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HealthyPhase 1/2NCT03583554

Electrophysiological Biomarkers of AV-101

A Phase 1/2 study testing AV-101 720 mg and AV-101 1440 mg in people with Healthy, run by Marijn Lijffijt, PhD at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 64 yearsHealthy volunteers can take part
Conditions the study is for
Healthy
What is being tested?
AV-101 720 mg and AV-101 1440 mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
18 participants
Where
1 siteUnited States
Study dates
1 Sep 2018to 19 Oct 2019
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 64 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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.
Show all 10Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Michael E. DeBakey VA Medical Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Electrophysiological Biomarkers of Kynurenine Pathway Modulator AV-101 in Healthy Volunteers: Treating Suicidal Veterans

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.

Read the 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.

Conditions
Healthy
Being tested
Placebo, AV-101 720 mg, AV-101 1440 mg
Keywords
Suicide, Kynurenine, metabolic pathway, Veterans, OEF/OIF/OND, electrophysiology, NMDA receptor, suicidal ideation
Medical subject headings
Suicide, Suicidal Ideation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PlaceboDrug

    Also called Placebo oral dose

    Single dose of 4 placebo oral capsules

  • AV-101 720 mgDrug

    Also called L-4-Chlorokynurenine

    Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules

  • AV-101 1440 mgDrug

    Also called L-4-Chlorokynurenine

    Single dose of 4 360 mg AV-101 oral capsules

Study groups in NCT03583554
Study groupRoleWhat they receive
Placebo, then AV-101 720mg, then AV-101 1440mgPlacebo comparatorParticipants 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).
Receives: Drug: Placebo; Drug: AV-101 720 mg; Drug: AV-101 1440 mg
AV-101 720mg, then AV-101 1440mg, then placeboExperimentalParticipants 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.
Receives: Drug: Placebo; Drug: AV-101 720 mg; Drug: AV-101 1440 mg
AV-101 1440mg, then placebo, then AV-101 720mgExperimentalParticipants 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).
Receives: Drug: Placebo; Drug: AV-101 720 mg; Drug: AV-101 1440 mg

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 4 hours

Secondary outcomes (6)

  1. 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.

    Measured: 4 hours

  2. 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).

    Measured: 4 hours

  3. 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.

    Measured: 5 hours

  4. 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

    Measured: 5 hours

  5. 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

    Measured: 5 hours

  6. 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).

    Measured: 5 hours

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jul 2018
  2. Study start1 Sep 2018
  3. Primary completion19 Oct 2019
  4. Study completion19 Oct 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Model description
placebo-controlled, randomized, double-blind, cross-over
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03583554
Sponsor's protocol ID
H-41830
Status last verified
Feb 2022
First submitted
16 May 2018
Last updated
17 Feb 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
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.

Publications

  • 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.

    PubMed 33318635

  • 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.

    PubMed 33825765

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing AV-101 720 mg and AV-101 1440 mg in people with Healthy, run by Marijn Lijffijt, PhD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean 40-Hz Auditory Steady State Response Power (time frame: 4 hours). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03583554, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2022.

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