Clinical trial NCT00727857: Efficacy and Safety of Pioglitazone and Metformin Combination Therapy in Treating Type 2 Diabetes Mellitus.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus
Keywords: Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus, Lipoatrophic
Dyslipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2008-08-04
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percent Change From Baseline in Glycosylated Hemoglobin
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Change From Baseline in Fasting Plasma Glucose
timeFrame: Baseline and Week 24
measure: Change From Baseline in Fasting Insulin
timeFrame: Baseline and Week 24
measure: Change From Baseline in Homeostasis Model Assessment - Insulin Resistance
timeFrame: Baseline and Week 24
measure: Median Percent Change From Baseline in High Sensitivity C-reactive Protein
timeFrame: Baseline and Week 24
measure: Change From Baseline in Adiponectin
timeFrame: Baseline and Week 24
measure: Change From Baseline in Total Cholesterol
timeFrame: Baseline and Week 24
measure: Change From Baseline in Low-Density Lipoprotein Cholesterol
timeFrame: Baseline and Week 24
measure: Change From Baseline in High-Density Lipoprotein Cholesterol
timeFrame: Baseline and Week 24
measure: Change From Baseline in Triglycerides
timeFrame: Baseline and Week 24
measure: Change From Baseline in Mean Low Density Lipoprotein Particle Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Mean Low Density Lipoprotein Particle Size
timeFrame: Baseline and Week 24
measure: Change From Baseline in Large Low Density Lipoprotein (L3) Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Intermediate-Density Low Density Lipoprotein Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Medium-Small Low Density Lipoprotein Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Small Low Density Lipoprotein Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Very Small Low Density Lipoprotein Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Mean High Density Lipoprotein Particle Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Mean High Density Lipoprotein Particle Size
timeFrame: Baseline and Week 24
measure: Change From Baseline in Large High Density Lipoprotein (H4+H5) Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Intermediate-Medium High Density Lipoprotein (H3) Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Small High Density Lipoprotein (H1+H2) Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Mean Very Low Density Lipoprotein Particle Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Mean Very Low Density Lipoprotein Particle Size
timeFrame: Baseline and Week 24
measure: Change From Baseline in Large-Chylomicrons Very Low Density Lipoprotein Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Medium-Intermediate Very Low Density Lipoprotein (V3+V4) Concentration
timeFrame: Baseline and Week 24
measure: Change From Baseline in Small Very Low Density Lipoprotein (V1+V2) Concentration
timeFrame: Baseline and Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Haleyville
country: United States
state: Alabama
city: Montgomery
country: United States
state: Alabama
city: Pell City
country: United States
state: Alabama
city: Phoenix
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Anaheim
country: United States
state: California
city: Artesia
country: United States
state: California
city: Dinuba
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Los Angeles,
country: United States
state: California
city: Norwalk
country: United States
state: California
city: Orange
country: United States
state: California
city: Santa Ana
country: United States
state: California
city: Santa Monica
country: United States
state: California
city: Pueblo
country: United States
state: Colorado
city: Altamonte Springs
country: United States
state: Florida
city: Coral Gables
country: United States
state: Florida
city: Hialeah
country: United States
state: Florida
city: Miami,
country: United States
state: Florida
city: Panama City
country: United States
state: Florida
city: Plantation
country: United States
state: Florida
city: St Petersburg
country: United States
state: Florida
city: St. Cloud
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Columbus
country: United States
state: Georgia
city: Boise
country: United States
state: Idaho
city: Coeur d' Alene,
country: United States
state: Idaho
city: Chicago
country: United States
state: Illinois
city: Flossmoor
country: United States
state: Illinois
city: Peoria
country: United States
state: Illinois
city: Elkhart
country: United States
state: Indiana
city: Shawnee,
country: United States
state: Kansas
city: Southfield
country: United States
state: Michigan
city: Chesterfield
country: United States
state: Missouri
city: Billings
country: United States
state: Montana
city: Elizabeth
country: United States
state: New Jersey
city: Fayetteville
country: United States
state: New York
city: New York
country: United States
state: New York
city: Durham
country: United States
state: North Carolina
city: Pinehurst
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Perrysburg
country: United States
state: Ohio
city: Zanesville
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Eugene
country: United States
state: Oregon
city: Fleetwood
country: United States
state: Pennsylvania
city: Norristown
country: United States
state: Pennsylvania
city: Cranston
country: United States
state: Rhode Island
city: Simpsonville,
country: United States
state: South Carolina
city: Varnville
country: United States
state: South Carolina
city: Fayetteville
country: United States
state: Tennessee
city: Corpus Christi
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: El Paso
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: McAllen
country: United States
state: Texas
city: Mission
country: United States
state: Texas
city: New Braunfels
country: United States
state: Texas
city: North Richland Hills
country: United States
state: Texas
city: San Antonio,
country: United States
state: Texas
city: Bountiful
country: United States
state: Utah
city: Salt Lake City
country: United States
state: Utah
city: Petersburg
country: United States
state: Virginia
city: Port Orchard
country: United States
state: Washington
city: Spokane
country: United States
state: Washington
city: Providencia-Santiago
country: Chile
city: Temuco
country: Chile
city: Zapopan
country: Mexico
state: Jalisco
city: Monterrey
country: Mexico
state: Nuevo Leon
city: Aibonito
country: Puerto Rico
city: Caguas
country: Puerto Rico
city: Ciales
country: Puerto Rico
city: Coto Laurel
country: Puerto Rico
city: Guayma
country: Puerto Rico
city: Guaynabo
country: Puerto Rico
city: Rio Piedras
country: Puerto Rico
Study officials:
affiliation: Takeda
name: VP Clinical Science Strategy
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.