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

Overview[ - collapse ][ - ]

Purpose 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.
ConditionDiabetes Mellitus
InterventionDrug: Pioglitazone and metformin
Drug: Pioglitazone
Drug: Metformin
PhasePhase 3
SponsorTakeda
Responsible PartyTakeda
ClinicalTrials.gov IdentifierNCT00727857
First ReceivedJuly 30, 2008
Last UpdatedJuly 27, 2011
Last verifiedJuly 2011

Tracking Information[ + expand ][ + ]

First Received DateJuly 30, 2008
Last Updated DateJuly 27, 2011
Start DateJune 2007
Estimated Primary Completion DateAugust 2008
Current Primary Outcome MeasuresPercent Change From Baseline in Glycosylated Hemoglobin [Time Frame: Baseline and Week 24] [Designated as safety issue: No]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.
Current Secondary Outcome Measures
  • Change From Baseline in Fasting Plasma Glucose [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between the value of Fasting Plasma Glucose collected at final visit or week 24 and Fasting Plasma Glucose collected at baseline.
  • Change From Baseline in Fasting Insulin [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between the Fasting Insulin value collected at final visit or week 24 and Fasting Insulin collected at baseline.
  • Change From Baseline in Homeostasis Model Assessment - Insulin Resistance [Time Frame: Baseline and Week 24] [Designated as safety issue: No]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).
  • Median Percent Change From Baseline in High Sensitivity C-reactive Protein [Time Frame: Baseline and Week 24] [Designated as safety issue: No]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
  • Change From Baseline in Adiponectin [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Adiponectin collected at final visit or week 24 and Adiponectin collected at baseline.
  • Change From Baseline in Total Cholesterol [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Total Cholesterol collected at final visit or week 24 and Total Cholesterol collected at baseline.
  • Change From Baseline in Low-Density Lipoprotein Cholesterol [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Low-Density Lipoprotein Cholesterol collected at final visit or week 24 and Low-Density Lipoprotein Cholesterol collected at baseline.
  • Change From Baseline in High-Density Lipoprotein Cholesterol [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between High-Density Lipoprotein Cholesterol collected at final visit or week 24 and High-Density Lipoprotein Cholesterol collected at baseline.
  • Change From Baseline in Triglycerides [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Triglycerides collected at final visit or week 24 and Triglycerides collected at baseline.
  • Change From Baseline in Mean Low Density Lipoprotein Particle Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Low Density Lipoprotein particle concentration collected at final visit or week 24 and Low Density Lipoprotein particle concentration collected at baseline.
  • Change From Baseline in Mean Low Density Lipoprotein Particle Size [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Low Density Lipoprotein collected at final visit or week 24 and Low Density Lipoprotein collected at baseline.
  • Change From Baseline in Large Low Density Lipoprotein (L3) Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Large Low Density Lipoprotein collected at final visit or week 24 and Large Low Density Lipoprotein collected at baseline.
  • Change From Baseline in Intermediate-Density Low Density Lipoprotein Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Intermediate-Density Low Density Lipoprotein collected at final visit or week 24 and Intermediate-Density Low Density Lipoprotein collected at baseline
  • Change From Baseline in Medium-Small Low Density Lipoprotein Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Medium-Small Low Density Lipoprotein collected at final visit or week 24 and Medium-Small Low Density Lipoprotein collected at baseline
  • Change From Baseline in Small Low Density Lipoprotein Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Small Low Density Lipoprotein collected at final visit or week 24 and Small Low Density Lipoprotein collected at baseline
  • Change From Baseline in Very Small Low Density Lipoprotein Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Very Small Low Density Lipoprotein collected at final visit or week 24 and Very Small Low Density Lipoprotein collected at baseline
  • Change From Baseline in Mean High Density Lipoprotein Particle Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between High Density Lipoprotein collected at final visit or week 24 and High Density Lipoprotein collected at baseline.
  • Change From Baseline in Mean High Density Lipoprotein Particle Size [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between High Density Lipoprotein collected at final visit or week 24 and High Density Lipoprotein collected at baseline.
  • Change From Baseline in Large High Density Lipoprotein (H4+H5) Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Large High Density Lipoprotein collected at final visit or week 24 and Large High Density Lipoprotein collected at baseline
  • Change From Baseline in Intermediate-Medium High Density Lipoprotein (H3) Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Intermediate-Medium High Density Lipoprotein collected at final visit or week 24 and Intermediate-Medium High Density Lipoprotein collected at baseline
  • Change From Baseline in Small High Density Lipoprotein (H1+H2) Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Small High Density Lipoprotein collected at final visit or week 24 and Small High Density Lipoprotein collected at baseline
  • Change From Baseline in Mean Very Low Density Lipoprotein Particle Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Very Low Density Lipoprotein collected at final visit or week 24 and Very Low Density Lipoprotein collected at baseline.
  • Change From Baseline in Mean Very Low Density Lipoprotein Particle Size [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Very Low Density Lipoprotein collected at final visit or week 24 and Very Low Density Lipoprotein collected at baseline.
  • Change From Baseline in Large-Chylomicrons Very Low Density Lipoprotein Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]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
  • Change From Baseline in Medium-Intermediate Very Low Density Lipoprotein (V3+V4) Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]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
  • Change From Baseline in Small Very Low Density Lipoprotein (V1+V2) Concentration [Time Frame: Baseline and Week 24] [Designated as safety issue: No]The change between Small Very Low Density Lipoprotein collected at final visit or week 24 and Small Very Low Density Lipoprotein collected at baseline

Descriptive Information[ + expand ][ + ]

Brief TitleEfficacy and Safety of Pioglitazone and Metformin Combination Therapy in Treating Type 2 Diabetes Mellitus.
Official TitleA 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
Brief Summary
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
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 TypeInterventional
Study PhasePhase 3
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
ConditionDiabetes Mellitus
InterventionDrug: Pioglitazone and metformin
Pioglitazone 15 mg /metformin 850 mg combination, tablets, orally, twice daily for up to 24 weeks.
Other Names:
ACTOPLUS METDrug: Pioglitazone
Pioglitazone 15 mg, tablets, orally, twice daily for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD4833
Drug: Metformin
Metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Other Names:
  • Fortamet
  • Glucophage
  • Glucophage XR
  • Glumetza
  • Riomet
Study Arm (s)
  • Experimental: Pioglitazone 15 mg /Metformin 850 mg BID
  • Active Comparator: Pioglitazone 15 mg BID
  • Active Comparator: Metformin 850 mg BID

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment600
Estimated Completion DateAugust 2008
Estimated Primary Completion DateAugust 2008
Eligibility Criteria
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
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesUnited States, Chile, Mexico, Puerto Rico

Administrative Information[ + expand ][ + ]

NCT Number NCT00727857
Other Study ID Numbers01-06-TL-OPIMET-008
Has Data Monitoring CommitteeNo
Information Provided ByTakeda
Study SponsorTakeda
CollaboratorsNot Provided
Investigators Study Director: VP Clinical Science Strategy Takeda
Verification DateJuly 2011

Locations[ + expand ][ + ]

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