A Phase 1/2 interventional study of Placebo and AV-101 720 mg in Healthy, sponsored by Marijn Lijffijt, PhD. Completed at 1 site in United States. Open to participants aged 18 Years to 64 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-02-17.
Sponsored by Marijn Lijffijt, PhD · Phase 1/2, Interventional, and Basic science
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.
714 studies on the registry are indexed under Suicide; 184 are open to participants now.
This study's enrollment of 18 is below the median of 103 across 572 interventional studies indexed under Suicide.
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Exclusion Criteria
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
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
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
Single dose of 4 placebo oral capsules
Also known as: Placebo oral dose
Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules
Also known as: L-4-Chlorokynurenine
Single dose of 4 360 mg AV-101 oral capsules
Also known as: L-4-Chlorokynurenine
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
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
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
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
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
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
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
Participants with eligible if they were between 18 and 64 years old, a US military veteran, and have no history of psychiatric illness.
| Milestone | Placebo, Then AV-101 720 mg, Then AV-101 1440 mg | AV-101 720 mg, Then AV-101 1440 mg, Then Placebo | AV-101 1440 mg, Then Placebo Then, AV-101 720 mg Then |
|---|---|---|---|
| Started | 4 | 4 | 4 |
| Completed | 4 | 4 | 4 |
| Not completed | 0 | 0 | 0 |
| Milestone | Placebo, Then AV-101 720 mg, Then AV-101 1440 mg | AV-101 720 mg, Then AV-101 1440 mg, Then Placebo | AV-101 1440 mg, Then Placebo Then, AV-101 720 mg Then |
|---|---|---|---|
| Started | 4 | 4 | 4 |
| Completed | 3 | 4 | 3 |
| Not completed | 1 | 0 | 1 |
| Withdrew: Did not receive treatment due to loss of contact | 1 | 0 | 1 |
| Milestone | Placebo, Then AV-101 720 mg, Then AV-101 1440 mg | AV-101 720 mg, Then AV-101 1440 mg, Then Placebo | AV-101 1440 mg, Then Placebo Then, AV-101 720 mg Then |
|---|---|---|---|
| Started | 3 | 4 | 3 |
| Completed | 3 | 4 | 3 |
| Not completed | 0 | 0 | 0 |
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.
| uV^2 | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| Mean 40-Hz Auditory Steady State Response Power | 0.34 ± 0.11 | 0.43 ± 0.11 | 0.60 ± 0.11 |
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.
| ng/Ml | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine | 0 ± 0 | 28,532 ± 21,462 | 51,450 ± 21,182 |
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).
| ng/Ml | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid | 0 ± 0 | 93 ± 48 | 412 ± 473 |
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.
| mm Hg | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| Mean Systolic Blood Pressure | 122.5 ± 2.7 | 119.6 ± 2.7 | 120.1 ± 2.7 |
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
| mm Hg | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| Mean Diastolic Blood Pressure | 80.8 ± 2.35 | 79 ± 2.35 | 76.3 ± 2.35 |
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
| beat per minute (bpm) | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| Mean Pulse | 68.8 ± 1.82 | 70.5 ± 1.82 | 69.9 ± 1.82 |
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).
| Units on a scale | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| Mean Profile of Moods Scale Total Score | 11.6 ± 1.65 | 12 ± 1.65 | 11.6 ± 1.65 |
Collected over 24 hours. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 0/12 (0%) | 0/12 (0%) | 0/12 (0%) |
| AV-101 720 mg | 0/12 (0%) | 0/12 (0%) | 1/12 (8.3%) |
| AV-101 1440 mg | 0/12 (0%) | 0/12 (0%) | 1/12 (8.3%) |
| Event | Placebo | AV-101 720 mg | AV-101 1440 mg |
|---|---|---|---|
| diarrheaGastrointestinal disorders | 0/12 | 0/12 | 1/12 |
| ElationNervous system disorders | 0/12 | 1/12 | 0/12 |
Twelve subjects started the study; 10 completed all visits. Baseline outcomes are provided for the 12 subjects who started the study.
| Age, Continuous(years) | All Study Participants |
|---|---|
| Mean | 31.33 ± 6.28 |
| Sex: Female, Male(Participants) | All Study Participants |
|---|---|
| Female | 1 |
| Male | 11 |
| Ethnicity (NIH/OMB)(Participants) | All Study Participants |
|---|---|
| Hispanic or Latino | 7 |
| Not Hispanic or Latino | 5 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | All Study Participants |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 2 |
| White | 10 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | All Study Participants |
|---|---|
| United States | 12 |
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Plan to share: No — 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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Studies of the drug tested here: Av-101