Clinical trial NCT03583554: Electrophysiological Biomarkers of AV-101
Official title: Electrophysiological Biomarkers of Kynurenine Pathway Modulator AV-101 in Healthy Volunteers: Treating Suicidal Veterans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Healthy
Keywords: Suicide
Kynurenine
metabolic pathway
Veterans
OEF/OIF/OND
electrophysiology
NMDA receptor
suicidal ideation
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: Michael E. DeBakey VA Medical Center
name: VistaGen Therapeutics, Inc.
First posted: 2018-07-11
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: placebo-controlled, randomized, double-blind, cross-over
Primary purpose: BASIC_SCIENCE

Brief summary: Suicide is 2-7x higher in Veterans than non-veterans, and may be related to brain kynurenine pathway (KP) dysregulation and NMDA receptor (NMDAR) hyperactivation. Experimental drug "AV-101" modulates the brain KP, with possible downstream NMDAR deactivation. The investigators will examine AV-101 NMDAR modulation by testing dose-response effects on resting state EEG, Mismatch Negativity, and P50 gating. Twelve healthy Operation Enduring Freedom (OEF) Operation Iraqi Freedom (OIF) and Operation New Dawn (OND) Veterans will be administered single dose AV-101 720 mg, 1440 mg, and placebo over 3 weeks in a randomized, double-blind, cross-over trial. Repeated measures General Linear Models will test dose-response effects. Suicide prevention is an important Veterans Affair (VA) mission. This study is a first step to testing anti-suicidal effects of AV-101 in Veterans.

Detailed description: Background: Suicide is the 10th leading cause of death in the US, and is 2-7 times higher in Veterans than age- and sex-matched civilians. Standard psychiatric medications (such as lithium) are anti-suicidal with prolonged use only, and do not impact acute suicidality. A priority for suicide prevention is to define novel treatment targets for safe and rapidly-acting interventions. Recent studies have associated suicide and medically severe suicide attempt (MSSA) with dysregulation of the brain kynurenine pathway (KP), which could predispose to excessive NMDAR activation, a molecular target purportedly involved in rapid improvement of suicidality with agents such as ketamine. AV-101 (4-chlorokynurenine, 4-Cl-KYN) is an oral pro-drug that targets KP dysregulation with downstream NMDAR deactivation. Phase-1 testing showed that AV-101 is metabolized to 7-Cl-KYN in 1.5 to 2 hours after intake.

Objective: Before testing possible anti-suicidal properties, biomarkers need to be defined to show that AV-101 engages the NMDAR. The objective of the current study is to define valid and sensitive neurophysiological markers with a dose-response relationship with AV-101 as evidence of NMDAR engagement, as well as study safety and tolerability.

Methods: The investigators will recruit 12 healthy and non-psychiatrically ill OEF/OIF/OND Veterans (age 25-64) who will receive two single doses of AV-101 (720 mg, 1440 mg) and placebo in a randomized, double-blind, crossover design with one week wash-out between conditions. Neurophysiological measures collected at baseline (pre-treatment) and hourly for 5 hours following medication intake are resting state EEG, Mismatch Negativity amplitude, and P50 sensory gating, measures sensitive to modulation of different NMDAR mechanisms. Repeated measures General Linear Models will be used to test dose-response relationships.

Eligibility criteria: Inclusion Criteria

* Age 21-64, inclusive
* US military Veteran
* Healthy volunteer.
* Subject and partner are both using at least 1 medically accepted contraception (double barrier) at randomization until 1 month after single dose

Exclusion Criteria

* History of any Axis 1 psychiatric condition
* History of psychosis in first-degree family members
* History of use of psychoactive medication
* Current use of any medication or vitamins except the pill (women)
* History of use of any substances of abuse, except for alcohol, caffeine, and nicotine
* Positive at tests for alcohol and illicit substance at screening and study visits.
* History of epilepsy, head injury, stroke, primary neurological disorder
* Clinically significant abnormal laboratory values, vital signs or ECG placing participants at risk for serious adverse events as determined by the study physician
* Pregnant or nursing
* Serious, unstable illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease

Primary outcomes:
measure: Mean 40-Hz Auditory Steady State Response Power
timeFrame: 4 hours
Secondary outcomes:
measure: Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine
timeFrame: 4 hours
measure: Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid
timeFrame: 4 hours
measure: Mean Systolic Blood Pressure
timeFrame: 5 hours
measure: Mean Diastolic Blood Pressure
timeFrame: 5 hours
measure: Mean Pulse
timeFrame: 5 hours
measure: Mean Profile of Moods Scale Total Score
timeFrame: 5 hours
Other outcomes:
Locations:
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center
state: Texas
Study officials:
affiliation: Baylor College of Medicine and the Michael E. DeBakey VA Medical Center
name: Marijn Lijffijt, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Murphy N, Ramakrishnan N, Vo-Le B, Vo-Le B, Smith MA, Iqbal T, Swann AC, Mathew SJ, Lijffijt M. A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-D-aspartate receptor blockade in healthy veterans. Neuropsychopharmacology. 2021 Mar;46(4):820-827. doi: 10.1038/s41386-020-00917-z. Epub 2020 Dec 14.
citation: Murphy N, Lijffijt M, Ramakrishnan N, Vo-Le B, Vo-Le B, Iqbal S, Iqbal T, O'Brien B, Smith MA, Swann AC, Mathew SJ. Does mismatch negativity have utility for NMDA receptor drug development in depression? Braz J Psychiatry. 2022 Jan-Feb;44(1):61-73. doi: 10.1590/1516-4446-2020-1685.