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Electrophysiological Biomarkers of AV-101

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03583554
Recruitment Status : Recruiting
First Posted : July 11, 2018
Last Update Posted : July 10, 2019
Michael Debakey Veterans Affairs Medical Center
VistaGen Therapeutics, Inc.
Information provided by (Responsible Party):
Marijn Lijffijt, PhD, Baylor College of Medicine

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: AV-101 720 mg Drug: Placebo 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: placebo-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 : September 1, 2018
Estimated Primary Completion Date : October 31, 2019
Estimated Study Completion Date : October 31, 2019

Arm Intervention/treatment
Placebo Comparator: Placebo
Drug: Placebo
Single dose of 4 placebo oral capsules
Other Name: Placebo oral dose

Active Comparator: AV-101 720 mg
One time 720 mg L-4-Chlorokynurenine
Drug: AV-101 720 mg
Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules
Other Name: L-4-Chlorokynurenine

Active Comparator: AV-101 1440 mg
One time 1440 mg L-4-Chlorokynurenine
Drug: AV-101 1440 mg
Single dose of 4 360 mg AV-101 oral capsules
Other Name: L-4-Chlorokynurenine

Primary Outcome Measures :
  1. Neurophysiological markers of AV-101 [ Time Frame: 5 hours ]
    Define valid and sensitive neurophysiological markers with a dose-response relationship with AV-101 (placebo, 720 mg, 1440 mg) as evidence of glutamate NMDA receptor (NMDAR) engagement

Secondary Outcome Measures :
  1. Change in plasma concentration kynurenine pathway metabolites [ Time Frame: 5 hours ]
    Assess change in blood plasma concentration of quinolinic acid and kynurenic acid from pre-treatment to 5 hours after dosing

  2. Incidence of adverse events (AEs) with the Patient Rated Inventory of Side Effects (PRISE) [ Time Frame: 24 hours ]
    7 item scale assessing side effects in the following symptom domains: Gastrointestinal, Heart, Skin, Nervous System, Eyes/Ears, Genital/Urinary, Sleep, Sexual Functioning. Each domain has multiple symptoms which can be identified. For each domain, the patient rates whether or not the symptoms are tolerable or distressing.

  3. Change in systolic and diastolic blood pressure [ Time Frame: 5 hours ]
    in mm Hg

  4. Change in mood with the Abbreviated Profile of Moods Scale (A-POMS) [ Time Frame: 5 hours ]
    40 item scale, each item scored on a scale from 0 (absent) - 4 (extreme). Assessed are score for tension (6 items; score ange 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 esteem-related affect (5 items, range 0-20).

  5. Change in dissociative state with Clinician Administered Dissociative States Scale (CADSS] [ Time Frame: 5 hours ]
    23 item scale assessing symptoms of dissociation, each item scored on a scale from 0 (absent) - 4 (extreme). Assessed is the total score (range: 0 - 92)

  6. Change in heart rate [ Time Frame: 5 hours ]
    heart beats per second (based on R-R interval in seconds)

  7. Change in red blood cell count [ Time Frame: 5 hours ]
    in 10^6/microL

  8. Change in white blood cell count [ Time Frame: 5 hours ]
    in 10^3/cubic mm

  9. Change in hemoglobin and albumin [ Time Frame: 5 hours ]
    in gram/dL

  10. Change in Aspartate aminotransferase (AST) [ Time Frame: 5 hours ]
    in U/L

  11. Change in bilirubin, blood urea nitrogen (BUN), creatine [ Time Frame: 5 hours ]
    in mg/dL

  12. Change in thyroid stimulating hormone (TSH) [ Time Frame: 5 hours ]
    in microU/mL

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03583554

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Contact: Marijn Lijffijt, PhD 713-798 5642
Contact: Bylinda Vo-Le, MS 713-689 9856

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United States, Texas
Michael E. DeBakey VA Medical Center Recruiting
Houston, Texas, United States, 77030
Contact: Marijn Lijffijt, PhD    713-798-5642   
Sub-Investigator: Sanjay J. Mathew, MD         
Sub-Investigator: Alan C. Swann, MD         
Sponsors and Collaborators
Marijn Lijffijt, PhD
Michael Debakey Veterans Affairs Medical Center
VistaGen Therapeutics, Inc.
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Principal Investigator: Marijn Lijffijt, PhD Baylor College of Medicine and the Michael E. DeBakey VA Medical Center

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Responsible Party: Marijn Lijffijt, PhD, Assistant Professor, Baylor College of Medicine Identifier: NCT03583554     History of Changes
Other Study ID Numbers: H-41830
First Posted: July 11, 2018    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: 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 a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Marijn Lijffijt, PhD, Baylor College of Medicine:
metabolic pathway
NMDA receptor
suicidal ideation