Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder

NCT02484456 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 15015115-M-0151
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depression

Keywords

Major Depression; Glycine Receptor Antagonist; 4-chlorokynurenine; Treatment Resistant; Glutamatergic System

Outcome Measures

Primary Outcomes (6)

• Model Adjusted Means for Hamilton Depression Rating Score

  The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.

  Post Dose Day 0

• Model Adjusted Means for Hamilton Depression Rating Score

  The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.

  Post Dose Day 1

• Model Adjusted Means for Hamilton Depression Rating Score

  The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.

  Post Dose Day 2

• Model Adjusted Means for Hamilton Depression Rating Score

  The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.

  Post Dose Day 3

• Model Adjusted Means for Hamilton Depression Rating Score

  The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.

  Post Dose Day 7

• Model Adjusted Means for Hamilton Depression Rating Score

  The Hamilton Depression Rating scale is a 17-item global measure of depressive symptoms on a 5-point scale ranging from 0 = not present to 4 = severe (full score values = 0,1,2,3,4). Some items rated on a scale of 0-2 (0, 1, 2) with 0 = not present to 2 = more severe. Total scores are a sum of the individual items. The maximum total score being 52 on the 17-point scale, and the minimum score being 0.Total scores of 0-7 are considered as being normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression.

  Post Dose Day 13

Secondary Outcomes (18)

• Model Adjusted Means for Beck Depression Score

  Post Dose Day 0

• Model Adjusted Means for Beck Depression Score

  Post Dose Day 1

• Model Adjusted Means for Beck Depression Score

  Post Dose Day 2

• Model Adjusted Means for Beck Depression Score

  Post Dose Day 3

• Model Adjusted Means for Beck Depression Score

  Post Dose Day 7

Study Arms (2)

AV 101 (4-chlorokynurenine), then Placebo

EXPERIMENTAL

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.

Drug: AV 101 (4-Chlorokynurenine); Other: Placebo Comparator

Placebo, then AV 101 (4-chlorokynurenine)

EXPERIMENTAL

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.

Drug: AV 101 (4-Chlorokynurenine); Other: Placebo Comparator

Interventions

AV 101 (4-Chlorokynurenine) DRUG

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.

Also known as: 4-Cl-KYN

AV 101 (4-chlorokynurenine), then Placebo; Placebo, then AV 101 (4-chlorokynurenine)

Placebo Comparator OTHER

Placebo

AV 101 (4-chlorokynurenine), then Placebo; Placebo, then AV 101 (4-chlorokynurenine)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 65 years of age.
• Subjects must have a level of understanding sufficient to agree to all required tests and examinations, sign an informed consent document and verify understanding. To verify this, subjects must score greater than or equal to 80% on the consent quiz.
• Subjects must fulfill Diagnostic and Statistical Manual (DSM)-IV or DSM-V criteria for MDD, single episode or recurrent without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P). Subjects must be experiencing a current major depressive episode of at least 4 weeks duration.
• Subjects must have an initial score of at least 18 on the HDRS at screening and at baseline of study phase I.
• Subjects must have a current or past history of lack of response to one adequate antidepressant trial (may be from the same chemical class) operationally defined using the modified-Antidepressant Treatment History Form (ATHF).

You may not qualify if:

• Current psychotic features or a diagnosis of schizophrenia or any other psychotic disorder as defined in the DSM-IV or DSM-V.
• Subjects with a history of DSM-IV drug or alcohol dependency or abuse (or alcohol use disorder per DSM-V),except for caffeine or nicotine dependence within the preceding 3 months.
• Head injury that results in loss of consciousness exceeding 5 minutes (for the imaging component of the study).
• Subjects with a DSM IV or DSM-V Axis II diagnosis of borderline or antisocial personality disorder.
• Pregnant or nursing women or women of child bearing potential not using at least 1 medically accepted means of contraception from the time of enrollment in the study until 1 month after completion of the second phase. Examples of medically accepted means of contraception include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine devices (IUD), tubal ligation, abstinence or partner with vasectomy. .
• Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
• Subjects with clinical hyperthyroidism or hypothyroidism.
• Subjects with one or more seizures without a clear and resolved etiology.
• Clinically significant abnormal laboratory tests.
• Treatment with a reversible monoamine oxidase inhibitor (MAOI) within 4 weeks of study phase II.
• Treatment with fluoxetine or aripiprazole within 5 weeks of study phase II.
• Treatment with any other disallowed concomitant medication or TMS 14 days before randomization.
• Treatment with clozapine or electroconvulsive therapy (ECT) within 1 month of randomization.
• Lifetime history of deep brain stimulation.
• Subjects who, in the Principal Investigator's judgment, pose a current serious suicidal or homicidal risk.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Johnston JN, Yuan P, Kadriu B, Akula N, Quintanilla B, Peng S, Jones GH, Schulmann A, Yavi M, Henter ID, McMahon FJ, Kalynchuk LE, Zarate CA Jr, Caruncho HJ. Response of iPSC-derived neurons from individuals with treatment-resistant depression to (2 R,6 R)-hydroxynorketamine and reelin: an exploratory study. Transl Psychiatry. 2025 Nov 18;15(1):524. doi: 10.1038/s41398-025-03724-6.

  PMID: 41257792 DERIVED

• Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, Yuan P, Farmer CA, Oppenheimer M, George JM, Adeojo LW, Snodgrass HR, Smith MA, Henter ID, Machado-Vieira R, Mannes AJ, Zarate CA. A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2020 Jul 29;23(7):417-425. doi: 10.1093/ijnp/pyaa025.

  PMID: 32236521 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

4-chlorokynurenine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Results Point of Contact

• Title: Zarate, Carlos
• Organization: National Institute of Mental Health

zaratec@mail.nih.gov

+1 301 451 0861

Study Officials

• Carlos A Zarate, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2015
• First Posted: June 29, 2015
• Study Start: October 14, 2015
• Primary Completion: February 21, 2019
• Study Completion: December 3, 2019
• Last Updated: April 11, 2022
• Results First Posted: March 2, 2022

Record last verified: 2019-12-03

Locations

US (1)