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NCT03583554

Electrophysiological Biomarkers of AV-101

Completed Phase 1, PHASE2 Results posted Last updated 17 February 2022
What this trial tests

Phase 1, PHASE2 trial testing Placebo in Healthy in 18 participants. Completed in 19 October 2019.

Timeline
1 September 2018
Primary endpoint
19 October 2019
19 October 2019

Quick facts

Lead sponsorMarijn Lijffijt, PhD
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designcrossover
Maskingtriple
Primary purposebasic science
Enrollment18
Start date1 September 2018
Primary completion19 October 2019
Estimated completion19 October 2019
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

Marijn Lijffijt, PhD — full company profile →

Who can join

Adults 18 to 64, any sex, with Healthy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Mean 40-Hz Auditory Steady State Response Power Primary · 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.

GroupValue95% CI
Placebo0.34± 0.11
AV-101 720 mg0.43± 0.11
AV-101 1440 mg0.60± 0.11
Peak Change in Plasma Concentration of AV-101 Marker 4-Chloro-kynurenine Secondary · 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.

GroupValue95% CI
Placebo0± 0
AV-101 720 mg28,532± 21,462
AV-101 1440 mg51,450± 21,182
Peak Change in Plasma Concentration of AV-101 Marker 7-Chloro-kynurenic Acid Secondary · 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).

GroupValue95% CI
Placebo0± 0
AV-101 720 mg93± 48
AV-101 1440 mg412± 473
Mean Systolic Blood Pressure Secondary · 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.

GroupValue95% CI
Placebo122.5± 2.7
AV-101 720 mg119.6± 2.7
AV-101 1440 mg120.1± 2.7
Mean Diastolic Blood Pressure Secondary · 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

GroupValue95% CI
Placebo80.8± 2.35
AV-101 720 mg79± 2.35
AV-101 1440 mg76.3± 2.35
Mean Pulse Secondary · 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

GroupValue95% CI
Placebo68.8± 1.82
AV-101 720 mg70.5± 1.82
AV-101 1440 mg69.9± 1.82
Mean Profile of Moods Scale Total Score Secondary · 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 0-2

GroupValue95% CI
Placebo11.6± 1.65
AV-101 720 mg12± 1.65
AV-101 1440 mg11.6± 1.65

Adverse events — posted to ClinicalTrials.gov

Time frame: 24 hours. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 0/12 (0%)
Deaths: 0/12
AV-101 720 mg
Serious: 0/12 (0%)
Deaths: 0/12
AV-101 1440 mg
Serious: 0/12 (0%)
Deaths: 0/12
Other adverse events (2 terms — click to expand)

ReactionSystemPlaceboAV-101 720 mgAV-101 1440 mg
diarrheaGastrointestinal disorders
ElationNervous system disorders

Data from ClinicalTrials.gov NCT03583554 adverse events section.

Sponsor's own description

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.

Publications & conference data

4 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Clinical specificity profile for novel rapid acting antidepressant drugs.
    Scala M, Fanelli G, De Ronchi D, Serretti A, et al · · 2023 · cited 33× · PMID 37381161 · DOI 10.1097/yic.0000000000000488
  2. A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-D-aspartate receptor blockade in healthy veterans.
    Murphy N, Ramakrishnan N, Vo-Le B, Vo-Le B, et al · · 2021 · cited 18× · PMID 33318635 · DOI 10.1038/s41386-020-00917-z
  3. Does mismatch negativity have utility for NMDA receptor drug development in depression?
    Murphy N, Lijffijt M, Ramakrishnan N, Vo-Le B, et al · · 2022 · cited 10× · PMID 33825765 · DOI 10.1590/1516-4446-2020-1685
  4. Investigational Drugs for the Treatment of Depression (Part 2): Glutamatergic, Cholinergic, Sestrin Modulators, and Other Agents.
    Vasiliu O. · · 2022 · cited 9× · PMID 35847011 · DOI 10.3389/fphar.2022.884155

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