Electrophysiological Biomarkers of AV-101

NCT ID: NCT03583554

Last Updated: 2022-02-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-01
• Study Completion Date: 2019-10-19

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.

Conditions

Healthy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Placebo, then AV-101 720mg, then AV-101 1440mg

Participants first received oral placebo. After at least 3 days wash-out participants get oral AV-101 720mg (matching placebo capsules). After at least 3 days wash-out participants get oral AV-101 1440mg (matching placebo capsules).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Single dose of 4 placebo oral capsules

AV-101 720 mg

Intervention Type: DRUG

Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules

AV-101 1440 mg

Intervention Type: DRUG

Single dose of 4 360 mg AV-101 oral capsules

AV-101 720mg, then AV-101 1440mg, then placebo

Participants first received oral AV-101 720mg (matching placebo capsules). After at least 3 days wash-out participants get oral AV-101 1440mg (matching placebo capsules). After at least 3 days wash-out participants get oral placebo.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Single dose of 4 placebo oral capsules

AV-101 720 mg

Intervention Type: DRUG

Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules

AV-101 1440 mg

Intervention Type: DRUG

Single dose of 4 360 mg AV-101 oral capsules

AV-101 1440mg, then placebo, then AV-101 720mg

Participants first received oral AV-101 1440mg (matching placebo capsules). After at least 3 days wash-out participants get oral placebo. After at least 3 days wash-out participants get oral AV-101 720mg (matching placebo capsules).

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Single dose of 4 placebo oral capsules

AV-101 720 mg

Intervention Type: DRUG

Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules

AV-101 1440 mg

Intervention Type: DRUG

Single dose of 4 360 mg AV-101 oral capsules

Interventions

Placebo

Single dose of 4 placebo oral capsules

Intervention Type: DRUG

AV-101 720 mg

Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules

Intervention Type: DRUG

AV-101 1440 mg

Single dose of 4 360 mg AV-101 oral capsules

Intervention Type: DRUG

Other Intervention Names

Placebo oral dose; L-4-Chlorokynurenine; L-4-Chlorokynurenine

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Michael E. DeBakey VA Medical Center

FED

Sponsor Role: collaborator

VistaGen Therapeutics, Inc.

INDUSTRY

Sponsor Role: collaborator

Marijn Lijffijt, PhD

OTHER

Sponsor Role: lead

Responsible Party

Marijn Lijffijt, PhD

Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Marijn Lijffijt, PhD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine and the Michael E. DeBakey VA Medical Center

Locations

Michael E. DeBakey VA Medical Center

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 33318635 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33825765 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Related Links

https://pubmed.ncbi.nlm.nih.gov/33318635/

Related Info

Other Identifiers

H-41830

Identifier Type: -

Identifier Source: org_study_id