Electrophysiological Biomarkers of AV-101

• Sponsor: Marijn Lijffijt, PhD (Other)
• Overall Status: Completed
• CT.gov ID: NCT03583554
• Collaborator: Michael E. DeBakey VA Medical Center (U.S. Fed), VistaGen Therapeutics, Inc. (Industry)
• Enrollment: 18
• Location: 1
• Arms: 3
• Actual Duration (Months): 13.6
• Patients Per Site Per Month: 1.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Placebo; Drug: AV-101 720 mg; Drug: AV-101 1440 mg	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: placebo-controlled, randomized, double-blind, cross-overplacebo-controlled, randomized, double-blind, cross-over
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: The research pharmacist compiles and has unique access to the randomization key
• Primary Purpose: Basic Science
• Official Title: Electrophysiological Biomarkers of Kynurenine Pathway Modulator AV-101 in Healthy Volunteers: Treating Suicidal Veterans
• Actual Study Start Date: Sep 1, 2018
• Actual Primary Completion Date: Oct 19, 2019
• Actual Study Completion Date: Oct 19, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo, then AV-101 720mg, then AV-101 1440mg 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; Single dose of 4 placebo oral capsules; Other Names: Placebo oral dose ; Drug: AV-101 720 mg; Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules; Other Names: L-4-Chlorokynurenine ; Drug: AV-101 1440 mg; Single dose of 4 360 mg AV-101 oral capsules; Other Names: L-4-Chlorokynurenine
Experimental: AV-101 720mg, then AV-101 1440mg, then placebo 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; Single dose of 4 placebo oral capsules; Other Names: Placebo oral dose ; Drug: AV-101 720 mg; Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules; Other Names: L-4-Chlorokynurenine ; Drug: AV-101 1440 mg; Single dose of 4 360 mg AV-101 oral capsules; Other Names: L-4-Chlorokynurenine
Experimental: AV-101 1440mg, then placebo, then AV-101 720mg 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; Single dose of 4 placebo oral capsules; Other Names: Placebo oral dose ; Drug: AV-101 720 mg; Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules; Other Names: L-4-Chlorokynurenine ; Drug: AV-101 1440 mg; Single dose of 4 360 mg AV-101 oral capsules; Other Names: L-4-Chlorokynurenine

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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).

3. 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.

4. 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

5. 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

6. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Michael E. DeBakey VA Medical Center	Houston	Texas	United States	77030

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Marijn Lijffijt, PhD, Baylor College of Medicine and the Michael E. DeBakey VA Medical Center

Study Documents (Full-Text)

• Study Protocol - Jun 14, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Marijn Lijffijt, PhD, Assistant Professor, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT03583554
• Other Study ID Numbers: H-41830
• First Posted: Jul 11, 2018
• Last Update Posted: Feb 17, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Marijn Lijffijt, PhD, Assistant Professor, Baylor College of Medicine: Suicide; Kynurenine; metabolic pathway; Veterans; OEF/OIF/OND; electrophysiology; NMDA receptor; suicidal ideation

Study Results

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 Detail	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.

Arm/Group Title	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
Arm/Group Description	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).	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.	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).
Period Title: Period 1
STARTED	4	4	4
COMPLETED	4	4	4
NOT COMPLETED	0	0	0
Period Title: Period 1
STARTED	4	4	4
COMPLETED	3	4	3
NOT COMPLETED	1	0	1
Period Title: Period 1
STARTED	3	4	3
COMPLETED	3	4	3
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All 12 study participants who started the study
Overall Participants	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.33 (6.28)
Sex: Female, Male (Count of Participants)
Female	1 8.3%
Male	11 91.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 58.3%
Not Hispanic or Latino	5 41.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 16.7%
White	10 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Mean 40-Hz Auditory Steady State Response Power
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AV-101 720 mg	AV-101 1440 mg
Arm/Group Description	Placebo Placebo: Single dose of 4 placebo oral capsules	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	One time 1440 mg L-4-Chlorokynurenine AV-101 1440 mg: Single dose of 4 360 mg AV-101 oral capsules
Measure Participants	10	10	10
Mean (Standard Error) [uV^2]	0.34 (0.11)	0.43 (0.11)	0.60 (0.11)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AV-101 720 mg	AV-101 1440 mg
Arm/Group Description	Outcomes across placebo	Outcomes across AV-101 720mg	Outcomes across AV-101 1440mg
Measure Participants	10	10	10
Mean (Standard Deviation) [ng/Ml]	0 (0)	28,532 (21,462)	51,450 (21,182)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AV-101 720 mg	AV-101 1440 mg
Arm/Group Description	Outcomes across placebo	Outcomes across AV-101 720mg	Outcomes across AV-101 1440mg
Measure Participants	10	10	10
Mean (Standard Deviation) [ng/Ml]	0 (0)	93 (48)	412 (473)

4. Secondary Outcome

Title	Mean Systolic Blood Pressure
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AV-101 720 mg	AV-101 1440 mg
Arm/Group Description	Outcomes across placebo	Outcomes across AV-101 720mg	Outcomes across AV-101 1440mg
Measure Participants	10	10	10
Mean (Standard Error) [mm Hg]	122.5 (2.7)	119.6 (2.7)	120.1 (2.7)

5. Secondary Outcome

Title	Mean Diastolic Blood Pressure
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AV-101 720 mg	AV-101 1440 mg
Arm/Group Description	Outcomes across placebo	Outcomes across AV-101 720mg	Outcomes across AV-101 1440mg
Measure Participants	10	10	10
Mean (Standard Error) [mm Hg]	80.8 (2.35)	79 (2.35)	76.3 (2.35)

6. Secondary Outcome

Title	Mean Pulse
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AV-101 720 mg	AV-101 1440 mg
Arm/Group Description	Outcomes across placebo	Outcomes across AV-101 720mg	Outcomes across AV-101 1440mg
Measure Participants	10	10	10
Mean (Standard Error) [beat per minute (bpm)]	68.8 (1.82)	70.5 (1.82)	69.9 (1.82)

7. Secondary Outcome

Title	Mean Profile of Moods Scale Total Score
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	AV-101 720 mg	AV-101 1440 mg
Arm/Group Description	Outcomes across placebo	Outcomes across AV-101 720mg	Outcomes across AV-101 1440mg
Measure Participants	10	10	10
Mean (Standard Error) [Units on a scale]	11.6 (1.65)	12 (1.65)	11.6 (1.65)

Adverse Events

Time Frame	24 hours
Adverse Event Reporting Description	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.
Arm/Group Title	Placebo		AV-101 720 mg		AV-101 1440 mg
Arm/Group Description	Placebo Placebo: Single dose of 4 placebo oral capsules		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		One time 1440 mg L-4-Chlorokynurenine AV-101 1440 mg: Single dose of 4 360 mg AV-101 oral capsules
All Cause Mortality
	Placebo		AV-101 720 mg		AV-101 1440 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)
Serious Adverse Events
	Placebo		AV-101 720 mg		AV-101 1440 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		AV-101 720 mg		AV-101 1440 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)
Gastrointestinal disorders
diarrhea	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1
Nervous system disorders
Elation	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0

Limitations/Caveats

The small number of subjects limits power.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.