Clinical trial NCT02484456
Conditions: Major Depression
Keywords: Major Depression Glycine Receptor Antagonist 4-chlorokynurenine Treatment Resistant Glutamatergic System
Sponsor: National Institute of Mental Health (NIMH)
Start date: 2015-10-14; Completion date: 2019-12-03
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Background:

\- Drugs and talk therapy help treat depression, but these treatments usually take quite a bit of time to work. Ketamine is a fast-acting antidepressant, but it has side effects like unusual dreams and experiences. The drug AV-101 may have the same antidepressant effects but fewer side effects. Researchers want to see if it is effective and safe for people with major depressive disorder.

Objective:

\- To see if the drug, AV-101 is safe and if it treats symptoms of major depressive disorder.

Eligibility:

\- Adults ages 18-65 with major depression without psychotic features.

Design:

* Participants will be screened under a separate protocol.
* Participants will stay in the hospital for 12-14 weeks.
* Phase 1 (2-7 weeks): participants will stop taking their medicines then not take any for 2 weeks. They will have several scans and other procedures.
* Phase 2 (6-7 weeks): 2 weeks each of study drug and placebo once a day, with 2 weeks of no drugs in between.
* Participants will have:
* Physical exams
* Interviews
* Frequent blood collection. A needle will place a small plastic tube in the arm. Some blood samples will be taken through this tube.
* 2 spinal taps (optional). The back will be numbed. A needle will insert a catheter between back bones. That will be left in for up to 30 hours. Spinal fluid will be collected through it.
* 5 scans. Participants will lie in a machine with a magnetic field. The machine takes pictures of the brain and brain chemicals.
* At the end of the study, participants will have medical evaluation, questions, and blood tests. Some may continue treatment at the clinic.

Detailed description:
Objective

Modulation of the NMDA receptor (NMDAR) complex or other components of glutamatergic signaling is likely involved in improvement of depressive symptoms and related constructs/dimensions of observable behavior and neurobiological measures. Current standard monoaminergic pharmacological approaches for major depressive disorder (MDD) have proven to be only modestly effective during acute depressive episodes. We have systematically tested different glutamatergic modulators in patients with mood disorders in order to develop improved therapeutics. We found that the NMDAR antagonist ketamine produces rapid antidepressant effects in patients with treatment-resistant depression (in MDD and Bipolar Disorder). However, despite being highly efficacious, the proof of concept ketamine produces psychotomimetic effects.

In the present protocol, we aim to evaluate a new glutamate-mediated mechanism associated with antidepressant efficacy by targeting the glycine receptor within the NMDA receptor. Targeting the glycine co-agonist site of the (NMDA) receptor may bypass potential adverse effects that occur with ketamine without affecting the robust efficacy observed. This may then result in the glutamate surge that has been associated with the rapid acting antidepressant effects of ketamine.

The present Phase 2 proof-of-concept study is designed to evaluate the antidepressant effects of AV 101 (L-4-chlorokynurenine or 4-Cl- KYN) in MDD; this is a synthetic compound which is enzymatically converted into the selective glycine/NMDAR antagonist 7-chlorokynurenine (7-Cl-KYNA) after crossing the blood brain barrier (BBB) and then reaching brain glial cells. In animal models of depression, 4-Cl-KYNA (AV 101) induced acute and prolonged antidepressant-like effects without exhibiting ketamine-like side effects as determined by the drug discrimination, conditioned place preference, and pre-pulse inhibition tests.

We will also evaluate the neurobiological mechanisms involved in the antidepressant response to AV 101. We expect that this effect may modulate glutamate transmission and reverse the clinical symptoms of depression. The demonstration that a glycine-antagonist produces antidepressant effects without psychotomimetic side effects would support the therapeutic relevance of the glycine site of the NMDAR and could direct the development of novel drug targets for the treatment of depression.

Study Population

Twenty-five individuals with treatment-resistant major depressive disorder (MDD) will be included.

Design

Male and female patients, ages 18 to 65 years, with a diagnosis of MDD, currently in an episode of major depression, will be recruited for this study. This study will consist of a randomized, double-blind crossover administration of either the glycine receptor antagonist AV 101 (1,080 or 1,440 mg/day given orally) or placebo for 2 weeks. The study will assess the efficacy in improving overall depressive symptomatology and tolerability of AV 101 in treatment-resistant MDD. Other aims of the study include: 1) determining whether changes in brain neurochemicals (e.g. glutamate) and peripheral biomarkers obtained via MRS and cerebrospinal fluid (CSF) correlate with antidepressant response (decrease in Hamilton Depression Rating Scale (HDRS) total scores) to AV 101 in patients with treatment-resistant MDD, and 2) examine other potential biomarkers of response.

Outcome Measures

Primary: Hamilton Rating Scale (HDRS) total score.

