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

This study has been completed.
Sponsor:
Information provided by:
Takeda
ClinicalTrials.gov Identifier:
NCT00727857
First received: July 30, 2008
Last updated: July 27, 2011
Last verified: July 2011
History of Changes
  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.


Condition Intervention Phase
Diabetes Mellitus
 Drug: Pioglitazone and metformin
Drug: Pioglitazone
Drug: Metformin
 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Takeda:

Primary Outcome Measures:
  • Percent 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.


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


Enrollment: 600
Study Start Date: June 2007
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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:
  • Fortamet
  • Glucophage
  • Glucophage XR
  • Glumetza
  • Riomet

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00727857

  Show 77 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: VP Clinical Science Strategy Takeda
  More Information

Additional Information:
ACTOPLUS MET® Package Insert  This link exits the ClinicalTrials.gov site
FDA Safety Alerts and Recalls  This link exits the ClinicalTrials.gov site

Publications:

Responsible Party: Sr. VP, Clinical Science, Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier: NCT00727857     History of Changes
Other Study ID Numbers: 01-06-TL-OPIMET-008, U1111-1114-0371
Study First Received: July 30, 2008
Results First Received: August 28, 2009
Last Updated: July 27, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Takeda:
Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
 Diabetes Mellitus, Lipoatrophic
Dyslipidemia
Drug Therapy

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
 Pioglitazone
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on June 13, 2013