Electrophysiological Biomarkers of AV-101

Study Overview
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Brief Summary
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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
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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.

Official Title
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Electrophysiological Biomarkers of Kynurenine Pathway Modulator AV-101 in Healthy Volunteers: Treating Suicidal Veterans

Conditions
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Healthy

Intervention / Treatment
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* Drug: Placebo
* Drug: AV-101 720 mg
* Drug: AV-101 1440 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: placebo-controlled, randomized, double-blind, cross-over
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo, then AV-101 720mg, then AV-101 1440mg<br>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<br>* Single dose of 4 placebo oral capsules<br>* Other names: Placebo oral dose;Drug: AV-101 720 mg<br>* Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules<br>* Other names: L-4-Chlorokynurenine;Drug: AV-101 1440 mg<br>* Single dose of 4 360 mg AV-101 oral capsules<br>* Other names: L-4-Chlorokynurenine;|
| Experimental: AV-101 720mg, then AV-101 1440mg, then placebo<br>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<br>* Single dose of 4 placebo oral capsules<br>* Other names: Placebo oral dose;Drug: AV-101 720 mg<br>* Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules<br>* Other names: L-4-Chlorokynurenine;Drug: AV-101 1440 mg<br>* Single dose of 4 360 mg AV-101 oral capsules<br>* Other names: L-4-Chlorokynurenine;|
| Experimental: AV-101 1440mg, then placebo, then AV-101 720mg<br>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<br>* Single dose of 4 placebo oral capsules<br>* Other names: Placebo oral dose;Drug: AV-101 720 mg<br>* Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules<br>* Other names: L-4-Chlorokynurenine;Drug: AV-101 1440 mg<br>* Single dose of 4 360 mg AV-101 oral capsules<br>* Other names: L-4-Chlorokynurenine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine | Assesses the peak change from baseline and corrected for placebo (placebo set at 0) across a 4 hours time frame after drug intake. 4-Chloro-kynurenine is the main ingredient of AV-101 and is a precursor of 7-Chloro-kynurenic acid. | 4 hours | 
| Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid | Assesses the peak change from baseline and corrected for placebo (placebo set at 0) across a 4 hours time frame after drug intake. 7-Chloro-kynurenic acid is the main metabolite of AV-101 (4-Chloro-kynurenine). | 4 hours | 
| Mean Systolic Blood Pressure | Systolic blood pressure Mean +/- SE averaged across all timepoints (including baseline). Systolic blood pressure was measured 15 minutes before drug intake and every 15 minutes from drug intake until 5 hours after intake controlled for time, with outcomes the mean per treatment arm obtained from Linear Mixed Model analysis. | 5 hours | 
| Mean Diastolic Blood Pressure | Diastolic blood pressure Mean +/- SE averaged across all timepoints (including baseline). Diastolic blood pressure was measured 15 minutes before drug intake and every 15 minutes from drug intake until 5 hours after intake controlled for time, with outcomes the mean per treatment arm obtained from Linear Mixed Model analysis | 5 hours | 
| Mean Pulse | Pulse Mean +/- SE averaged across all timepoints (including baseline). Pulse was measured 15 minutes before drug intake and every 15 minutes from drug intake until 5 hours after intake controlled for time, with outcomes the mean per treatment arm obtained from Linear Mixed Model analysis | 5 hours | 
| Mean Profile of Moods Scale Total Score | POMS total score Mean +/- SE averaged across all timepoints (including baseline). Systolic blood pressure was measured directly before drug intake and every hours from drug intake until 5 hours after intake controlled for time, with outcomes the mean per treatment arm obtained from Linear Mixed Model analysis The POMS is a 40 item scale. Each item is scored on a 0 (absent) - 4 (extreme) scale. POMS total score ranges from 0 to 160. Higher scores mean more extreme dysregulated mood. Subscales are tension (6 items; score anger 0-24), depression (6 items, range 0-24), fatigue (5 items, range 0-20), vigor (6 items, range 0-24), confusion (5 items, range 0-20), anger (7 items, range 0-28), and mania-related affect (5 items, range 0-20). | 5 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Suicide, Kynurenine, metabolic pathway, Veterans, OEF/OIF/OND, electrophysiology, NMDA receptor, suicidal ideation