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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Avandamet 6 mg/1500 mg (ttd)
* Drug: Avandamet 4 mg/1000 mg (ttd)
* Drug: Avandamet 2 mg/500 mg (ttd)
* Drug: Avandamet 8 mg/ 2000 mg (ttd)
* Drug: Metformin 500 mg (ttd)
* Drug: Metformin 1000 mg (ttd)
* Drug: Metformin 1500 mg (ttd)
* Drug: Metformin 2000 mg (ttd)


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Metformin<br>MET began at a total daily dose of 500 mg and could be increased up to a maximum dose of MET 2000 mg. The dose level was to be increased unless a tolerability issue existed at the current dose level. | Drug: Metformin 500 mg (ttd)<br>* One placebo capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal.<br>Drug: Metformin 1000 mg (ttd)<br>* One 500 mg capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal.<br>Drug: Metformin 1500 mg (ttd)<br>* One 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsules will be taken in the PM with the evening meal.<br>Drug: Metformin 2000 mg (ttd)<br>* Two 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsule will be taken in the PM with the evening meal.<br>|
| Active Comparator: Avandamet (Rosiglitazone maleate/metformin hydrochloride)<br>AVM began at a total daily dose of 4 mg/500 mg and could be increased up to a maximum dose of AVM 8 mg/2000 mg | Drug: Avandamet 6 mg/1500 mg (ttd)<br>* One 2 mg/ 500 mg capsule will be taken in the AM with the morning meal Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal<br>Drug: Avandamet 4 mg/1000 mg (ttd)<br>* One 2 mg/500 mg capsule will be taken in the AM with the morning meal. One 2 mg/500 mg capsule will be taken in the PM with the evening meal.<br>Drug: Avandamet 2 mg/500 mg (ttd)<br>* one placebo capsule will be taken in the AM with the morning meal one 2 mg/ 500 mg capsule will be taken in the PM with the evening meal.<br>Drug: Avandamet 8 mg/ 2000 mg (ttd)<br>* Two 2 mg/ 500 mg capsules will be taken in the AM with the morning meal. Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c at Week 80 | Blood was taken for serum HbA1c measurements. Change from baseline was calculated as the Week 80 value minus the baseline value. Last observation carried forward (LOCF) was not used for this analysis. | Baseline and Week 80 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in HbA1c at Week 80 | Blood was taken for serum Hb1AC measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values. | Baseline and Week 80 | 
| Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80 | Blood was taken for serum Hb1AC measurements. Hb1AC responders were described as participants having achieved Hb1AC <=6% and <7% at Week 80 with LOCF from Week 32. | Week 80 | 
| Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80 | Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value. | Baseline and Week 80 | 
| Change From Baseline in FPG at Week 80 | Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values. | Baseline and Week 80 | 
| Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80 | Blood was taken for serum FPG measurements. FPG responders were described as participants having achieved FPG <=6 mmol/L (110 mg/dL) and <7 mmol/L (126 mg/dL) Hb1AC at Week 80 with LOCF from Week 32. | Week 80 | 
| Number of Participants Achieving Treatment Failure | Treatment failure was defined as an HbA1c level >= 7% after Week 32 or withdrawal due to insufficient therapeutic effect (ITE) at any time. | Randomization to treatment failure (up to Week 80) | 
| Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80 | Blood was taken for measurement of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Percent change from baseline at Week 80 was based on log transformed data. Geometric mean, GM; standard error, SE. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Week 80 | 
| Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants ) | Blood was taken for measurement of adiponectin. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only. | Baseline and Week 80 | 
| Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants) | Blood was taken for measurement of CRP. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only. | Baseline and Week 80 | 
| Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants). | Blood was taken for measurement of FFA. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only. | Baseline and Week 80 | 
| Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants) | Blood was taken for fasting insulin measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only. | Baseline and Week 80 | 
| Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants) | Blood was taken for C-peptide measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only. | Baseline and Week 80 | 
| Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants) | Blood was taken for measurement of homeostasis model assessment for insulin sensitivity (HOMA-S) and beta-cell function (HOMA-B). Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only. GM, geometric mean; SE, standard error. | Baseline and Week 80 | 
| Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG | The ratio Delta I/Delta G is calculated based on the oral glucose tolerance test (OGTT), where Delta I = (30 minute immunoreactive insulin minus 0 minute immunoreactive insulin) and Delta G = (30 minute plasma glucose minus 0 minute plasma glucose). The 0 minute values are fasting insulin and glucose; the 30 minute values are taken 30 minutes after the oral glucose challenge. This outcome measure was analyzed for a subset of participants in the US and Mexico only. | Baseline and Week 80 | 
| Number of Participants at Final Dose Level |  | Baseline to Week 80 or withdrawal | 
| Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants) | BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100%. This outcome measure was analyzed for a subset of participants in the bone study only. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants) | BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants) | BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants) | BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants) | BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants) | BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80 | Blood was taken for measurement of serum calcium. Percent change from baseline was based on log transformed data. Geometric mean, GM; standard error, SE. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Weeks 12, 32, 56, and 80 | 
| Percent Change From Baseline in Intact Parathyroid Hormone at Week 80 | Blood was taken for measurement of intact parathyroid hormone. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Week 80 | 
| Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80 | Blood was taken for measurement of 25-hydroxy vitamin D. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Week 80 | 
| Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80 | Blood was taken for measurement of estradiol. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of female participants in the bone study only. n is the number of evaluable participants, which is the number of female participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80 | Blood was taken for measurement of CTX. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80 | Blood was taken for measurement of P1NP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Weeks 20, 56, and 80 | 
| Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80 | Blood was taken for measurement of BSAP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest. | Baseline and Weeks 20, 56, and 80 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fasting Plasma Glucose, Dual energy X ray absorptiometry (DXA), Drug-naive, Type 2 diabetes mellitus, Bone Mineral Density, Hyperglycemia, HbA1c