Study In People With Type 2 Diabetes

A Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel-Group, Placebo-Controlled, Study To Evaluate Efficacy, Safety And Tolerability Of Oral GW677954 Capsules (2.5, 5, 10, 15 And 20 Mg Once A Day) As A Monotherapy (Diet and/or exercise treated) Or As An Add-On To Metformin For 16 Weeks Duration In Subjects With Type 2 Diabetes Mellitus

Inclusion criteria

• Subjects with T2DM as defined by the criteria of the ADA and/or recognized by WHO Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [American Diabetes Association, 2004], for at least 3 months preceding screening (see Section 15.3, Appendix 3:, "Diagnosis and Classification of Diabetes Mellitus").
• To be eligible for Randomization into the trial, a subject must satisfy all of the following glycemic criteria:

• HbA1c level via central laboratory at the pre-screening visit
• If HbA1c ≥ 8.0% but ≤ 10.0%: subject may proceed to Randomization;
• If HbA1c ≥ 7.8% but < 8.0%, subject not eligible to proceed, but may be retested once to establish eligibility (or lack thereof). If HbA1c level ≥ 8.0% upon retest, subject is eligible to proceed; otherwise they should be withdrawn.
• If HbA1c < 7.8%, subject not eligible to proceed (no retest allowed).
• FPG level via central laboratory at the pre-screening visit must be < 270 mg/dL (15.0 mmol/L). FPG may be retested within a week to confirm eligibility (or lack thereof).
• Concurrent T2DM therapy:

• Diet and/or exercise treated: Must not have taken antidiabetic medication for at least 2 months prior to the pre-screening visit, OR
• Metformin monotherapy: Subjects entering the study on metformin must be on the same dose, formulation and regimen of metformin for at least 2 months prior to the pre-screening visit, AND
• TZDs and insulin are excluded in the 3 months prior to the Screening visit for all subjects.
• Males and females who are 18 to 70 years of age inclusive at the time of Screening.
• If female, eligible to enter and participate in this study:

• If of non-childbearing potential (i.e., physiologically incapable of becoming pregnant (tubal ligation), including any female who is post-menopausal [>1 year without menstrual period]); or,
• If of child-bearing potential, has a negative pregnancy test at Screening (serum), at Randomization (urine) and:

• Has a male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject, or
• Uses double-barrier methods of contraception; condoms with the use of caps (with spermicide) and IUDs are acceptable, or
• Uses hormonal contraceptives (oral, depots, patches etc) with double- barrier methods of contraception as outlined above, or
• Abstains from sexual intercourse, or
• Is with a same sex partner and does not participate in bisexual activities where there is any risk of pregnancy.
• Body Mass Index (BMI): ≥25 and ≤40 kg/m² and weigh at least 50 kg at Screening.
• If subject is a smoker, must be able to abstain while in clinic at each visit.
• Subject has given full written informed consent prior to any study related procedures are performed.

Exclusion criteria

Exclusion criteria

• Metabolic Disease including:

• Diagnosis of Type 1 diabetes mellitus
• Uncorrected thyroid dysfunction. (NOTE: subjects with hypothyroidism on a stable dose of thyroid replacement therapy for at least 1 month prior to Screening, and who have a screening thyroid stimulating hormone (TSH) within the upper limit of normal may participate).
• Significant weight gain or loss (defined as > 5% of total body weight) within the 3 months prior to Screening.
• Previous use of insulin for treatment of hyperglycemia within 3 months of Screening.
• History of recent clinically significant cardiovascular disease including:

