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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Pioglitazone Reverses Defects in Mitochondrial Biogenesis in Patients With T2DM

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00402012
• Other study ID #: PBRC 26027
• Status: Completed
• Phase: Phase 4
• First received: November 17, 2006
• Last updated: December 17, 2015
• Start date: November 2006
• Est. completion date: December 2007

Study information

• Verified date: December 2015
• Source: Pennington Biomedical Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: December 2007
• Est. primary completion date: December 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

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.

Locations

Country	Name	City	State
United States	Pennington Biomedical Research Center	Baton Rouge	Louisiana

Sponsors (2)

Lead Sponsor	Collaborator
Pennington Biomedical Research Center	Takeda Pharmaceuticals North America, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in skeletal muscle mitochondrial number (electron microscopy + qPCR of mtDNA) and mitochondrial gene expression in T2DM patients treated with pioglitazone (vs. placebo)		baseline and after intervention	No
Secondary	insulin sensitivity for insulin suppression of free fatty acid and glucose disposal		baseline and after intervention	No
Secondary	electron transport chain activity; mitochondrial content by MRS (ATP max)		baseline and after intervention	No
Secondary	intra hepatic and intra myocellular lipid by MRS; mitochondrial content by MRS (ATP max) post weight loss period		baseline ,after treatment and after weight loss	No