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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02484456
Recruitment Status : Completed
First Posted : June 29, 2015
Results First Posted : March 2, 2022
Last Update Posted : April 11, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

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.

Condition or disease Intervention/treatment Phase
Major Depression Drug: AV 101 (4-Chlorokynurenine) Other: Placebo Comparator Phase 2

Show Show detailed description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101 (4-chlorokynurenine) in Major Depressive Disorder
Actual Study Start Date : October 14, 2015
Actual Primary Completion Date : February 21, 2019
Actual Study Completion Date : December 3, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants
Drug Information available for: Glycine

Arm Intervention/treatment
Experimental: AV 101 (4-chlorokynurenine), then Placebo
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)
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.
Other Name: 4-Cl-KYN

Other: Placebo Comparator
Placebo

Experimental: Placebo, then AV 101 (4-chlorokynurenine)
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)
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.
Other Name: 4-Cl-KYN

Other: Placebo Comparator
Placebo




Primary Outcome Measures :
  1. Model Adjusted Means for Hamilton Depression Rating Score [ Time Frame: Post Dose Day 0 ]
    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.

  2. Model Adjusted Means for Hamilton Depression Rating Score [ Time Frame: Post Dose Day 1 ]
    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.

  3. Model Adjusted Means for Hamilton Depression Rating Score [ Time Frame: Post Dose Day 2 ]
    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.

  4. Model Adjusted Means for Hamilton Depression Rating Score [ Time Frame: Post Dose Day 3 ]
    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.

  5. Model Adjusted Means for Hamilton Depression Rating Score [ Time Frame: Post Dose Day 7 ]
    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.

  6. Model Adjusted Means for Hamilton Depression Rating Score [ Time Frame: Post Dose Day 13 ]
    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.


Secondary Outcome Measures :
  1. Model Adjusted Means for Beck Depression Score [ Time Frame: Post Dose Day 0 ]
    The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.

  2. Model Adjusted Means for Beck Depression Score [ Time Frame: Post Dose Day 1 ]
    The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.

  3. Model Adjusted Means for Beck Depression Score [ Time Frame: Post Dose Day 2 ]
    The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.

  4. Model Adjusted Means for Beck Depression Score [ Time Frame: Post Dose Day 3 ]
    The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.

  5. Model Adjusted Means for Beck Depression Score [ Time Frame: Post Dose Day 7 ]
    The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.

  6. Model Adjusted Means for Beck Depression Score [ Time Frame: Post Dose Day 13 ]
    The Beck Depression Inventory (BDI) is a 21-item measure of depression with each question on a 4-point scale ranging from 0=minimal to 3 = more severe (full list score values = 0,1,2,3). Total scores are a sum of individual items. The minimal depression = 0-13, mild depression = 14-19, moderate depression = 20-28, and severe depression = 29-63. The maximum score being 63 and the minimum possible score = 0.

  7. Model Adjusted Means for Hamilton Anxiety Rating Score [ Time Frame: Post Dose Day 0 ]
    The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.

  8. Model Adjusted Means for Hamilton Anxiety Rating Score [ Time Frame: Post Dose Day 1 ]
    The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.

  9. Model Adjusted Means for Hamilton Anxiety Rating Score [ Time Frame: Post Dose Day 2 ]
    The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.

  10. Model Adjusted Means for Hamilton Anxiety Rating Score [ Time Frame: Post Dose Day 3 ]
    The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.

  11. Model Adjusted Means for Hamilton Anxiety Rating Score [ Time Frame: Post Dose Day 7 ]
    The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.

  12. Model Adjusted Means for Hamilton Anxiety Rating Score [ Time Frame: Post Dose Day 13 ]
    The Hamilton Anxiety Rating Scale (HAM-A) is a 14-item global measure of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe) (full score list = 0,1,2,3,4), with a total score range of 0-56 (0 = minimum score and 56 = maximum), where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Total scores are a sum of individual items.

  13. Model Adjusted Means for Montgomery-Asberg Depression Rating Score [ Time Frame: Post Dose Day 0 ]
    The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.

  14. Model Adjusted Means for Montgomery-Asberg Depression Rating Score [ Time Frame: Post Dose Day 1 ]
    The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.

  15. Model Adjusted Means for Montgomery-Asberg Depression Rating Score [ Time Frame: Post Dose Day 2 ]
    The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.

  16. Model Adjusted Means for Montgomery-Asberg Depression Rating Score [ Time Frame: Post Dose Day 3 ]
    The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.

  17. Model Adjusted Means for Montgomery-Asberg Depression Rating Score [ Time Frame: Post Dose Day 7 ]
    The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.

  18. Model Adjusted Means for Montgomery-Asberg Depression Rating Score [ Time Frame: Post Dose Day 13 ]
    The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item global measure evaluating core symptoms of depression. Questions concern how the patient has felt over the past week. Each item is rated on a scale from 0 to 6, with 0 being "normal/not present" and 6 being "extreme" (full score list = 0,1,2,3,4,5,6). Maximum score = 60, minimum score = 0. Total scores are a sum of the individual items.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • 18 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).

EXCLUSION CRITERIA:

  • 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.
  • Positive HIV test
  • Contraindications to MRS (metal in body, claustrophobia, etc for imaging)
  • No structured psychotherapy will be permitted during the total duration of the study. Subjects unable or unwilling to stop psychotherapy will be unable to participate in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02484456


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)
  Study Documents (Full-Text)

Documents provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT02484456    
Other Study ID Numbers: 150151
15-M-0151
First Posted: June 29, 2015    Key Record Dates
Results First Posted: March 2, 2022
Last Update Posted: April 11, 2022
Last Verified: December 3, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Major Depression
Glycine Receptor Antagonist
4-chlorokynurenine
Treatment Resistant
Glutamatergic System
Additional relevant MeSH terms:
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Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders