Acute and Long-Term Outcome Investigations of Fenofibrate on Severely Burned Patients

Study Overview
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Brief Summary
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The purpose of this study is to learn the following: whether long-term treatment (6 months) with fenofibrate will decrease burn related sugar and fat increased in the blood and help prevent muscle loss and improve wound healing.

Detailed Description
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Following severe burn injury in human patients the mitochondrial fat oxygenation 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. Diacylglycerol, acyl- Coenzyme A(CoA) or acylcarnitine) are the direct inhibitors of insulin action, rather than tissue triglycerides(TG) itself. In other words, impaired mitochondrial fatty acid oxygenation is the mechanism that causes altered lipid metabolism that ultimately contributes to insulin resistance. Accumulation of active fatty acid products, such as Diacylglycerol, acyl-CoA or acylcarnitine esters in muscle cells is due to the rate of uptake of plasma free fatty acids(FFA) exceeding the rate of oxygenation within muscle due principally to a reduced capacity of mitochondria to oxidize fatty acids. Decreasing 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. The investigators propose that increased tissue PKC activity will be associated with increased tissue concentration of Diacylglycerol, acyl-CoA or acylcarnitine. The investigators hypothesize that the treatment of patients with the peroxisome proliferator-activated receptor (PPAR) alpha antagonist 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.

Official Title
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Acute and Long-Term Outcome Investigations of Fenofibrate on Severely Burned Patients

Conditions
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Second or Third Degree Burns

Intervention / Treatment
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* Drug: Fenofibrate
* Drug: Sugar Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥40% Burn ages 4-20years body weight ≥10kg Exclusion Criteria: <40% burn ages <4->20 years body weight <10kg Respiratory insufficiency Multiple fractures History of cancer in last 5 years Bilirubin>3mg/dL Serum Creatinine>3mg/dL after fluid resuscitation Glutamyl-Oxaloacetic Transaminase(GOT) >40 Units/L Glutamyl-Pyruvate Transminase(GPT) >51 Units/L Associated head injuries requiring therapy Associated injuries to the chest or abdomen requiring surgery Receipt of any experimental drug other than the ones supplied within two months of study Any metal in body including rods, cardiac defibrillators, pacemaker, etc Orthopedic casting which would prevent placement in MRI Hepatitis Abnormal EKG Electrical burns

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Sugar pill<br>pill | Drug: Sugar Pill<br>* pill every day for 6 months<br>* Other names: Placebo;|
| Active Comparator: Fenofibrate<br>ppar-alpha agonist | Drug: Fenofibrate<br>* Pill 54 mg or 160 mg tablets every day for 6 months Dosing-5mg/kg up to 160 mg for 6 months<br>* Other names: Lofibra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitochondrial fatty acid oxygenation | Changes in mitochondrial oxygen consumption, Palmitoyl-CoA, palmitoyl-L-Carnitine, Pyruvate, Malate, Malonyl-CoA | 6 months post injury | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | Muscle amino acid uptake, protein synthesis and breakdown. Insulin receptor tyrosine kinase activity, insulin receptor substrate activity,protein kinase C activity,glucose uptake and enrichment. Fractioned synthetic rate of plasma proteins | 6month post injury | 
| Protein Metabolism |  | 6 months post injury | 
| Glucose Metabolism |  | 6 months post injury | 
| Amino Acid Metabolism |  | 6 months post injury | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Burn, Fenofibrate, PPAR alpha agonist, insulin sensitivity, mitochondrial