Assessment of the Treatment of Severely Burned With Anabolic Agents on Clinical Outcomes, Recovery and Rehabilitation

Assessment of the Treatment of the Severely Burned With Anabolic Agents on Clinical Outcomes, Recovery and Rehabilitation

The purpose of the program is to study and characterize the outcome of burn injury with particular attention to improving the rehabilitation of burn survivors, including children. Various agents are assessed for effectiveness on long term burn outcome, such as growth hormone, oxandrolone, propranolol,ketoconazole, inhospital exercise and home exercise.

Study Overview

• Status: Terminated
• Conditions: Burns
• Intervention / Treatment: Procedure: Stable Isotope Infusion Study; Procedure: Collection of blood and tissues; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Drug: Humatrope; Drug: Ketoconazole; Drug: Oxandrolone; Drug: Propranolol; Drug: Oxandrolone and propranolol combined; Drug: Humatrope and propranolol combined; Drug: Placebo; Behavioral: Exercise--Hospital supervised intensive exercise program; Behavioral: Home exercise program

Detailed Description

The University of Texas Medical Branch(UTMB) project improves outcomes for severely burned children by instituting and evaluating two modifications to traditional rehabilitation: (1) an intensive rehabilitation program including active resistance exercise; (2) long term administration of anabolic agents.

Effectiveness is assessed by comparison with functional outcomes achieved in traditional outpatient rehabilitation programs. Results indicate improvement in strength, endurance and bone density with these modifications. The project also maintains a longitudinal database that includes measures of cardiopulmonary function, growth and maturation, bone density, range of motion, and psychosocial adjustment.

• Study Type: Interventional
• Enrollment (Actual): 1126
• Phase: Phase 2; Phase 3

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: No older than 76 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Burn 30% Total Body Surface Area (TBSA) or greater
• Ages 0-80 yrs
• Negative pregnancy test
• Informed consent

Exclusion Criteria:

• Untreated malignancy, known history of AIDS, Aids Related Complex, HIV
• Recent history of myocardial infarction (6 wks)
• Tuberculosis, arthritis, cirrhosis, hyperlipidemia, bone or endocrine diseases, autoimmune diseases
• Chronic glucocorticoid or non steroidal anti inflammatory drug therapy
• Diabetes mellitus prior to burn injury
• Renal insufficiency (defined by creatinine >3.0 mg/dl)
• Hepatic disease (bilirubin > 3.0 mg/dl)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Humatrope subcutaneous(SQ) 0.05-0.2 mg/kg/day for up to 2 years post burn	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Drug: Humatrope; Humatrope (Growth Hormone) dose:0.05mg - 0.2mg/kg/day SQ daily for up to 2 years post burn injury.; Other Names: Growth Hormone; recombinant human growth hormone
Experimental: 2; Ketoconazole by mouth (PO) given twice a day throughout hospitalization for up to 2 years post burn	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Drug: Ketoconazole; Ketoconazole administration (or other glucocorticoid blocker--itraconazole or fluconazole) PO daily for up to 2 years post burn injury; Other Names: itraconazole; fluconazole
Experimental: 3; Oxandrolone PO given daily throughout hospitalization for up to 2 years post burn	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Drug: Oxandrolone; oxandrolone (or other anabolic steroid-testosterone or nandrolone) daily for up to 2 years post burn injury; Other Names: nandrolone; testosterone
Experimental: 4; Propranolol PO given daily throughout hospitalization for up to 2 years post burn	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Drug: Propranolol; Propranolol (or other beta adrenergic blocker--metoprolol, inderol), PO administration daily for up to 2 years post burn injury.; Other Names: metoprolol; inderol
Experimental: 5; Oxandrolone and propranolol PO to be given daily for up to 2 years post burn	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Drug: Oxandrolone and propranolol combined; Daily administration of oxandrolone and propranolol to be given for up to 2 years post burn injury.; Other Names: nandrolone; testosterone; metoprolol; inderol
Experimental: 6; Humatrope SQ and Propranolol PO to be given daily for up to 2 years post burn	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Drug: Humatrope and propranolol combined; Humatrope (growth hormone) and propranolol administration daily for up to 2 years post burn injury.; Other Names: Growth Hormone; metoprolol; recombinant human growth hormone; inderol
Placebo Comparator: 7; Placebo PO to be given for up to 2 years post burn	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Drug: Placebo; placebo to be given once a day for up to two years post burn injury.; Other Names: control
Experimental: 8; Exercise--hospital supervised intensive exercise program	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Behavioral: Exercise--Hospital supervised intensive exercise program; intensive exercise program supervised by trained personnel in the hospital environment for six up to twelve week program.; Other Names: exercise; aerobic exercise; intensive exercise; exercise rehabilitation program; hospital based exercise
Experimental: 9; Exercise--home or community based exercise program	Procedure: Stable Isotope Infusion Study; 1-8 hour stable isotope infusion study to be done following each surgery. Tagged isotopes to assess uptake into blood and tissues.; Procedure: Collection of blood and tissues; Blood draw with each stable isotope infusion study and weekly Tissue biopsy: skin, fat, muscle at stable isotope infusion study; Procedure: Radiology testing: Dual-energy X-ray absorptiometry (DEXA), ultrasound, MRI; Testing to be done following every stable isotope infusion study to measure muscle, fat and bone tissues.; Behavioral: Home exercise program; Home intensive exercise program: training occurs in hospital then patient sent home to continue exercise program for six weeks and up to 12 weeks at home.; Other Names: intensive exercise; Home exercise; exercise rehabilitation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measures of muscle wasting, weakness, immunosuppression chronic bone loss and decreased growth with increases in metabolic, hemodynamic, inflammatory and scarring responses.	Dual Energy X-Ray Absorptiometry measurements will be utilized to measure muscle wasting	Admission to burn unit and up to 2 years post burn and yearly after that

Collaborators and Investigators

• Sponsor: The University of Texas Medical Branch, Galveston
• Collaborators: National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); U.S. Department of Education
• Investigators: Study Director: David N Herndon, MD, University of Texas

Publications and helpful links

General Publications

• Jeschke MG, Williams FN, Finnerty CC, Rodriguez NA, Kulp GA, Ferrando A, Norbury WB, Suman OE, Kraft R, Branski LK, Al-mousawi AM, Herndon DN. The effect of ketoconazole on post-burn inflammation, hypermetabolism and clinical outcomes. PLoS One. 2012;7(5):e35465. doi: 10.1371/journal.pone.0035465. Epub 2012 May 11.
• Alloju SM, Herndon DN, McEntire SJ, Suman OE. Assessment of muscle function in severely burned children. Burns. 2008 Jun;34(4):452-9. doi: 10.1016/j.burns.2007.10.006. Epub 2008 Feb 20.
• Guillory AN, Herndon DN, Silva MB 3rd, Andersen CR, Suman OE, Finnerty CC. Oxandrolone Coadministration Does Not Alter Plasma Propranolol Concentrations in Severely Burned Pediatric Patients. J Burn Care Res. 2017 Jul/Aug;38(4):243-250. doi: 10.1097/BCR.0000000000000494.
• Herndon DN, Voigt CD, Capek KD, Wurzer P, Guillory A, Kline A, Andersen CR, Klein GL, Tompkins RG, Suman OE, Finnerty CC, Meyer WJ, Sousse LE. Reversal of Growth Arrest With the Combined Administration of Oxandrolone and Propranolol in Severely Burned Children. Ann Surg. 2016 Sep;264(3):421-8. doi: 10.1097/SLA.0000000000001844.
• Sousse LE, Herndon DN, Mlcak RP, Lee JO, Andersen CR, Zovath AJ, Finnerty CC, Suman OE. Long-Term Administration of Oxandrolone Improves Lung Function in Pediatric Burned Patients. J Burn Care Res. 2016 Sep-Oct;37(5):273-7. doi: 10.1097/BCR.0000000000000356.
• Diaz EC, Herndon DN, Lee J, Porter C, Cotter M, Suman OE, Sidossis LS, Borsheim E. Predictors of muscle protein synthesis after severe pediatric burns. J Trauma Acute Care Surg. 2015 Apr;78(4):816-22. doi: 10.1097/TA.0000000000000594.
• Kraft R, Herndon DN, Finnerty CC, Cox RA, Song J, Jeschke MG. Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study. Shock. 2015 Mar;43(3):222-7. doi: 10.1097/SHK.0000000000000294.
• Patel P, Sallam HS, Ali A, Chandalia M, Suman O, Finnerty CC, Herndon DN, Abate N. Changes in fat distribution in children following severe burn injury. Metab Syndr Relat Disord. 2014 Dec;12(10):523-6. doi: 10.1089/met.2014.0098. Epub 2014 Sep 11.
• Chondronikola M, Meyer WJ, Sidossis LS, Ojeda S, Huddleston J, Stevens P, Borsheim E, Suman OE, Finnerty CC, Herndon DN. Predictors of insulin resistance in pediatric burn injury survivors 24 to 36 months postburn. J Burn Care Res. 2014 Sep-Oct;35(5):409-15. doi: 10.1097/BCR.0000000000000017.
• Hardee JP, Porter C, Sidossis LS, Borsheim E, Carson JA, Herndon DN, Suman OE. Early rehabilitative exercise training in the recovery from pediatric burn. Med Sci Sports Exerc. 2014 Sep;46(9):1710-6. doi: 10.1249/MSS.0000000000000296.
• Finnerty CC, Ali A, McLean J, Benjamin N, Clayton RP, Andersen CR, Mlcak RP, Suman OE, Meyer W, Herndon DN. Impact of stress-induced diabetes on outcomes in severely burned children. J Am Coll Surg. 2014 Apr;218(4):783-95. doi: 10.1016/j.jamcollsurg.2014.01.038. Epub 2014 Jan 24.
