Safety and Efficacy Study of Metaglidasen in Type 2 Diabetes in Patients Suboptimally Controlled on Insulin

Inclusion Criteria:

• Type 2 diabetes (as described by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus24) treated with insulin alone (a stable dose of long and/or intermediate-acting insulin or pre-mixed insulin e.g., "70/30") ≥ 30 units/day for at least 3 months, but poorly controlled on their existing therapy
• Or, patients treated with insulin (as above) in combination with non-TZD hypoglycemic agents (e.g., a sulfonylurea, metformin, acrabose, or Byetta for at least 3 months, but poorly controlled on their existing therapy
• Or, patients treated with fixed doses of short-acting insulin in combination with intermediate-acting insulin for at least 3 months, but poorly controlled on their existing therapy
• Patients in last 2 categories must be willing to discontinue the use of OHA and/or short-acting insulin (or change to pre-mixed insulin) for at least 26 weeks.
• Male or female, 18-75 years of age
• Provide informed consent and agree to comply with study requirements
• Current monotherapy insulin dose regimen ≥ 30 units/day (stable for 8-week Run-in/stabilization Period); or patients who need insulin dose adjustment must have a stabilized dose ≥ 30 units/day. Patients must not have taken TZDs within 5 months of screening
• All female patients must be surgically sterile, post-menopausal (at least 40 years of age with no history of menses for at least 2 years) or agree to use adequate contraception(s) that must include a barrier method (other methods may include oral contraceptives, double barrier methods, intra-uterine devices, or abstinence). Depo contraceptives are excluded
• Female patients must not be pregnant or lactating
• BMI 26-44 kg/m2
• Hemoglobin A1c must be ≥7.5%, ≤11.5% at both Screening and Visit 4
• Patients must have a FPG ≤ 220 mg/dl
• Patients must have liver function tests ≤ 2X the upper limits of normal for AST, ALT, and bilirubin, and ≤ 2.5X the upper limits of normal for ALP and GGT
• Patients must have serum creatinine ≤ 1.8 mg/dl for males and ≤ 1.5 mg/dl for females and BUN ≤ 40 mg/dl
• Fecal occult blood test must be negative
• All other clinical laboratory parameters must be within normal limits or considered not clinically significant for participation in this study, including: hematology, coagulation, other serum chemistry, and other urinalysis parameters
• TSH must be ≤ 3x ULN and patient clinically euthyroid in opinion of investigator. If TSH is > ULN but ≤ 3x ULN, and patient is clinically euthyroid, FT4 should be drawn and must be WNL
• Electrocardiogram (ECG) must be normal, or considered not clinically significant, for participation in this study
• Patients must have a blood pressure ≤ 160/90 mm/hg including hypertensive patients controlled with medication

Exclusion Criteria:

Patients will be excluded from study participation if any of the following applies:

• History of diabetes secondary to pancreatitis or pancreatectomy
• Requirement for short-acting insulin during the study
• Weight loss > 10 pounds in the three months prior to study
• History of TZD use (Actos or Avandia) within 5 months of Screening Visit
• History of TZD discontinuation due to side effect or lack of efficacy
• Prior history of endoscopically or radiographically documented peptic ulcer disease within last 5 years (unless patient had documented H. pylori infection with subsequent treatment and no recurrence)
• Prior history of GI bleeding within last 5 years (except for hemorrhoids or perianal disease)
• Known infection with the human immunodeficiency virus (HIV) or history of viral hepatitis type B or C
• History of congestive heart failure within last 5 years (NYHA Class III-IV)
• History of significant pulmonary disease, myocardial infarction, cerebrovascular accident, or nephrotic syndrome within last 1 year
• Elevated creatine phosphokinase (> 2X the upper limits of normal)
• Malignancy within the last 5 years (except resected basal cell carcinoma)
• Ongoing active infection, as evidenced by symptoms such as temperature > 38.5° C and/or clinically significant elevation in WBC count (i.e., not asymptomatic colonization)
• Change in treatment with lipid-lowering agent after screening visit
• Current or expected requirement for anticoagulant therapy [except for low- dose (≤ 325 mg/d) aspirin]
• Current or expected treatment with phenytoin
• Current or anticipated treatment with non-steroidal anti-inflammatory drugs (i.e., naproxen, ibuprofen, Vioxx, Celebrex, indomethacin, etc.). However, patients may take aspirin < 325 mg/day for cardiovascular prophylaxis
• Known hypersensitivity to NSAIDs
• Treatment with any other investigational therapy within the 30 days prior to Screening Visit
• History of illicit drug or alcohol abuse within last 1 year
• Current or expected treatment with systemic corticosteroids (except topical, ophthalmic, intra-articular, or inhaled at a dose < 1600 μg/day)
• Any other condition that compromises the ability of the patient to provide informed consent or to comply with the objectives and procedures of this protocol, as judged by the investigator.