NCT04244058

Changes in Glutamatergic Neurotransmission of Severe TBI Patients

Suspended EARLY_PHASE1 Last updated 30 September 2022

What this trial tests

EARLY_PHASE1 trial testing Amantadine + L-DOPA in Disorder of Consciousness in 30 participants. Suspended.

Timeline

23 September 2020

Primary endpoint
30 May 2023

30 June 2023

Quick facts

Lead sponsor	Weill Medical College of Cornell University
Phase	EARLY_PHASE1
Status	Suspended
Study type	INTERVENTIONAL
Allocation	non randomized
Design	crossover
Masking	single
Primary purpose	basic science
Enrollment	30
Start date	23 September 2020
Primary completion	30 May 2023
Estimated completion	30 June 2023
Sites	1 location across United States

Drugs / interventions tested

• Amantadine + L-DOPA — full drug profile →
• NMDA blocker — full drug profile →

Conditions studied

• Disorder of Consciousness — all drugs for Disorder of Consciousness →
• Traumatic Brain Injury — all drugs for Traumatic Brain Injury →

Sponsor

Weill Medical College of Cornell University

Who can join

Adults 18 to 75, any sex, with Disorder of Consciousness or Traumatic Brain Injury. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Current Clinical Trials in Traumatic Brain Injury.
   Ahmed Z. · · 2022 · cited 23× · PMID 35624914 · DOI 10.3390/brainsci12050527