Changes in Glutamatergic Neurotransmission of Severe TBI Patients

NCT04244058 | Suspended Early Phase 1 DMC FDA Drug

• 1 other identifier: 19-09020845
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Studies in patients with disorders of consciousness (DOC) after severe brain injury implicate dysfunction of the anterior forebrain mesocircuit dysfunction a key underlying mechanism. The anterior forebrain metabolism in DOC is markedly downregulated across brain regions underpinning highly elaborated cognitive behaviors demonstrating a collapse of the level of synaptic background activity required for consistent goal-directed behavior and arousal regulation. Since dopamine levels are one of the primary controllers of the level of synaptic background activity within these forebrain structures and in regulating excitatory glutamatergic homeostasis, the investigators propose to investigate the specific contribution of presynaptic dopamine function in glutamatergic neurotransmission in posttraumatic DOC. The aim of the present study is to measure metabotropic glutamate receptors 5 occupancy in the main gutamatergic structures of the brain using (3-\[18F\]fluoro-5-(2-pyridinylethynyl)benzonitrile)-positron emission tomography ( \[18F\]FPEB-PET) at rest and following a short pharmacological challenge with amantadine, an N-methyl-D-aspartate receptor (NMDA-R) antagonist, following L-DOPA, and amantadine + L-DOPA. Using this novel technique in DOC the investigators will characterize the relevance of a presynaptic deficiency to synthesize and/or release dopamine in the final regulation of excitatory interneurons of the anterior forebrain mesocircuit. It is unknown whether glutamatergic neurotransmission is affected across the population of subjects with DOC and, if this condition is secondary to a presynaptic dopaminergic failure of the anterior forebrain mesocircuit (i.e., down-regulation). Since the investigators previously identified the existence of a presynaptic dopaminergic deficit in these subjects due to a failure in the biosynthesis of dopamine, the investigators will evaluate if by providing the main biological substrate of the biosynthesis process (i.e., L-DOPA) the glutamatergic system regains homeostasis. The investigators therefore propose to investigate patients with posttraumatic DOC using \[18F\]FPEB-PET at rest and following short pharmacological challenges aimed at increasing glutamate and dopamine release.

Conditions

Disorder of Consciousness; Traumatic Brain Injury

Keywords

Positron emission tomography; 18F-FPEB; NMDA; Dopamine; mGlu5-R; Molecular neuroimaging; Traumatic brain injury; Disorders of consciousness

Outcome Measures

Primary Outcomes (1)

• Delta % changes in binding potential nondisplaceable (%ΔBPnd)

  BPnd induced by pharmacological challenges using AMT, L-DOPA and, AMT+L-DOPA (%ΔBPnd-AMT, L- DOPA and AMT+L-DOPA, respectively).

  Day 1 and Day 2

Secondary Outcomes (1)

• Coma Recovery Scale Revised

  Day 1 and Day 2

Study Arms (2)

NMDA blocker

ACTIVE COMPARATOR

Comprehensive functional analyses of dynamic \[18F\]FPEB-PET signal at rest will be carried out in normal volunteers and patients with DOC due to severe brain injury over a 24-month time period. In each study, we will first evaluate mGluR5 occupancy within the frontal cortex, anterior cingulate cortex, insula, striatum and thalamus. Then, a single dose of amantadine (AMT), a compound that blocks NMDA-R and increases glutamate levels at the synaptic cleft, will be given to each subject or patient and at the time corresponding to the peak of the dose, a second \[18F\]FPEB-PET will be acquired.

Drug: NMDA blocker

NMDA blocker + L-DOPA

EXPERIMENTAL

All the patients with DOC that participate in ARM 1 will follow the same methodology of ARM 1: measurement of mGluR5 occupancy at rest and following NMDA-R blockade with AMT by means of \[18F\]FPEB-PET after premedication with L-DOPA introduced 1 hour prior each \[18F\]FPEB-PET acquisitions.

Drug: Amantadine + L-DOPA

Interventions

Amantadine + L-DOPA DRUG

Amantadine 150 mg L-DOPA 375mg/carbidopa 75mg

NMDA blocker + L-DOPA

NMDA blocker DRUG

NMDA blocker

NMDA blocker

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 75 years of age, inclusive.
• Patients with disorder of consciousness (vegetative state, minimally conscious state, emerged from minimally conscious state) following severe brain injuries.
• Male or non-pregnant female.
• Medically stable.
• Informed consent from a Legally Authorized Representative.

You may not qualify if:

• Medical instability.
• Clinical history of moderate to severe hypertension or heart arrhythmia.
• Use of stimulants or dopamine blocker during the 24 hours previous to the study.
• Absence of a legally authorized representative (LAR) to sign the consent form.
• Normal Volunteers
• Age between 18 and 75 years old, inclusive.
• Absence of cardiological, neurological and/or psychiatric diseases.
• Absence of familiar antecedents of sudden death of unknown reason.
• Male or non-pregnant female.
• Informed consent signed.
• \- Caffeine or alcohol intake in the last 24 hours previous to the study.

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (1)

Weill Cornell Medicine

New York, New York, 10065, United States

Location

Related Publications (3)

• Fridman EA, Osborne JR, Mozley PD, Victor JD, Schiff ND. Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury. Brain. 2019 Jul 1;142(7):1887-1893. doi: 10.1093/brain/awz118.

  PMID: 31505542 BACKGROUND

• Fridman EA, Schiff ND. Neuromodulation of the conscious state following severe brain injuries. Curr Opin Neurobiol. 2014 Dec;29:172-7. doi: 10.1016/j.conb.2014.09.008. Epub 2014 Oct 3.

  PMID: 25285395 BACKGROUND

• Fridman EA, Beattie BJ, Broft A, Laureys S, Schiff ND. Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain. Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6473-8. doi: 10.1073/pnas.1320969111. Epub 2014 Apr 14.

  PMID: 24733913 BACKGROUND

Related Links

• Weill Cornell Medicine Consortium for the Advanced Study of Brain Injury (CASBI)

MeSH Terms

Conditions

Consciousness Disorders; Brain Injuries, Traumatic

Interventions

Amantadine; Levodopa

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Dihydroxyphenylalanine; Catecholamines; Amines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Tyrosine

Study Officials

• Esteban A Fridman, MD, PhD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants will be unaware of the medication used during the pharmacological challenge for the PET approach.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2020
• First Posted: January 28, 2020
• Study Start: September 23, 2020
• Primary Completion: May 30, 2023
• Study Completion: June 30, 2023
• Last Updated: September 30, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data will be available from publication date up to 3 years.
• Access Criteria: Only under a data-sharing agreement.

Locations

US (1)