• Finnerty CC, Herndon DN. Is propranolol of benefit in pediatric burn patients? Adv Surg. 2013;47:177-97. doi: 10.1016/j.yasu.2013.02.001. No abstract available.
• Finnerty CC, Mabvuure NT, Ali A, Kozar RA, Herndon DN. The surgically induced stress response. JPEN J Parenter Enteral Nutr. 2013 Sep;37(5 Suppl):21S-9S. doi: 10.1177/0148607113496117.
• Ray S, Ju X, Sun H, Finnerty CC, Herndon DN, Brasier AR. The IL-6 trans-signaling-STAT3 pathway mediates ECM and cellular proliferation in fibroblasts from hypertrophic scar. J Invest Dermatol. 2013 May;133(5):1212-20. doi: 10.1038/jid.2012.499. Epub 2013 Jan 10.
• Kraft R, Herndon DN, Finnerty CC, Hiyama Y, Jeschke MG. Association of postburn fatty acids and triglycerides with clinical outcome in severely burned children. J Clin Endocrinol Metab. 2013 Jan;98(1):314-21. doi: 10.1210/jc.2012-2599. Epub 2012 Nov 12.
• Herndon DN, Rodriguez NA, Diaz EC, Hegde S, Jennings K, Mlcak RP, Suri JS, Lee JO, Williams FN, Meyer W, Suman OE, Barrow RE, Jeschke MG, Finnerty CC. Long-term propranolol use in severely burned pediatric patients: a randomized controlled study. Ann Surg. 2012 Sep;256(3):402-11. doi: 10.1097/SLA.0b013e318265427e.
• Porro LJ, Herndon DN, Rodriguez NA, Jennings K, Klein GL, Mlcak RP, Meyer WJ, Lee JO, Suman OE, Finnerty CC. Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy. J Am Coll Surg. 2012 Apr;214(4):489-502; discussion 502-4. doi: 10.1016/j.jamcollsurg.2011.12.038.
• Traber MG, Leonard SW, Traber DL, Traber LD, Gallagher J, Bobe G, Jeschke MG, Finnerty CC, Herndon D. alpha-Tocopherol adipose tissue stores are depleted after burn injury in pediatric patients. Am J Clin Nutr. 2010 Dec;92(6):1378-84. doi: 10.3945/ajcn.2010.30017. Epub 2010 Sep 29.
• Branski LK, Herndon DN, Barrow RE, Kulp GA, Klein GL, Suman OE, Przkora R, Meyer W 3rd, Huang T, Lee JO, Chinkes DL, Mlcak RP, Jeschke MG. Randomized controlled trial to determine the efficacy of long-term growth hormone treatment in severely burned children. Ann Surg. 2009 Oct;250(4):514-23. doi: 10.1097/SLA.0b013e3181b8f9ca.

Helpful Links

• University of Texas web page to describe funded program
• burn care web site includes information on funded grant project

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2004
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): July 15, 2019

Study Registration Dates

• First Submitted: December 26, 2007
• First Submitted That Met QC Criteria: May 9, 2008
• First Posted (Estimate): May 12, 2008

Study Record Updates

• Last Update Posted (Actual): November 29, 2019
• Last Update Submitted That Met QC Criteria: November 26, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: exercise; anabolic agents
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Bone Density Conservation Agents; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Androgens; Cytochrome P-450 CYP2C19 Inhibitors; Anabolic Agents; Propranolol; Hormones; Ketoconazole; Itraconazole; Testosterone; Metoprolol; Fluconazole; Nandrolone; Methyltestosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate; Oxandrolone; Nandrolone Decanoate; Nandrolone phenpropionate
• Other Study ID Numbers: 04-157; P50GM060338 (U.S. NIH Grant/Contract); NIDILRR 90DP0043-03-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No