Ignite Creation Date:
2024-05-06 @ 7:12 AM
Last Modification Date:
2024-10-26 @ 11:45 AM
Study NCT ID:
NCT02484456
Status:
COMPLETED
Last Update Posted:
2022-04-11
First Post:
2015-06-26
Brief Title:
Antidepressant Effects of the Glycine Receptor Antagonist AV-101 4-chlorokynurenine in Major Depressive Disorder
Sponsor:
National Institute of Mental Health NIMH
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101 4-chlorokynurenine in Major Depressive Disorder
Status:
COMPLETED
Status Verified Date:
2019-12-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
- 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 constructsdimensions 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 glycineNMDAR 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 1080 or 1440 mgday 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 eg 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 effectresponse include changes in prefrontal glutamate levels measured with 7T H-MRS
Modulation of the NMDA receptor NMDAR complex or other components of glutamatergic signaling is likely involved in improvement of depressive symptoms and related constructsdimensions 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 glycineNMDAR 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 1080 or 1440 mgday 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 eg 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 effectresponse include changes in prefrontal glutamate levels measured with 7T H-MRS
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 15-M-0151 | None | None | None |