Electrophysiological Biomarkers of AV-101

Marijn Lijffijt, PhD

Status and phase: Completed; Phase 2; Phase 1

Conditions: Healthy

Treatments: Drug: AV-101 1440 mg; Drug: AV-101 720 mg; Drug: Placebo

Study type: Interventional

Funder types: Other; Other U.S. Federal agency; Industry

Identifiers

NCT03583554

H-41830

Details and patient eligibility

About

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.

Full 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.

Enrollment: 18 patients

Sex: All

Ages: 18 to 64 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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18 participants in 3 patient groups, including a placebo group

Placebo, then AV-101 720mg, then AV-101 1440mg

Placebo Comparator group

Description:

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).

Treatment:

Drug: Placebo

Drug: AV-101 720 mg

Drug: AV-101 1440 mg

AV-101 720mg, then AV-101 1440mg, then placebo

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: AV-101 720 mg

Drug: AV-101 1440 mg

AV-101 1440mg, then placebo, then AV-101 720mg

Experimental group

Description:

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).

Treatment:

Drug: Placebo

Drug: AV-101 720 mg

Drug: AV-101 1440 mg