"TAKE TIME" Pioglitazone Reverses Defects in Mitochondrial Biogenesis in Patients With T2DM

This study has been completed.
Sponsor:
Collaborator:
Takeda Pharmaceuticals North America, Inc.
Information provided by:
Pennington Biomedical Research Center
ClinicalTrials.gov Identifier:
NCT00402012
First received: November 17, 2006
Last updated: July 27, 2010
Last verified: July 2010
  Purpose

This study is designed to look at the effect of Pioglitazone treatment on the body's ability to burn food in order to produce energy.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: Pioglitazone
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Pioglitazone Reverses Defects in Mitochondrial Biogenesis in Patients With T2DM

Resource links provided by NLM:


Further study details as provided by Pennington Biomedical Research Center:

Primary Outcome Measures:
  • Change in skeletal muscle mitochondrial number (electron microscopy + qPCR of mtDNA) and mitochondrial gene expression in T2DM patients treated with pioglitazone (vs. placebo) [ Time Frame: baseline and after intervention ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • insulin sensitivity for insulin suppression of free fatty acid and glucose disposal [ Time Frame: baseline and after intervention ] [ Designated as safety issue: No ]
  • electron transport chain activity; mitochondrial content by MRS (ATP max) [ Time Frame: baseline and after intervention ] [ Designated as safety issue: No ]
  • intra hepatic and intra myocellular lipid by MRS; mitochondrial content by MRS (ATP max) post weight loss period [ Time Frame: baseline ,after treatment and after weight loss ] [ Designated as safety issue: No ]

Enrollment: 24
Study Start Date: November 2006
Study Completion Date: December 2007
Primary Completion Date: December 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: 1
Experimental: 2 Drug: Pioglitazone
During the double-blind, 12 weeks treatment period, subjects will self-administer study medication (pioglitazone or equivalent volume of placebo) 30 mg/day each morning. The dose of pioglitazone will be increased to 45 mg/day after 4 weeks if the fasting plasma glucose is higher than 100mg/dl or the HbA1C is higher than 7%. This dose has proven tolerability, safety and efficacy for type 2 diabetes and has previously been used at the Pennington Center in studies on pioglitazone.
Other Name: TZD

Detailed Description:

Skeletal muscle mitochondrial defects are a sine qua non of insulin resistance in patients with T2DM. Pioglitazone decreases free fatty acid levels and restores mitochondria number in adipose tissue whereas high fat diet and lipid infusion decreases genes involved in mitochondrial biogenesis. Increased lipid flux from diet or adipose tissue into skeletal muscle might be the cause of decreased mitochondrial biogenesis. The purpose of this study is to determine if 22 weeks treatment with Pioglitazone can increase mitochondrial biogenesis in muscle in 30 uncomplicated T2DM patients that were previously not taking TZD's. This Phase IV, randomized, double-blind, placebo controlled, clinical trial will consist of 3 phases: a screening, a placebo / Pioglitazone phase (12 weeks) and a weight loss period (6-10 weeks). The primary endpoint is to identify the changes in skeletal muscle mitochondria number and gene expression. Secondary endpoints include MRS measured mitochondrial capacity, insulin sensitivity for glucose disposal and insulin suppression of free fatty acids, electron transport chain activity, mitochondrial content and intra hepatic and intra myocellular lipid. Metformin and Sulfonylurea will be used as standardized oral therapy to maintain HbA1C < 7.0. After completing the protocol, patients will be offered a very low calorie liquid diet (800kcal/d) to assist them in losing weight. During this period they will continue on their previously randomized treatment. When patients lose 10% of their body weight, patients will be switched to a weight maintenance diet (meal replacement with 1 can of glucerna at breakfast and lunch with a "healthy" dinner) for 10 days. MRS measured mitochondrial capacity will again be determined to see if weight loss + pioglitazone has more effect on mitochondrial function than pioglitazone alone.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women aged 18-70 with Type 2 diabetes as defined by:

    • Fasting plasma glucose > 126 mg/dL at entry
    • Or a two-hour OGTT glucose > 200mg/dL
    • Or current treatment with one or two oral anti-diabetic drugs, except TZD
    • Or currently using insulin
  • Fasting plasma glucose < 200mg/dL at entry
  • BMI >27.0 and <45.0kg/m2
  • Adequate contraception for women (including, but not limited to: oral contraception, hysterectomy, tubal ligation, or post-menopausal as defined by > 6 months without a menstrual cycle and FSH > 40 mIU/ml).

Exclusion Criteria:

  • Significant renal, cardiac, liver, lung, or neurological disease (controlled hypertension is acceptable if baseline bp < 140/90 on medications).
  • Prior use of other thiazolidinediones (rosiglitazone [AVANDIATM], pioglitazone [ACTOSTM])
  • Use of drugs known to affect energy metabolism or body weight: including, but not limited to: orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc.
  • Pregnancy
  • Alcohol or other drug abuse
  • Unwilling or unable to abstain from caffeine (48h) and tobacco (24h) prior to metabolic rate measurements
  • Increased liver function tests at baseline (AST/ALT/GGT/or alkaline phosphatase greater than 2.5 times the upper limit of normal)
  • Metal objects that would interfere with the measurement of body composition /MRS such as implanted rods, surgical clips, etc.
  • HbA1C of > 10%.
  • NYHA class III/IV CHF is an exclusionary cardiac condition.
  • history of deep vein thrombosis (DVT) or pulmonary embolism (PE)
  • varicose veins
  • major surgery on the abdomen, pelvis, or lower extremities within previous 3 months
  • cancer (active malignancy with or without concurrent chemotherapy)
  • rheumatoid disease
  • bypass graft in limb
  • known genetic factor (Factor V Leiden, etc) or hypercoagulable state
  • diagnosed peripheral arterial or vascular disease, or intermittent claudication
  • family history of primary DVT or PE (pulmonary embolism)
  • peripheral neuropathy
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00402012

Locations
United States, Louisiana
Pennington Biomedical Research Center
Baton Rouge, Louisiana, United States, 70808
Sponsors and Collaborators
Pennington Biomedical Research Center
Takeda Pharmaceuticals North America, Inc.
Investigators
Principal Investigator: Steven R Smith, M.D. Pennington Biomedical Research Center
  More Information

No publications provided by Pennington Biomedical Research Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Steven R Smith, Pennigton Biomedical Research Center
ClinicalTrials.gov Identifier: NCT00402012     History of Changes
Other Study ID Numbers: PBRC26027
Study First Received: November 17, 2006
Last Updated: July 27, 2010
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Pennington Biomedical Research Center:
Diabetes Mellitus, Type 2

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

ClinicalTrials.gov processed this record on August 21, 2014