A Type 2 Diabetes Study of the Longer-Term Glycemic Effect of AVANDAMET vs. Metformin

A Randomized, Parallel Group, Double-blind, Multi-center Study Comparing the Efficacy and Safety of AVANDAMET and Metformin After 80 Weeks of Treatment.

This study will evaluate the longer-term glycemic effect of two medicines approved for initial treatment of type 2 diabetes. The study consists of a 2 week screening period (2 study visits), followed by an 80 week double-blind treatment period (11 study visits). Also, a sub-study was included to look at changes in bone mineral density (BMD) at the lumbar spine.

This was a phase IV, randomized, double-blind, global, multi-centre study. The study consisted of a 2 week screening period followed by an 80 week double-blind treatment period. Subjects who met all eligibility requirements were randomized in a 1:1 ratio, stratified by country, gender (male and female) and pre-screening HbA1c (≤9% or>9) either to MET or AVM. When the substudy was added, a new randomization was created for the participating centers. Those subjects in the bone sub-study were stratified by country, gender (male, premenopausal female, and postmenopausal female), pre-screening HbA1c (i.e., ≤9%; >9%), and either to MET or AVM.

At randomization, Visit 3 (Week 0), subjects were initiated at Dose Level 1. Treatment with AVM was initiated at a dose of 4 mg/500 mg and titrated up to a maximum total daily dose of AVM 8 mg/2000 mg. Treatment with MET therapy was initiated at a dose of 500 mg and titrated up to a maximum daily dose of 2000mg.

Inclusion Criteria:

• The subject provides written informed consent.
• The subject is male or female and 18 to 75 years of age at the time of pre-screening.
• The subject has an established clinical diagnosis of type 2 diabetes according to recommended guidelines (e.g., American Diabetes Association, International Diabetes Federation, World Health Organization, Canadian Diabetes Association, or American Association of Clinical Endocrinologists).
• The subject is currently treated with diet and exercise, and has not taken more than 2 weeks of an anti-diabetic monotherapy or insulin in the past 6 months.
• The subject has a BMI >25 kg/m2 at pre-screening.
• The subject has a Quest HbA1c 7.5% to 10.5% at pre-screening.
• The subject has a fasting capillary blood glucose 126 mg/dL (7mmol/L), as measured by the site staff at week 0.
• If the subject is a pre-menopausal female of child-bearing potential, she agrees to practice acceptable contraceptive measures (e.g. oral birth control pills, Norplant, Depo-Provera, an intrauterine device (IUD), a diaphragm with spermicide or a condom with spermicide, or abstinence) at least 1 month before screening, during the study, and for 30 days after the last dose of study medication is taken
• The subject is able and willing to perform self-monitoring of blood glucose as specified in this protocol.

Exclusion Criteria:

• The subject has taken an oral anti-diabetic monotherapy or insulin for more than 14 days in the past 6 months.
• The subject has presence of clinically significant renal or hepatic disease (serum creatinine 1.5 mg/dL (132.6 mol/L) for males and 1.4 mg/dL (123.8 mol/L) for females): ALT, AST, total bilirubin, or alkaline phosphatase >2.5 times the upper limit of the normal (ULN) reference range.
• The subject has anemia defined by hemoglobin concentration <11g/dL (110g/L) for males or <10g/dL (100g/L) for females.
• Presence of unstable or severe angina, coronary insufficiency or New York Heart Association (NYHA) class III-IV or any congestive heart failure requiring pharmacologic treatment.
• The subject has systolic blood pressure >160 mmHg or diastolic blood pressure >90 mmHg
• The subject has a chronic disease requiring intermittent or chronic treatment with oral, intravenous, or intra-articular corticosteroids (i.e., only use of topical, inhaled or nasal corticosteroids is permitted).
• The subject has acute or chronic metabolic acidosis or a history of diabetic ketoacidosis.
• The subject has a clinically significant abnormality which in the judgment of the investigator makes the subject unsuitable for inclusion in the study (e.g., physical examination, laboratory tests, or electrocardiogram, etc).
• The subject has used an investigational agent within 30 days or 5 half-lives (whichever was longer) prior to pre-screening.
• The subject is a female who is lactating, pregnant, or planned to become pregnant.
• The subject has a prior history of severe edema or a medically serious fluid related event (e.g., heart failure).
• The subject has a history of macular edema.
• The subject has significant hypersensitivity (e.g., difficulty swallowing, difficulty breathing, and tachycardia or skin reaction) to TZDs, biguanides, or compounds with similar chemical structures.
• The subject has a diagnosis of cancer (other than squamous, basal cell, or cervical cancer in-situ) in the past 3 years and is receiving treatment for cancer.
• The subject has a history or suspicion of drug abuse or alcohol abuse within the last 6 months.
• The subject is known to have severe lactose intolerance.
• The subject is not willing to comply with visits and procedures described in the protocol.
• The subject has a disease that may affect bone turnover including, but not limited to: Paget's disease, hypercalcemia, hypocalcemia, hyperparathyroidism, hyperthyroidism, osteomalacia, metastatic bone disease
• The subject has a weight of greater than 300 lbs (136.4 kg).
• The subject has received treatment with bisphosphonates (≥1 month cumulative treatment within the last 12 months) or fluoride (dose greater than 10mg/day within the previous 5 years).