Efficacy and Safety of Pioglitazone and Metformin Combination Therapy in Treating Type 2 Diabetes Mellitus.

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of pioglitazone, twice daily (BID), combined with metformin versus pioglitazone taken alone and metformin taken alone in treating Type 2 Diabetes Mellitus.

Detailed Description
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Pioglitazone hydrochloride (ACTOS®) is a member of a class of oral antidiabetic agents known as thiazolidinediones, which act by reducing insulin resistance. Insulin resistance is a key feature of dysmetabolic syndrome and has been suggested to be the common pathophysiologic basis of both atherosclerosis and type 2 diabetes. Pioglitazone binds to peroxisome proliferator-activated receptors, an effect that is associated with altered transcription of genes capable of influencing carbohydrate and lipid metabolism. Metformin hydrochloride is an oral antihyperglycemic drug not chemically or pharmacologically related to thiazolidinediones. Metformin is a biguanide, which has been shown to be effective in improving glycemic control in diabetic patients. Metformin inhibits hepatic glucose production, most likely through an inhibition of gluconeogenesis, and its use is associated with an improvement in tissue sensitivity to insulin. In accordance with published algorithms for the use of combination therapy for the treatment of type 2 diabetes, physicians have traditionally combined metformin with other antidiabetic agents. This study will determine the effect of a fixed-dose combination of metformin with pioglitazone, compared to metformin monotherapy and pioglitazone monotherapy. Study participation is anticipated to be approximately 6.5 months.

Official Title
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A Phase 3b, Double-Blind, Randomized Study to Determine the Efficacy and Safety of Pioglitazone HCl and Metformin HCl Fixed-Dose Combination Therapy Compared to Pioglitazone HCl Monotherapy and to Metformin HCl Monotherapy in the Treatment of Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Pioglitazone and metformin
* Drug: Pioglitazone
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Has type 2 diabetes. Has received no treatment with antidiabetic medication in the 12 weeks prior to Screening, other than short-term use defined as less than or equal to 15 days. A glycosylated hemoglobin greater than or equal to 7.5% and less than or equal to 10.0% at Screening. Body mass index less than or equal to 45 kg/m2. Has received counseling on lifestyle modification for type 2 diabetes, including diet and exercise. Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. Stable condition as determined by a physician. Exclusion Criteria Type 1 diabetes. Unstable angina or heart failure of any etiology with New York Heart Association functional class III or IV. History of myocardial infarction, cerebrovascular accident, percutaneous coronary intervention, coronary artery bypass graft, or transient ischemic attack in the 6 months prior to Screening. Male participant has a serum creatinine level greater than or equal to 1.5 mg per dL or female subject has a serum creatinine level greater than or equal to 1.4 mg per dL. Has a triglyceride level greater than 500 mg per dL. Male participant has a hemoglobin level less than 10.5 g per dL or female subject has a hemoglobin level less than 10.0 g per dL. Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice. History of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic drinks per day) within 2 years prior to Screening. Has been discontinued from a thiazolidinedione or metformin therapy due to lack of efficacy or clinical or laboratory signs of intolerance. Previous history of cancer, other than basal cell or stage 1 squamous cell carcinoma, that has not been in remission for at least 5 years prior to the first dose of study medication. History of acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma. Any disease or condition at Screening or Randomization that would compromise safety, might affect life expectancy, or make it difficult to successfully manage and follow the subject according to the protocol. Currently participating in another investigational study or has participated in an investigational study within 30 days prior to randomization. Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including: Antidiabetic medications other than study medication Chronically used oral or parenteral glucocorticoids Niacin greater than 200 mg per day, including niacin-containing products such as Advicor Chronically used steroid-joint injections

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Pioglitazone 15 mg /Metformin 850 mg BID<br> | Drug: Pioglitazone and metformin<br>* Pioglitazone 15 mg /metformin 850 mg combination, tablets, orally, twice daily for up to 24 weeks.<br>* Other names: ACTOPLUS MET;|
| Active Comparator: Pioglitazone 15 mg BID<br> | Drug: Pioglitazone<br>* Pioglitazone 15 mg, tablets, orally, twice daily for up to 24 weeks.<br>* Other names: AD4833;|
| Active Comparator: Metformin 850 mg BID<br> | Drug: Metformin<br>* Metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.<br>* Other names: Riomet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Glycosylated Hemoglobin | The change between the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at final visit or week 24 and Glycosylated Hemoglobin collected at baseline. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose | The change between the value of Fasting Plasma Glucose collected at final visit or week 24 and Fasting Plasma Glucose collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Fasting Insulin | The change between the Fasting Insulin value collected at final visit or week 24 and Fasting Insulin collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Homeostasis Model Assessment - Insulin Resistance | The change between Homeostasis Model Assessment of Insulin Resistance collected at final visit or week 24 and Homeostasis Model Assessment of Insulin Resistance collected at baseline. Homeostasis Model Assessment measures insulin resistance, calculated by insulin times glucose, divided by a constant (22.5). | Baseline and Week 24 | 
| Median Percent Change From Baseline in High Sensitivity C-reactive Protein | Measurement for High Sensitivity C-reactive Protein was collected at final visit or week 24 and at baseline. Percent change from baseline is calculated as: [(Week 24 - baseline levels)/baseline]*100 | Baseline and Week 24 | 
| Change From Baseline in Adiponectin | The change between Adiponectin collected at final visit or week 24 and Adiponectin collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Total Cholesterol | The change between Total Cholesterol collected at final visit or week 24 and Total Cholesterol collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Low-Density Lipoprotein Cholesterol | The change between Low-Density Lipoprotein Cholesterol collected at final visit or week 24 and Low-Density Lipoprotein Cholesterol collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in High-Density Lipoprotein Cholesterol | The change between High-Density Lipoprotein Cholesterol collected at final visit or week 24 and High-Density Lipoprotein Cholesterol collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Triglycerides | The change between Triglycerides collected at final visit or week 24 and Triglycerides collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Mean Low Density Lipoprotein Particle Concentration | The change between Low Density Lipoprotein particle concentration collected at final visit or week 24 and Low Density Lipoprotein particle concentration collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Mean Low Density Lipoprotein Particle Size | The change between Low Density Lipoprotein collected at final visit or week 24 and Low Density Lipoprotein collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Large Low Density Lipoprotein (L3) Concentration | The change between Large Low Density Lipoprotein collected at final visit or week 24 and Large Low Density Lipoprotein collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Intermediate-Density Low Density Lipoprotein Concentration | The change between Intermediate-Density Low Density Lipoprotein collected at final visit or week 24 and Intermediate-Density Low Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Medium-Small Low Density Lipoprotein Concentration | The change between Medium-Small Low Density Lipoprotein collected at final visit or week 24 and Medium-Small Low Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Small Low Density Lipoprotein Concentration | The change between Small Low Density Lipoprotein collected at final visit or week 24 and Small Low Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Very Small Low Density Lipoprotein Concentration | The change between Very Small Low Density Lipoprotein collected at final visit or week 24 and Very Small Low Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Mean High Density Lipoprotein Particle Concentration | The change between High Density Lipoprotein collected at final visit or week 24 and High Density Lipoprotein collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Mean High Density Lipoprotein Particle Size | The change between High Density Lipoprotein collected at final visit or week 24 and High Density Lipoprotein collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Large High Density Lipoprotein (H4+H5) Concentration | The change between Large High Density Lipoprotein collected at final visit or week 24 and Large High Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Intermediate-Medium High Density Lipoprotein (H3) Concentration | The change between Intermediate-Medium High Density Lipoprotein collected at final visit or week 24 and Intermediate-Medium High Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Small High Density Lipoprotein (H1+H2) Concentration | The change between Small High Density Lipoprotein collected at final visit or week 24 and Small High Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Mean Very Low Density Lipoprotein Particle Concentration | The change between Very Low Density Lipoprotein collected at final visit or week 24 and Very Low Density Lipoprotein collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Mean Very Low Density Lipoprotein Particle Size | The change between Very Low Density Lipoprotein collected at final visit or week 24 and Very Low Density Lipoprotein collected at baseline. | Baseline and Week 24 | 
| Change From Baseline in Large-Chylomicrons Very Low Density Lipoprotein Concentration | The change between Large-Chylomicrons Very Low Density Lipoprotein collected at final visit or week 24 and Large-Chylomicrons Very Low Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Medium-Intermediate Very Low Density Lipoprotein (V3+V4) Concentration | The change between Medium-Intermediate Very Low Density Lipoprotein collected at final visit or week 24 and Medium-Intermediate Very Low Density Lipoprotein collected at baseline | Baseline and Week 24 | 
| Change From Baseline in Small Very Low Density Lipoprotein (V1+V2) Concentration | The change between Small Very Low Density Lipoprotein collected at final visit or week 24 and Small Very Low Density Lipoprotein collected at baseline | Baseline and Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic, Dyslipidemia, Drug Therapy