Secondary: Proportion of subjects achieving remission (HDRS less than or greater than 7) and response (greater than or equal to 50% reduction from baseline in HDRS total score); change from baseline in Hamilton Anxiety Rating Scale (HAM-A), Montgomery-Asberg Depression Rating Scale (MADRS), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores. Surrogate biomarkers of drug effect/response include: changes in prefrontal glutamate levels measured with 7T H-MRS.

Arms: arm 1: After a two-week drug-free period, participants received daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days followed by a two-week washout period; then crossover to placebo phase with daily dose of placebo pill for two weeks. arm 2: After a two-week drug-free period, participants received daily dose of placebo pill for two weeks followed by two-week washout period; then crossover to AV 101 treatment phase with daily oral dose of AV 101 (4-chlorokynurenine) monotherapy 1,080mg/day for seven days, then dose increased to AV 101 1,440mg/day for next seven days.
Interventions: intervention 1: AV 101 (4-Chlorokynurenine) intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: L-4-chlorokynurenine (4-Cl-KYN) was developed as a prodrug that is rapidly converted in vivo to its active metabolite 7-chlorokynurenic acid (7-Cl-KYNA), a well-characterized N-Methyl-D-aspartate receptor (NMDAR) antagonist at the glycine site. intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
PI name: Carlos A. Zarate, MD 
Date: 05-15-18 
Protocol number: 15-M-0151 
Version:Am C 
 
1
Protocol Title:  An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-
chlorokynurenine) in Major Depressive Disorder  
 
Abbreviated Title: Antidepressant effect of AV101 
 
Protocol Number: 15-M-0151 
 
1.  PRÉCIS  
a. Objective  
Modulation of the NMDA receptor (NMDAR) complex or other components of glutamatergic signaling is 
likely involved in improvement of depressive symptoms and related constructs/dimensions of observable behavior 
and neurobiological measures. Current standard monoaminergic pharmacological approaches for major depressive 
disorder (MDD) have proven to be only modestly effective during acute depressive episodes. We have 
systematically tested different glutamatergic modulators in patients with mood disorders in order to develop 
improved therapeutics. We found that the NMDAR antagonist ketamine produces rapid antidepressant effects in 
patients with treatment-resistant depression (in MDD and Bipolar Disorder). However, despite being highly 
efficacious, the proof of concept ketamine produces psychotomimetic effects.  
In the present protocol, we aim to evaluate a new glutamate-mediated mechanism associated with 
antidepressant efficacy by targeting the glycine receptor within the NMDA receptor. Targeting the glycine co-
agonist site of the (NMDA) receptor may bypass potential adverse effects that occur with ketamine without 
affecting the robust efficacy observed. This may then result in the “glutamate surge” that has been associated with 
the rapid acting antidepressant effects of ketamine.  
The present Phase 2 proof-of-concept study is designed to evaluate the antidepressant effects of AV-101 (L-4-
chlorokynurenine or 4-Cl- KYN) in MDD; this is a synthetic compound which is enzymatically converted into the 
selective glycine/NMDAR antagonist 7-chlorokynurine (7-Cl-KYNA) after crossing the blood brain barrier (BBB) 
and then reaching brain glial cells. In animal models of depression, 4-Cl-KYNA (AV-101) induced acute and 
prolonged antidepressant-like effects without exhibiting ketamine-like side effects as determined by the drug 
discrimination, conditioned place preference, and pre-pulse inhibition tests.  
We will also evaluate the neurobiological mechanisms involved in the antidepressant response to AV-101. We 
expect that this effect may modulate glutamate transmission and reverse the clinical symptoms of depression. The 
demonstration that a glycine-antagonist produces antidepressant effects without psychotomimetic side effects would 
support the therapeutic relevance of the glycine site of the NMDAR and could direct the development of novel drug 
targets for the treatment of depression.  
b. Design 
Male and female patients, ages 18 to 65 years, with a diagnosis of MDD, currently in an episode of major 
depression, will be recruited for this study. This study will consist of a randomized, double-blind crossover 
administration of either the glycine receptor antagonist AV-101 (1,080 or 1,440 mg/day given orally) or placebo for 
2 weeks. The study will assess the efficacy in improving overall depressive symptomatology and tolerability of 
AV-101 in treatment-resistant MDD. Other aims of the study include: 1) determining whether changes in brain 
neurochemicals (e.g. glutamate) and peripheral biomarkers obtained via MRS and cerebrospinal fluid (CSF) 
correlate with antidepressant response (decrease in Hamilton Depression Rating Scale (HDRS) total scores) to 
AV-101 in patients with treatment-resistant MDD, and 2) examine other potential biomarkers of response. 
c. Outcome Measures  
Primary: Hamilton Rating Scale (HDRS) total score.  


