Healthy
Conditions
Keywords
Suicide, Kynurenine, metabolic pathway, Veterans, OEF/OIF/OND, electrophysiology, NMDA receptor, suicidal ideation
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.
Interventions
DRUGPlacebo
Single dose of 4 placebo oral capsules
DRUGAV-101 720 mg
Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules
DRUGAV-101 1440 mg
Single dose of 4 360 mg AV-101 oral capsules
Sponsors
Michael E. DeBakey VA Medical Center
VistaGen Therapeutics, Inc.
Marijn Lijffijt, PhD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
The research pharmacist compiles and has unique access to the randomization key
Intervention model description
placebo-controlled, randomized, double-blind, cross-over
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean 40-Hz Auditory Steady State Response Power | 4 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine | 4 hours | 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. |
| Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid | 4 hours | 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). |
| Mean Profile of Moods Scale Total Score | 5 hours | 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). |
| Mean Diastolic Blood Pressure | 5 hours | 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 |
| Mean Pulse | 5 hours | 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 |
| Mean Systolic Blood Pressure | 5 hours | 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. |
Countries
United States
Participant flow
Recruitment details
Participants with eligible if they were between 18 and 64 years old, a US military veteran, and have no history of psychiatric illness.
Pre-assignment details
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 by arm
| Arm | Count |
|---|---|
| All Study Participants All 12 study participants who started the study | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 2 | Did not receive treatment due to loss of contact | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 31.33 years STANDARD_DEVIATION 6.28 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 0 / 12 | 1 / 12 | 1 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
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.
Time frame: 4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean 40-Hz Auditory Steady State Response Power | 0.34 uV^2 | Standard Error 0.11 |
| AV-101 720 mg | Mean 40-Hz Auditory Steady State Response Power | 0.43 uV^2 | Standard Error 0.11 |
| AV-101 1440 mg | Mean 40-Hz Auditory Steady State Response Power | 0.60 uV^2 | Standard Error 0.11 |
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
Time frame: 5 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Diastolic Blood Pressure | 80.8 mm Hg | Standard Error 2.35 |
| AV-101 720 mg | Mean Diastolic Blood Pressure | 79 mm Hg | Standard Error 2.35 |
| AV-101 1440 mg | Mean Diastolic Blood Pressure | 76.3 mm Hg | Standard Error 2.35 |
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).
Time frame: 5 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Profile of Moods Scale Total Score | 11.6 Units on a scale | Standard Error 1.65 |
| AV-101 720 mg | Mean Profile of Moods Scale Total Score | 12 Units on a scale | Standard Error 1.65 |
| AV-101 1440 mg | Mean Profile of Moods Scale Total Score | 11.6 Units on a scale | Standard Error 1.65 |
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
Time frame: 5 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Pulse | 68.8 beat per minute (bpm) | Standard Error 1.82 |
| AV-101 720 mg | Mean Pulse | 70.5 beat per minute (bpm) | Standard Error 1.82 |
| AV-101 1440 mg | Mean Pulse | 69.9 beat per minute (bpm) | Standard Error 1.82 |
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.
Time frame: 5 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Systolic Blood Pressure | 122.5 mm Hg | Standard Error 2.7 |
| AV-101 720 mg | Mean Systolic Blood Pressure | 119.6 mm Hg | Standard Error 2.7 |
| AV-101 1440 mg | Mean Systolic Blood Pressure | 120.1 mm Hg | Standard Error 2.7 |
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.
Time frame: 4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine | 0 ng/Ml | Standard Deviation 0 |
| AV-101 720 mg | Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine | 28,532 ng/Ml | — |
| AV-101 1440 mg | Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine | 51,450 ng/Ml | — |
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).
Time frame: 4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid | 0 ng/Ml | Standard Deviation 0 |
| AV-101 720 mg | Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid | 93 ng/Ml | Standard Deviation 48 |
| AV-101 1440 mg | Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid | 412 ng/Ml | Standard Deviation 473 |