Metabolic Therapy for Traumatic Brain Injury (MT-TBI)

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Metabolic crisis is a state of energy insufficiency due to impaired mitochondrial function as indicated by cerebral microdialysis lactate/pyruvate ratio (LPR). We have performed safety analysis of glucose and sodium lactate infusions in humans and have demonstrated proof of concept that these fuels alter brain metabolism. We will conduct a multicenter, adaptive design-based, proof of concept unblinded phase 2 study of up to 3 candidate supplemental fuels infused over 3 hours in patients with severe traumatic brain injury undergoing standard of care multimodality monitoring with cerebral microdialysis.

Condition or disease	Intervention/treatment	Phase
Brain Injuries, Traumatic	Drug: Glucose; Drug: Lactate; Drug: Beta-hydroxybutyrate	Phase 1; Phase 2

Detailed Description:

Metabolic crisis is a state of energy insufficiency due to impaired mitochondrial function as indicated by cerebral microdialysis lactate/pyruvate ratio (LPR). We have performed safety analysis of glucose and sodium lactate infusions in humans and have demonstrated proof of concept that these fuels alter brain metabolism. Animal TBI studies have demonstrated proof of concept for all three candidate fuels. We will conduct a multicenter, adaptive design-based, proof of concept unblinded phase 2 study of up to 3 candidate supplemental fuels infused over 3 hours in patients with severe TBI undergoing standard of care multimodality monitoring with cerebral microdialysis. The three candidate fuels are be glucose, sodium lactate, and beta-hydroxybutyrate, with doses to be established in animal models. Infusions will be guided by point of care testing to achieve the ideal blood concentration during the infusion during the infusion.

This is a 5-year safety study using a parallel intervention model with 4 arms, open-label, non-randomized.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	170 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Metabolic Therapy for Traumatic Brain Injury
Estimated Study Start Date :	October 2017
Estimated Primary Completion Date :	December 2020
Estimated Study Completion Date :	June 2021

Arms and Interventions

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Arm	Intervention/treatment
No Intervention: Control; Standard of Care
Experimental: Glucose; Infusion of glucose as supplemental fuel (dosage form = solute, dosage to be determined, frequency = 1x, duration = 3hr)	Drug: Glucose; Less than one fifth of one ounce of glucose mixed in standard saline solution will be administered through a standard venous drip line or through the microdialysis catheter as part of standard brain chemistry analyses.
Experimental: Lactate; Infusion of sodium lactate as supplemental fuel (dosage form = solute, dosage TBD, frequency = 1x, duration = 3hr)	Drug: Lactate; Less than two thirds of an ounce of lactate mixed in standard saline solution will be administered through a standard venous drip line or through the microdialysis catheter as part of the standard brain chemistry analyses.; Other Name: Sodium lactate
Experimental: Beta-hydroxybutyrate; Infusion of beta-hydroxybutyrate as supplemental fuel (dosage form = solute, dosage TBD, frequency = 1x, duration = 3hr)	Drug: Beta-hydroxybutyrate; Less than one tenth of one ounce of hydroxybutyrate mixed in standard saline solution will be administered through a standard venous drip line or through the microdialysis catheter as part of the standard brain chemistry analyses.

Outcome Measures

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Primary Outcome Measures :

1. Normalization of the cerebral microdialysis lactate/pyruvate ratio (LPR) [ Time Frame: 30 days ]
   LPR obtained from measures of fluid through a brain catheter is a marker of metabolic crisis

Secondary Outcome Measures :

1. Safety endpoints [ Time Frame: 30 days, 6 months, 12 months ]
   Treatment effect at least noninferior to available comparators, using all-cause mortality within each timeframe
2. Frontal lobe atrophy [ Time Frame: 6 months post injury ]
   Frontal lobe atrophy obtained from brain imaging using magnetic resonance imaging at follow-up visit
3. Glasgow Outcome Scale - Extended [ Time Frame: 6 months, 12 months ]
   Functional outcome assessment
4. Mayo-Portland Adaptability Inventory-4 [ Time Frame: 6 months, 12 months ]
   Physical, cognitive, emotional, behavioral, and social assessment
5. Trail Making Test [ Time Frame: 6 months, 12 months ]
   Assessment of attention and executive ability
6. Post-traumatic Amnesia Questionnaire [ Time Frame: 6 months, 12 months ]
   Assessment of orientation to person, place and time, and retention of new information
7. Hooper Visual Organization Test [ Time Frame: 6 months, 12 months ]
   Assessment of visuoperception

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Adult patients seen in the Medical Center Emergency Department
• Adult patients transferred to the Neurocritical Intensive Care Unit with a physician's diagnosis of brain injury.

Exclusion Criteria:

• Pregnancy at time of injury
• History of diabetes mellitus
• History of hemodynamic instability
• Known terminal illness which alters brain functioning
• Diagnosed AIDS progressed to AIDS dementia
• Known history of chronic severe neurological disturbance
• Severe retardation
• Previous severe diminished mental capacity
• No command of either English or Spanish
• Arrest for a felony

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Courtney Real, BSN RN	310-267-7433	creal@mednet.ucla.edu
Contact: David L McArthur, PhD MPH	310-825-0688	dmca@ucla.edu

Locations

United States, California
David Geffen School of Medicine at UCLA	Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Steven Cohen, MHA 310-794-1801 steven.cohen@mednet.ucla.edu

Sponsors and Collaborators

University of California, Los Angeles

Investigators

Principal Investigator:	Paul Vespa, MD	University of California Los Angeles, Department of Neurosurgery

More Information

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Publications:

Glenn TC, Martin NA, Horning MA, McArthur DL, Hovda DA, Vespa P, Brooks GA. Lactate: brain fuel in human traumatic brain injury: a comparison with normal healthy control subjects. J Neurotrauma. 2015 Jun 1;32(11):820-32. doi: 10.1089/neu.2014.3483. Epub 2015 Mar 31.

Glenn TC, Martin NA, McArthur DL, Hovda DA, Vespa P, Johnson ML, Horning MA, Brooks GA. Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis. J Neurotrauma. 2015 Jun 1;32(11):811-9. doi: 10.1089/neu.2014.3482. Epub 2015 Mar 11.

Vespa P, McArthur DL, Stein N, Huang SC, Shao W, Filippou M, Etchepare M, Glenn T, Hovda DA. Tight glycemic control increases metabolic distress in traumatic brain injury: a randomized controlled within-subjects trial. Crit Care Med. 2012 Jun;40(6):1923-9. doi: 10.1097/CCM.0b013e31824e0fcc.

Vespa P, Bergsneider M, Hattori N, Wu HM, Huang SC, Martin NA, Glenn TC, McArthur DL, Hovda DA. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 2005 Jun;25(6):763-74.

Vespa P, Tubi M, Claassen J, Buitrago-Blanco M, McArthur D, Velazquez AG, Tu B, Prins M, Nuwer M. Metabolic crisis occurs with seizures and periodic discharges after brain trauma. Ann Neurol. 2016 Apr;79(4):579-90. doi: 10.1002/ana.24606. Epub 2016 Feb 28.

Xu Y, McArthur DL, Alger JR, Etchepare M, Hovda DA, Glenn TC, Huang S, Dinov I, Vespa PM. Early nonischemic oxidative metabolic dysfunction leads to chronic brain atrophy in traumatic brain injury. J Cereb Blood Flow Metab. 2010 Apr;30(4):883-94. doi: 10.1038/jcbfm.2009.263. Epub 2009 Dec 23.

Bouzat P, Magistretti PJ, Oddo M. Hypertonic lactate and the injured brain: facts and the potential for positive clinical implications. Intensive Care Med. 2014 Jun;40(6):920-1. doi: 10.1007/s00134-014-3312-x. Epub 2014 May 1.

Bouzat P, Sala N, Suys T, Zerlauth JB, Marques-Vidal P, Feihl F, Bloch J, Messerer M, Levivier M, Meuli R, Magistretti PJ, Oddo M. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensive Care Med. 2014 Mar;40(3):412-21. doi: 10.1007/s00134-013-3203-6. Epub 2014 Jan 30.

Responsible Party:	Paul Vespa, MD, Professor, University of California, Los Angeles
ClinicalTrials.gov Identifier:	NCT02776488 History of Changes
Other Study ID Numbers:	MT01
First Posted:	May 18, 2016
Last Update Posted:	June 26, 2017
Last Verified:	June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No
Plan Description:	All PHI will be expunged from records before any sharing occurs

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Keywords provided by Paul Vespa, MD, University of California, Los Angeles:

brain trauma, metabolic therapy

Additional relevant MeSH terms:

Wounds and Injuries; Brain Injuries; Brain Injuries, Traumatic; Brain Diseases	Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System