Mitochondrial Oxidation and Insulin Resistance in Burn Patients Treated With Fenofibrate

This study has been withdrawn prior to enrollment.
(Principal Investigator Changed)
Sponsor:
Collaborator:
Shriners Hospitals for Children
Information provided by (Responsible Party):
The University of Texas, Galveston
ClinicalTrials.gov Identifier:
NCT00732485
First received: August 8, 2008
Last updated: December 10, 2012
Last verified: December 2012
  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:

  1. Will fenofibrate given to burn patients with insulin resistance restore their insulin sensitivity?
  2. What is the relationship between mitochondrial dysfunction in muscle tissue as the causative mechanism of burn related insulin resistance?
  3. 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 2
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: The Role of Mitochondrial Oxidation on Insulin Resistance in Burn Patients Treated With Fenofibrate

Resource links provided by NLM:


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 ]

Enrollment: 0
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:

  1. 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.
  2. Fatty acids, or their active intracellular products (e.g., DAG, acyl-CoenzymeA (Co-A), or acylcarnitine), are the direct inhibitors of insulin action, rather than tissue triglycerides (TG) itself. In other words, impaired mitochondrial fatty acid oxidation is the mechanism that causes altered lipid metabolism that ultimately contributes to insulin resistance.
  3. 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 free fatty acid (FFA) exceeding the rate of oxidation within muscle due principally to a reduced capacity of mitochondria to oxidize fatty acids.
  4. 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.
  5. Treatment of patients with the peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate will improve mitochondrial capacity to oxidize fatty acids.
  6. 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, Texas

Exclusion Criteria:

  • Abnormal liver and kidney function,
  • Pregnancy,
  • Diabetes mellitus,
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00732485

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:
Responsible Party: The University of Texas, 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: December 10, 2012
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 April 17, 2014