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

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.

Study Overview

• Status: Terminated
• Conditions: Second or Third Degree Burns
• Intervention / Treatment: Drug: Sugar Pill; Drug: Fenofibrate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Galveston, Texas, United States, 77551
      • University of Texas Medical Branch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The University of Texas Medical Branch, Galveston
• Collaborators: Shriners Hospitals for Children

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: March 22, 2012
• First Submitted That Met QC Criteria: April 9, 2012
• First Posted (Estimate): April 10, 2012

Study Record Updates

• Last Update Posted (Actual): November 29, 2019
• Last Update Submitted That Met QC Criteria: November 26, 2019
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: insulin sensitivity; mitochondrial; Fenofibrate; Burn; PPAR alpha agonist
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Fenofibrate
• Other Study ID Numbers: 11-106