NRX101 for Suicidal Treatment Resistant Bipolar Depression

Study Overview
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Brief Summary
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NMDA antagonist drugs have shown to reduce symptoms of depression and suicidal ideation. NeuroRx has developed NRX-101 (fixed dose combination of D-cycloserine and lurasidone) for oral use in the treatment of bipolar depression with suicidal ideation. This study will test the hypothesis that NRX-101 is superior to lurasidone alone (standard of care) in maintaining remission from symptoms of depression (primary endpoint) and suicidal ideation or behavior (declared secondary endpoint) over a six week period of twice-daily oral dosing.

Detailed Description
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Background and Rationale: NMDA antagonist drugs have shown to reduce symptoms of depression and suicidal ideation. NRX-101 is composed of D-cycloserine (DCS) an NMDA antagonist and lurasidone (5HT2a atypical antipsychotic and antidepressant). In a phase 2 clinical study of bipolar depression and acute suicidal ideation and behavior, (in patients requiring hospitalization) patients received an initial infusion of ketamine and then NRX-101 for 6 weeks. In that phase 2 study, NRX-101 showed the ability to maintain remission from depression and suicidality over 6 weeks when taken twice daily. In this current out patient study, patients with bipolar depression and subacute suicidality (not requiring hospitalization), ketamine will not be used. Primary Objective: To test the hypothesis that treatment with NRX-101 is superior to standard of care (lurasidone) in improving symptoms of depression as measured by the total Montgomery Åsberg Depression Rating Scale (MADRS-10) score in patients with bipolar depression and subacute suicidal ideation and behavior (SSIB) which does not require hospitalization. Secondary Objectives: • To test the hypothesis that treatment with NRX-101 is superior to standard of care (lurasidone) in reducing suicidality in depressed bipolar patients with SSIB, as measured by the Columbia Suicide Severity Rating Scale (C-SSRS) Methodology: : A multi-center, randomized, double-blind, trial in which patients with bipolar depression (MADRS ≥30) and subacute levels of suicidal ideation (C-SSRS 3 or 4, not requiring hospitalization) are randomized to receive twice daily oral NRX-101 or lurasidone (standard of care).

Official Title
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Comparison of NRX-101 to Standard of Care (Lurasidone) for Treatment-resistant Bipolar Depression With Suicidal Ideation and Behavior

Conditions
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Bipolar Depression, