Clinical trial NCT03583554
Conditions: Healthy
Keywords: Suicide Kynurenine metabolic pathway Veterans OEF/OIF/OND electrophysiology NMDA receptor suicidal ideation
Sponsor: Marijn Lijffijt, PhD
Start date: 2018-09-01; Completion date: 2019-10-19
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

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.

Arms: arm 1: 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). arm 2: 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. arm 3: 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).
Interventions: intervention 1: Placebo intervention 2: AV-101 720 mg intervention 3: AV-101 1440 mg
Intervention descriptions: intervention 1: Single dose of 4 placebo oral capsules intervention 2: Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules intervention 3: Single dose of 4 360 mg AV-101 oral capsules

Protocol documents:
Prot_000.pdf: 
Biomarkers of kynurenine pathway modulator AV-101:  first steps to treating suicidal 
Veterans 
 
NCT03583554 
 
Document data: 6/14/2017 
 
 
 


Biomarkers of kynurenine pathway modulator AV-101:  first steps to treating suicidal 
Veterans 
 
Background: Suicide is the 10th leading cause of death in the U.S.1, and is 2-7 times higher in 
Veterans than age- and sex-matched civilians2.  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).  KP dysregulation manifests as high levels 
of neurotoxic quinolinic acid (QUIN), a glutamate receptor (NMDAR) agonist, relative to picolinic 
acid (PIC), a QUIN antagonist, and low neuroprotective kynurenic acid (KYNA), an NMDAR 
glycine B site antagonist3. High QUIN/PIC or low KYNA predispose to excessive NMDAR 
activation, a molecular target purportedly 
involved in rapid improvement of suicidality 
with agents such as ketamine4. AV-101 (4-
chlorokynurenine, 4-Cl-KYN) is an oral pro-
drug that could reverse KP dysregulation 
with downstream NMDAR deactivation. 
AV-101 stimulates astrocyte-produced 7-
chlorokynurenic 
acid 
(7-Cl-KYNA), 
a 
potent NMDAR glycine B site antagonist5, 
and 
microglia-produced 
4-chloro-3-
hydroxyanthanillic acid (4-Cl-3-HAA), an 
indirect QUIN inhibitor6 (see Figure). 
Phase-1 testing showed that AV-101 is 
safe for use in humans, and 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 which is thought to underlie rapid improvement in 
suicidality. 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. Outcomes will provide pivotal data for competitive grant 
proposals focused on effects of AV-101, and KP and NMDAR modulation on moderate to severe 
suicidal ideation or behaviors in active duty military personnel or Veterans. 
Methods: We 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. Subjects will 
be recruited using our infrastructure that we use to successfully recruit Veterans with mood- or 
anxiety disorders. Medication and placebo will be provided to us by courtesy of VistaGen 
Therapeutics (per Mark Smith, MD, VistaGen Chief Medical Officer). Repeated measures General 
Linear Models will be used to test dose-response relationships.  PI Dr. Lijffijt, Ph.D., and a senior 
research coordinator will screen subjects and conduct research procedures.  Dr. Lijffijt will perform 
neurophysiology and statistical analyses. Drs. Swann and Mathew will monitor subject safety. 
 
References: 1LCWK1 (2016), www.cdc.gov/nchs/nvss/mortality/lcwk1.htm; 2USDVA (2016), 
Suicide among veterans and other Americans 2001-2014, Office of Suicide Prevention; 3Bryleva, 
Brundin (2017), Curr Top Behav Neurosci 31:269-84; 4Price, Mathew (2015), CNS Drugs 26:181-
8; 5Hokari et al (1996), Neuroreport 20:15-8; 6Yates et al. (2006), J Neurotrauma 23:866-81. 
AV-101 (4-Cl-KYN)
4-Cl-3-HAA
7-Cl-KYNA
QUIN ↓
NMDAR activation ↓
activation
suppression
Microglia
Astrocyte