Multiple Dose Study Of PF-04937319 In Patients With Type 2 Diabetes

• Safety Endpoints: Safety and tolerability of PF 04937319 will be assessed by physical examinations, adverse event and hypoglycemia monitoring, 12 lead ECGs, vital sign, and clinical safety laboratory measurements. [ Time Frame: 5 months ] [ Designated as safety issue: Yes ]
• Single Dose PK endpoints: Cmax, Tmax, and AUC(0-Tau) [ Time Frame: 5 months ] [ Designated as safety issue: No ]
• Day 6 PK Endpoints: Cmax, Tmax, and AUC(0-8) [ Time Frame: 5 months ] [ Designated as safety issue: No ]
• Multiple Dose PK Endpoints: Cmax(ss), Tmax(ss), AUC(0-Tau,ss), AUC(0-8), AUC(0-last), half life, Cmin(ss), Cav(ss), Ae%, CL/F, Vz/F; accumulation ratios AUC(0-Tau,ss)/AUC(0-Tau,sd) and Cmax(ss)/Cmax(sd), as the data permit. [ Time Frame: 5 months ] [ Designated as safety issue: No ]
• PD Endpoint: glucose excursion (change from Day -1 baseline) in response to a liquid meal test (MMTT) on Days 1 and 14. [ Time Frame: 5 months ] [ Designated as safety issue: No ]

• Insulin and C peptide (changes from Day -1 baseline) during an MMTT on Days 1 and 14. [ Time Frame: 5 months ] [ Designated as safety issue: No ]
• Average daily glucose (change from Day -1 baseline) on Days 1, 6, and 14. [ Time Frame: 5 months ] [ Designated as safety issue: No ]
• Fasting plasma glucose (change from Day 1 pre dose baseline) on Days 1 through 15. [ Time Frame: 5 months ] [ Designated as safety issue: No ]
• Lipids (change from baseline), including: TG, TC, HDL cholesterol, and LDL cholesterol, at times specified in the SOA. [ Time Frame: 5 months ] [ Designated as safety issue: Yes ]
• Lactate (change from baseline), at times specified in the SOA. [ Time Frame: 5 months ] [ Designated as safety issue: Yes ]

The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-04937319 following multiple (14 days) escalating oral doses in patients with type 2 diabetes.

• Diabetes Mellitus, Type 2
• NIDDM

• Drug: PF-04937319
  Subjects will be dosed with PF-04937319 for 14 days. The doses planned are 10, 30, 100 and 300 mg QD. All doses will be administered as tablets (10 and 100 mg strengths). In each Cohort, 9 patients will receive PF 04937319 and 3 will receive placebo. An additional cohort of 12 patients (9 active, 3 placebo) may be performed to explore a QD or BID dose. The dose for this additional cohort could be a dose already studied or a new dose that is within the exposure stopping criteria.
• Drug: Placebo
  Placebo to match PF-04937319 will be provided. Subjects will be dosed for 14 days. In each cohort 9 subjects will receive PF-04937319 and 3 will receive placebo.

• Experimental: PF-04937319
  Intervention: Drug: PF-04937319
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Patients with type 2 diabetes mellitus who are taking metformin only.
• Treatment should be stable, where this is defined as no change in the treatment, including dose, over the past 2 months. Regimens may include once daily and twice daily dosing only.
• Male and/or female patients (females will be women of non childbearing potential)
• Body Mass Index (BMI) of 18.5 to 45.0 kg/m2; and a total body weight >50 kg (110 lbs).
• HbA1c between 7.0% and 10.0%.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Patients who have chronic conditions other than T2DM (for example, hypercholesterolemia or hypertension) but are controlled by either diet or stable (for the last 2 months) doses of medications may be included as well (for example, a subject with hypercholesterolemia on appropriate treatment is eligible).
• Evidence or history of diabetic complications with significant end organ damage, eg, proliferative retinopathy and/or macular edema, creatinine clearance less than 60 mL/min
• Any condition possibly affecting drug absorption (eg, gastrectomy)
• History of stroke or transient ischemic attack or myocardial infarction within the past 6 months
• History of coronary artery bypass graft or stent implantation.
• Clinically significant peripheral vascular disease (eg, manifested by claudication).
• Any history or clinical evidence of congestive heart failure, NYHA Classes II to IV.
• One or more self reported significant/severe/requiring treatment episodes of hypoglycemia within the last 3 months, or two or more self reported significant/severe/requiring treatment episodes of hypoglycaemia within the last 6 months.
• Current history of angina/unstable angina.
• Milk or soy allergy