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| Name | Class |
|---|---|
| Michael E. DeBakey VA Medical Center | FED |
| VistaGen Therapeutics, Inc. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
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| 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. |
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| 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). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | Single dose of 4 placebo oral capsules |
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| 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 |
| 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 |
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Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Marijn Lijffijt, PhD | Baylor College of Medicine and the Michael E. DeBakey VA Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Michael E. DeBakey VA Medical Center | Houston | Texas | 77030 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33318635 | Result | 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. | |
| 33825765 |
| Label | URL |
|---|---|
| Related Info | View source |
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This study is in collaboration with industry partner Vistagen Therapeutics, which provides study medication. Protected health information (PHI) and protected personal information (PII) will not be shared with Vistagen. Study outcomes will be shared as publications.
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This is a randomized cross-over design, meaning that all subjects received all doses. Total recruited was 18, and total randomized was 12. Ten subjects completed all study visits.
Participants with eligible if they were between 18 and 64 years old, a US military veteran, and have no history of psychiatric illness.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo, Then AV-101 720 mg, Then AV-101 1440 mg | Participants first received a single dose of oral placebo. After at least 3 days wash-out participants got a single dose of oral AV-101 720mg (matching placebo capsules). After at least 3 days wash-out participants got a single dose of oral AV-101 1440mg (matching placebo capsules). |
| FG001 | AV-101 720 mg, Then AV-101 1440 mg, Then Placebo | Participants first received a single dose of oral AV-101 720mg (matching placebo capsules). After at least 3 days wash-out participants got a single dose of oral AV-101 1440mg (matching placebo capsules). After at least 3 days wash-out participants got a single dose of oral placebo. |
| FG002 | AV-101 1440 mg, Then Placebo Then, AV-101 720 mg Then | Participants first received a single dose of oral AV-101 1440mg (matching placebo capsules). After at least 3 days wash-out participants got a single dose of oral placebo. After at least 3 days wash-out participants got a single dose of oral AV-101 720mg (matching placebo capsules). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
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Twelve subjects started the study; 10 completed all visits. Baseline outcomes are provided for the 12 subjects who started the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | All 12 study participants who started the study |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Error | uV^2 | 4 hours |
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24 hours
Asked by study team if experiencing any health complications last 24 hours since study intake. Any health complications not related to the study medication were also asked about when subjects at study visits from the moment that they were enrolled in the study until they had completed the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Placebo Placebo: Single dose of 4 placebo oral capsules | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| diarrhea | Gastrointestinal disorders | Non-systematic Assessment | diarrhea |
The small number of subjects limits power.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Marijn Lijffijt, Assistant Professorq | Baylor College of Medicine and Michael E. DeBakey VA Medical Center | 713-798-5642 | marijn.lijffijt@bcm.edu |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 14, 2017 | Oct 9, 2020 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D013405 | Suicide |
| D059020 | Suicidal Ideation |
| ID | Term |
|---|---|
| D016728 | Self-Injurious Behavior |
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
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placebo-controlled, randomized, double-blind, cross-over
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The research pharmacist compiles and has unique access to the randomization key
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| AV-101 720 mg | Drug | Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules |
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| AV-101 1440 mg | Drug | Single dose of 4 360 mg AV-101 oral capsules |
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| 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 |
| 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. |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Ethnicity (self-report) | Count of Participants | Participants |
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| Race (NIH/OMB) | Race (self-report) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG002 | AV-101 1440 mg | One time 1440 mg L-4-Chlorokynurenine AV-101 1440 mg: Single dose of 4 360 mg AV-101 oral capsules |
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| Secondary | 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. | Posted | Mean | Standard Deviation | ng/Ml | 4 hours |
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| Secondary | 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). | Posted | Mean | Standard Deviation | ng/Ml | 4 hours |
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| Secondary | 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. | Posted | Mean | Standard Error | mm Hg | 5 hours |
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| Secondary | 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 | Posted | Mean | Standard Error | mm Hg | 5 hours |
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| Secondary | 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 | Posted | Mean | Standard Error | beat per minute (bpm) | 5 hours |
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| Secondary | 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). | Posted | Mean | Standard Error | Units on a scale | 5 hours |
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| 12 |
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | AV-101 720 mg | One time 720 mg L-4-Chlorokynurenine AV-101 720 mg: Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules | 0 | 12 | 0 | 12 | 1 | 12 |
| EG002 | AV-101 1440 mg | One time 1440 mg L-4-Chlorokynurenine AV-101 1440 mg: Single dose of 4 360 mg AV-101 oral capsules | 0 | 12 | 0 | 12 | 1 | 12 |
| Elation | Nervous system disorders | Non-systematic Assessment | Elation (self-report) |
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