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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This study has been withdrawn prior to enrollment.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

August 8, 2008
December 10, 2012
August 2008
December 2012   (final data collection date for primary outcome measure)
Insulin sensitivity on glucose and protein metabolism [ Time Frame: From admission to burn unit to 6 months post burn ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00732485 on ClinicalTrials.gov Archive Site
  • 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 ]
Same as current
Not Provided
Not Provided
 
Mitochondrial Oxidation and Insulin Resistance in Burn Patients Treated With Fenofibrate
The Role of Mitochondrial Oxidation on Insulin Resistance in Burn Patients Treated With Fenofibrate

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?

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.
Interventional
Phase 2
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Burn
  • Drug: fenofibrate
    Fenofibrate, PO, 5 mg/kg/day from admission to 6 months post burn
  • Drug: placebo
    Placebo, sugar pill, from admission to 6 months post burn
  • Active Comparator: Fenofibrate
    Intervention: Drug: fenofibrate
  • Placebo Comparator: Placebo
    Intervention: Drug: placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Withdrawn
0
December 2013
December 2012   (final data collection date for primary outcome measure)

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,
Both
7 Years to 20 Years
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
 
NCT00732485
07-389, SHC 08-GAL-006
Yes
The University of Texas, Galveston
The University of Texas, Galveston
Shriners Hospitals for Children
Principal Investigator: David Herndon, MD University of Texas Medical Branch, Galveston
The University of Texas, Galveston
December 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP