Electrophysiological Biomarkers of AV-101

NCT03583554 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: H-41830
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

Suicide; Kynurenine; metabolic pathway; Veterans; OEF/OIF/OND; electrophysiology; NMDA receptor; suicidal ideation

Outcome Measures

Primary Outcomes (1)

• Mean 40-Hz Auditory Steady State Response Power

  Mean power (in microVolt squared; uV\^2) of 40-Hz Auditory Steady State Response (ASSR; an auditory task using 40Hz click trains) calculated across 38-42Hz. Mean +/- SE across pre-treatment baseline and 4 post-treatment measures one every hour controlled for time, with outcomes the mean per treatment arm obtained from Linear Mixed Model analysis.

  4 hours

Secondary Outcomes (6)

• Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine

  4 hours

• Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid

  4 hours

• Mean Systolic Blood Pressure

  5 hours

• Mean Diastolic Blood Pressure

  5 hours

• Mean Pulse

  5 hours

Study Arms (3)

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

PLACEBO COMPARATOR

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).

Drug: Placebo; Drug: AV-101 720 mg; Drug: AV-101 1440 mg

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

EXPERIMENTAL

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.

Drug: Placebo; Drug: AV-101 720 mg; Drug: AV-101 1440 mg

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

EXPERIMENTAL

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).

Drug: Placebo; Drug: AV-101 720 mg; Drug: AV-101 1440 mg

Interventions

Placebo DRUG

Single dose of 4 placebo oral capsules

Also known as: Placebo oral dose

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

AV-101 720 mg DRUG

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

Also known as: L-4-Chlorokynurenine

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

AV-101 1440 mg DRUG

Single dose of 4 360 mg AV-101 oral capsules

Also known as: L-4-Chlorokynurenine

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

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Marijn Lijffijt, PhD: lead
• Michael E. DeBakey VA Medical Center: collaborator
• VistaGen Therapeutics, Inc.: collaborator

Study Sites (1)

Michael E. DeBakey VA Medical Center

Houston, Texas, 77030, United States

Location

Related Publications (2)

• 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.

  PMID: 33318635 RESULT

• 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.

  PMID: 33825765 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Suicide; Suicidal Ideation

Condition Hierarchy (Ancestors)

Self-Injurious Behavior; Behavioral Symptoms; Behavior

Limitations and Caveats

The small number of subjects limits power.

Results Point of Contact

• Title: Dr. Marijn Lijffijt, Assistant Professorq
• Organization: Baylor College of Medicine and Michael E. DeBakey VA Medical Center

marijn.lijffijt@bcm.edu

713-798-5642

Study Officials

• Marijn Lijffijt, PhD

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The research pharmacist compiles and has unique access to the randomization key
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Model Details: placebo-controlled, randomized, double-blind, cross-over

Study Record Dates

• First Submitted: May 16, 2018
• First Posted: July 11, 2018
• Study Start: September 1, 2018
• Primary Completion: October 19, 2019
• Study Completion: October 19, 2019
• Last Updated: February 17, 2022
• Results First Posted: February 17, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)