• History or ECG evidence of prior myocardial infarction within 6 months prior to Screening.
• Current unstable angina or history of unstable angina in past 6 months.
• Coronary revascularization including percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) surgery that is either planned or occurred in the 6 months prior to Screening.
• Clinically significant arrhythmia or valvular heart disease.
• Congestive heart failure (CHF) with New York Heart Association (NYHA) Class II-IV symptoms (see Section 15.4, Appendix 4).
• Blood pressure > 160/100 mmHg or resting heart rate > 100 bpm. Note: subjects using antihypertensives [e.g., beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, calcium channel blockers and diuretics] must be on stable doses during the 30 days prior to Screening and during the trial.
• Has a QTc interval (Bazett's) > 440 msec in males and > 450 msec in females at Screening.
• Clinically significant ECG abnormalities which, in the opinion of the Investigator, may affect the interpretation of safety data, or which otherwise, contraindicates participation in a clinical trial with a new chemical entity.
• History of chronic pancreatitis.
• Familial hypercholesterolemia.
• TGs ≥800 mg/dL (8.96 mmol/L) at Screening.
• Serum creatinine at screening > 1.4 mg/dL (124 µmol/L) for women, or > 1.5 mg/dL (133 µmol/L) for men.
• Clinically significant anemia defined by hemoglobin concentrations <12.0 g/dL or < 120.0 g/L for males and < 11.0 g/dL or < 110.0 g/L for females.
• History of significant co-morbid diseases (e.g., cholelithiasis, gastrointestinal disease, etc.) that would preclude participation in the study.
• Documented history of hepato-biliary disease including a history of, or positive laboratory results for hepatitis (hepatitis B surface antigen and/or hepatitis C antibody) at Screening, and/or clinically significant hepatic enzyme elevation including:

•Any one of the following enzymes greater than 2.5 times the upper limit of normal (ULN) value at Screening:

• Alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)
• Alkaline phosphatase (ALP)
• Total or direct bilirubin > 1.5 times the ULN at Screening, unless consistent with presumed or diagnosed Gilbert's disease.
• History of metabolic acidosis, rhabdomyolysis, myalgia, myositis or myopathy after taking statins or fibrates.
• Any subject who has withdrawn therapy due to AEs after taking a PPARγ or a PPARα/γ dual agonist, either marketed (e.g., troglitazone, rosiglitazone or pioglitazone) or under current or previous clinical investigation.
• Signs or symptoms of myositis at Screening (or upon 1 repeat test), and/or creatinine phosphokinase (CPK)≥3.0 times ULN
• Is currently taking or has taken any of the following medications in the 3 months prior to the pre-screening visit:

• Anti-obesity agents (including fat absorption blocking agents)
• St. John's Wort
• Warfarin and other oral anticoagulants (excluding aspirin and non-steroidal anti-inflammatory drugs)
• Digoxin
• Oral or injectable corticosteroids (inhaled and intranasal steroids are acceptable)
• Use of antidiabetic agents (other than metformin) in the 2 months prior to the pre-screening visit.
• Use of TZDs in the 3 months prior to the pre-screening visit.
• Methotrexate, cyclosporine or monoclonal antibodies (e.g., alemtuzumab, gemtuzumab ozogamicin, rituximab, trastuzumab, ibritumomab, tiuxetan) for rheumatoid arthritis or psoriasis.
• Atypical antipsychotic medications [e.g., aripiprazole (Abilify), risperidone (Risperdal), clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon)].
• Antiretroviral drugs
• Use of lipid lowering agents within 3 months prior to the pre-screening visit. This includes statins, fibrates, ezetimibe (Zetia), niacin and bile acid sequestrants.
• Monoamine oxidase inhibitors
• History of cancer except for the following:

• Basal cell carcinoma or superficial squamous cell carcinoma treated by local excision.
• Cervical cancer in situ treated definitively more than 6 months prior to screening.
• Women who are lactating, pregnant, or planning to become pregnant.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to any drug chemically related to the study drug.
• Known allergy to any of the capsule excipients, or history of drug or other allergy, which, in the opinion of the responsible study physician, contradicts participation. Hypersensitivity to metformin or any of its components (for subjects entering on metformin).
• Has a history of substance and/or alcohol abuse within the past year as determined by the Investigator at screening or during treatment:

• Unwilling to refrain from the use of illicit drugs and adhere to other protocol-stated restrictions while participating in the study.
• History of alcohol abuse defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint of beer or 1 measure of spirits or 1 glass of wine.
• Received treatment with a new molecular entity (investigational drug) during the previous 4 months or participated in any other trial during the previous 3 months, or has participated in a previous study with GW677954. A new molecular entity is defined as any compound not in Phase 3. (The washout is from last dose of investigational product in the previous study until the first dose of investigational product.)
• Likely to be non-compliant, in the investigator's opinion, with respect to the protocol and related scheduled visits.
• Subject has any concomitant medical condition which in the opinion of the investigator makes them unsuitable to participate in the study.
• Subject is either an immediate family member of a participating investigator, study coordinator, employee of an investigator; or is a member of the staff conducting the study.