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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: Pioglitazone and metformin; Drug: Pioglitazone; Drug: Metformin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 600
• Phase: Phase 3

Contacts and Locations

Study Locations

• Chile
  • Providencia-Santiago, Chile
  • Temuco, Chile
• Mexico
  • Jalisco
    • Zapopan, Jalisco, Mexico
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico
• Puerto Rico
  • Aibonito, Puerto Rico
  • Caguas, Puerto Rico
  • Ciales, Puerto Rico
  • Coto Laurel, Puerto Rico
  • Guayma, Puerto Rico
  • Guaynabo, Puerto Rico
  • Rio Piedras, Puerto Rico
• United States
  • Alabama
    • Birmingham, Alabama, United States
    • Haleyville, Alabama, United States
    • Montgomery, Alabama, United States
    • Pell City, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
    • Tucson, Arizona, United States
  • California
    • Anaheim, California, United States
    • Artesia, California, United States
    • Dinuba, California, United States
    • Long Beach, California, United States
    • Los Angeles,, California, United States
    • Norwalk, California, United States
    • Orange, California, United States
    • Santa Ana, California, United States
    • Santa Monica, California, United States
  • Colorado
    • Pueblo, Colorado, United States
  • Florida
    • Altamonte Springs, Florida, United States
    • Coral Gables, Florida, United States
    • Hialeah, Florida, United States
    • Miami,, Florida, United States
    • Panama City, Florida, United States
    • Plantation, Florida, United States
    • St Petersburg, Florida, United States
    • St. Cloud, Florida, United States
    • Tampa, Florida, United States
  • Georgia
    • Columbus, Georgia, United States
  • Idaho
    • Boise, Idaho, United States
    • Coeur d' Alene,, Idaho, United States
  • Illinois
    • Chicago, Illinois, United States
    • Flossmoor, Illinois, United States
    • Peoria, Illinois, United States
  • Indiana
    • Elkhart, Indiana, United States
  • Kansas
    • Shawnee,, Kansas, United States
  • Michigan
    • Southfield, Michigan, United States
  • Missouri
    • Chesterfield, Missouri, United States
  • Montana
    • Billings, Montana, United States
  • New Jersey
    • Elizabeth, New Jersey, United States
  • New York
    • Fayetteville, New York, United States
    • New York, New York, United States
  • North Carolina
    • Durham, North Carolina, United States
    • Pinehurst, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Perrysburg, Ohio, United States
    • Zanesville, Ohio, United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
  • Oregon
    • Eugene, Oregon, United States
  • Pennsylvania
    • Fleetwood, Pennsylvania, United States
    • Norristown, Pennsylvania, United States
  • Rhode Island
    • Cranston, Rhode Island, United States
  • South Carolina
    • Simpsonville,, South Carolina, United States
    • Varnville, South Carolina, United States
  • Tennessee
    • Fayetteville, Tennessee, United States
  • Texas
    • Corpus Christi, Texas, United States
    • Dallas, Texas, United States
    • El Paso, Texas, United States
    • Houston, Texas, United States
    • McAllen, Texas, United States
    • Mission, Texas, United States
    • New Braunfels, Texas, United States
    • North Richland Hills, Texas, United States
    • San Antonio,, Texas, United States
  • Utah
    • Bountiful, Utah, United States
    • Salt Lake City, Utah, United States
  • Virginia
    • Petersburg, Virginia, United States
  • Washington
    • Port Orchard, Washington, United States
    • Spokane, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pioglitazone 15 mg /Metformin 850 mg BID	Drug: Pioglitazone and metformin; Pioglitazone 15 mg /metformin 850 mg combination, tablets, orally, twice daily for up to 24 weeks.; Other Names: ACTOPLUS MET
Active Comparator: Pioglitazone 15 mg BID	Drug: Pioglitazone; Pioglitazone 15 mg, tablets, orally, twice daily for up to 24 weeks.; Other Names: ACTOS®; AD4833
Active Comparator: Metformin 850 mg BID	Drug: Metformin; Metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.; Other Names: Glucophage; Glucophage XR; Glumetza; Fortamet; Riomet

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Perez A, Zhao Z, Jacks R, Spanheimer R. Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Curr Med Res Opin. 2009 Dec;25(12):2915-23. doi: 10.1185/03007990903350011.
• Perez A, Jacks R, Arora V, Spanheimer R. Effects of pioglitazone and metformin fixed-dose combination therapy on cardiovascular risk markers of inflammation and lipid profile compared with pioglitazone and metformin monotherapy in patients with type 2 diabetes. J Clin Hypertens (Greenwich). 2010 Dec;12(12):973-82. doi: 10.1111/j.1751-7176.2010.00389.x. Epub 2010 Nov 8.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: July 30, 2008
• First Submitted That Met QC Criteria: July 30, 2008
• First Posted (Estimate): August 4, 2008

Study Record Updates

• Last Update Posted (Estimate): July 29, 2011
• Last Update Submitted That Met QC Criteria: July 27, 2011
• Last Verified: July 1, 2011

More Information

Terms related to this study

• Keywords: Drug Therapy; Dyslipidemia; Type II Diabetes; Glucose Metabolism Disorder; Dysmetabolic Syndrome; Diabetes Mellitus, Lipoatrophic
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin; Pioglitazone
• Other Study ID Numbers: 01-06-TL-OPIMET-008; U1111-1114-0371 (Registry Identifier: WHO)