Mitochondrial Oxidation and Insulin Resistance in Burn Patients Treated With Fenofibrate - Full Text View

Sponsor:	The University of Texas, Galveston
Collaborator:	Shriners Hospitals for Children
Information provided by:	The University of Texas, Galveston
ClinicalTrials.gov Identifier:	NCT00732485

Purpose

Major burn injury causes significant insulin resistance on glucose and protein metabolism that persists for up to 6 months after the acute injury

This project proposes to answer the following questions:

Will fenofibrate given to burn patients with insulin resistance restore their insulin sensitivity?
What is the relationship between mitochondrial dysfunction in muscle tissue as the causative mechanism of burn related insulin resistance?
To what extent will the restored insulin sensitivity affect glucose and protein metabolism in muscle, regenerating wounds and the liver, i.e. ameliorate burn related hyperglycemia and protein catabolism?

Condition	Intervention	Phase
Burn	Drug: fenofibrate Drug: placebo	Phase II Phase III

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:	The Role of Mitochondrial Oxidation on Insulin Resistance in Burn Patients Treated With Fenofibrate

Resource links provided by NLM:

MedlinePlus related topics: Burns Diabetes Medicines

Drug Information available for: Insulin Insulin beef Procetofen

U.S. FDA Resources

Further study details as provided by The University of Texas, Galveston:

Primary Outcome Measures:

Insulin sensitivity on glucose and protein metabolism [ Time Frame: From admission to burn unit to 6 months post burn ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Systemic glucose homeostasis [ Time Frame: Admission to 6 months post burn ] [ Designated as safety issue: No ]
Muscle protein balance [ Time Frame: Admission to 6 months post burn ] [ Designated as safety issue: No ]
Wound protein balance [ Time Frame: Admission to 6 months post burn ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	August 2008
Estimated Study Completion Date:	December 2013
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Fenofibrate	Drug: fenofibrate Fenofibrate, PO, 5 mg/kg/day from admission to 6 months post burn
Placebo Comparator: Placebo	Drug: placebo Placebo, sugar pill, from admission to 6 months post burn

Detailed Description:

The following specific hypotheses will be investigated:

Following severe burn injury in human patients the mitochondrial fat oxidation capacity is decreased in muscle. This is associated with a corresponding progression in the severity of the resistance to the action of insulin on glucose disposal and protein synthesis and breakdown in muscle, regenerating wound and liver.
Fatty acids, or their active intracellular products (e.g., DAG, acyl-CoA, or acylcarnitine), are the direct inhibitors of insulin action, rather than tissue TG itself. In other words, impaired mitochondrial fatty acid oxidation is the mechanism that causes altered lipid metabolism that ultimately contributes to insulin resistance.
Accumulation of active fatty acid products, such as DAG, acyl-CoA, or acylcarnitine esters in muscle cells is due to the rate of uptake of plasma FFA exceeding the rate of oxidation within muscle due principally to a reduced capacity of mitochondria to oxidize fatty acids.
Decreased insulin sensitivity in muscle is related to impaired insulin signaling. This will be reflected by increased activity of protein kinase C (PKC). Because PKC is thought to exert its regulatory effect primarily on either tyrosine kinase activity on the insulin receptor or downstream kinase insulin receptor substrate (IRS) phosphorylation, these elements of the insulin signaling cascade will be decreased. In turn, elements of insulin signaling related to the response of muscle glucose (PI3 kinase) and protein (P70S6k) metabolism will be reduced. We propose that increased tissue PKC activity will be associated with increased tissue concentration of DAG, acyl-CoA, or acylcarnitine.
Treatment of patients with the peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate will improve mitochondrial capacity to oxidize fatty acids.
Insulin sensitivity in muscle, skin and liver in terms of both glucose and protein metabolism will be improved by fenofibrate treatment.

Eligibility

Ages Eligible for Study:	7 Years to 20 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients > 7 years old with burns covering 40% or more of body surface who are admitted to the Shriners Hospital for Children, Galveston, TX

Exclusion Criteria:

Abnormal liver and kidney function,
Pregnancy,
Diabetes mellitus,

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00732485

Contacts

Contact: David N Herndon, MD

409-770-6733

dherndon@utmb.edu

Locations

United States, Texas
Shriners Hospital for Children	Recruiting
Galveston, Texas, United States, 77550
Contact: Celeste C Finnerty, PhD 409-770-6567 ccfinner@utmb.edu
Principal Investigator: David N Herndon, MD

Sponsors and Collaborators

The University of Texas, Galveston

Shriners Hospitals for Children

Investigators

Principal Investigator:

David Herndon, MD

University of Texas Medical Branch, Galveston

More Information

Publications:

Cree MG, Zwetsloot JJ, Herndon DN, Qian T, Morio B, Fram R, Sanford AP, Aarsland A, Wolfe RR. Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. Ann Surg. 2007 Feb;245(2):214-21.

Responsible Party:	David Herndon, MD, Principal Investigator, University of Texas Medical Branch (UTMB), Galveston
ClinicalTrials.gov Identifier:	NCT00732485 History of Changes
Other Study ID Numbers:	07-389, SHC 08-GAL-006
Study First Received:	August 8, 2008
Last Updated:	June 21, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by The University of Texas, Galveston:

Burn injury
Fenofibrate
Insulin resistance
Mitochondrial function
Fat oxidation

PPAR
Protein
Glucose
Wound

Additional relevant MeSH terms:

Burns
Insulin Resistance
Wounds and Injuries
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Fenofibrate

Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 09, 2012