PI name: Carlos A. Zarate, MD 
Date: 05-15-18 
Protocol number: 15-M-0151 
Version:Am C 
 
2
Secondary: Proportion of subjects achieving remission (HDRS 7DQGUHVSRQVHUHGXFWLRQIURP
baseline in HDRS total score); change from baseline in Hamilton Anxiety Rating Scale (HAM-A), Montgomery-
Asberg Depression Rating Scale (MADRS), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores. 
Surrogate biomarkers of drug effect/response include: changes in prefrontal glutamate levels measured with 7T 1H-
MRS.  
 
 


PI name: Carlos A. Zarate, MD 
Date: 05-15-18 
Protocol number: 15-M-0151 
Version:Am C 
 
3
 
2.  STATISTICAL ANALYSIS 
a. Analysis of data/study outcomes 
The double blind will be broken and the randomization status of each participant will be revealed only after the 
completion of this study in all 20 individuals. An interim blinded analysis may be performed no more than one time 
(for example, at the request of the PI’s Board of Scientific Counsellors) to inform ongoing scientific efforts and 
productivity of the Branch; however, this interim analysis will not serve as the basis for decisions to change study 
procedures or to terminate the study.(Specific Aim 1) To assess the efficacy of AV-101 compared with placebo in 
improving overall depressive symptomatology over a two-week course of treatment in patients with treatment-
resistant MDD currently experiencing a major depressive episode.   
The primary aim will be accomplished by assessing the efficacy of two weeks of oral AV-101 (1,080 or 1,440 
mg/day) compared with placebo in improving overall depressive symptomatology. The primary assessment of 
efficacy is a comparison of HDRS scores between treatment groups.   
The difference between AV-101 and placebo will be examined using a linear mixed model with restricted 
maximum likelihood estimation where drug and time are within subjects factors.  Drug and time main effects and 
their interaction will be included in the model as within subjects factors. Baseline scores for each phase will be used 
as a time-dependent covariate.  A random intercept and subject effect will be included if they contribute 
significantly to the model.  Schwarz’s Bayesian criteria will be used to examine the most appropriate covariance 
structure prior to formal analyses, where a compound symmetry structure will be used in another is not preferred. 
Bonferroni corrected post hoc tests will be used to follow up on a significant drug by time interaction.  Cohen’s d 
will be calculated to describe the effect size.   
Additional follow-up analyses may examine the potential for carryover effects within the crossover study.  
First, an additional phase variable may be added to the original statistical model.  Second, results in the first phase 
of the study may be examined separately to understand whether any drug effect remains in a parallel-like design. 
Secondary analyses will be conducted in the same manner for BPRS, CADSS, C-SSRS, HAM-A, MADRS, 
PANAS, SHAPS, SSI, TEPS, and YMRS. A similar statistical model will be used to examine secondary measures.  
Bonferroni-like corrections will be used to determine the significance of secondary analyses. 
Criteria for significance 
Significance will be evaluated at p<.05, two-tailed.   
Analyses will be based on the intent-to-treat (ITT) principle where all randomized subjects who receive 
baseline and at least one post-baseline assessment will be included. A subject will be considered a responder if the 
HDRS WRWDOVFRUHKDVGHFUHDVHGE\RUPRUHIURPEDVHOLQHWRHQGSRLQW5HVSRQVHUDWHVZLOOEHDQDO\]HGXVLQJ
McNemar’s test for repeated measures categorical outcomes.  
Safety and tolerability assessments will be based on the safety analysis set which will include all randomized 
subjects who are given study treatment. 
The incidence rate of adverse events will be tabulated by preferred term and system organ class; serious 
adverse events, adverse events leading to death, and adverse events leading to withdrawal of subjects will be 
tabulated for each treatment group.   
Analyses of surrogate neurobiological markers 
Multiple logistic regression models (for categorical outcome, response vs. non-response) will evaluate 
candidate biological markers for independent association with outcomes. For these models, we will compute robust 
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PI name: Carlos A. Zarate, MD 
Date: 05-15-18 
Protocol number: 15-M-0151 
Version:Am C 
 
4
b. Power analysis 
Previous studies by our group (see Background) demonstrated improvement in depression at 72 hours with an 
effect size of d=0$VVXPLQJĮ WZR-WDLOHGSDWLHQWVZLWK0''ZRXOGSURYLGHSRZHUWRGHWHFWDQ
effect of the same size as previously reported with a double-blind crossover study. We are primarily interested in 
detecting drugs with a large effect size that oFFXUVZLWKLQDVKRUWSHULRGRIWLPHKVDVWKHUHDUHDOUHDG\PDQ\
antidepressants with small effect sizes after 2 weeks of treatment. This is the reason for not studying a much larger 
number of patients; in addition, the current study design uses a crossover design.  
c. Accrual number 
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crossover double-blind portion of the study, then 25 MDD patients need to be recruited.