7 and 8).

Efficacy measurements: (1) Glycemic control : FPG, HbA1c, β-cell Function Parameters(Φs, Φd, Φb, Φ, Φob, T), Insulin Secretion Rate (determined from C-peptide deconvolution), 1st and 2nd phase insulin secretion, Insulin response after arginine injection, Insulin sensitivity index, glucose, insulin, C-peptide total and incremental area under the curve.

Inclusion criteria:

• Patient has T2DM diagnosed within the past 5 years

• Patient is >18 and <65 years of age

• Patient is not pregnant, breast feeding and unlikely to conceive

• Patient understands the study procedures, and agrees to participate in the study by giving written informed consent

• Patient meets one of the following criteria:

  1. Patient is currently not on an AHA and has a Visit 1 HbA1c ≥6.5% and ≤10%. OR
  2. Patient is currently on AHA monotherapy or low dose (i.e. ≤50% maximum labeled dose of each agent) oral combination therapy and has a Screening/Visit 1 HbA1c ≥6.5% and ≤9.5%.

• At visit 2, patient has a HbA1c of ≥6.5% and ≤10%

Exclusion Criteria:

• Patient has type 1 diabetes mellitus
• Patient required insulin therapy within 12 weeks of Visit 1. Note: patients who received a brief period of insulin treatment (e.g., several days during a hospitalization) and who are no longer requiring insulin treatment may participate
• Patient is currently or within 12 weeks of Visit 1 taking a TZD agent as monotherapy or in combination
• Patient is currently or within 12 weeks of Visit 1 taking Byetta.
• Patient is on corticosteroids
• Patient has a history of malignancy ≤5 years prior to signing informed consent, or >5 years without documentation of remission/cure Exception: Adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Melanoma, leukemia, lymphoma and myeloproliferative disorders of any duration are excluded -Patient is on chemotherapy
• Patient received another investigational drug in the last 12 weeks.
• Patients with concomitant liver disease and or AST > 3 fold upper limit of normal
• Patients with kidney disease or CR>1.4 mg/dl
• Patients with anemia ( Hb <11 gr in male 10 gr in female)
• Patient with active vascular disease (coronary, peripheral or cerebrovascular)
• Patient has poorly controlled hypertension defined as systolic blood pressure >160 mm Hg or diastolic >95 mm Hg
• Proliferative retinopathy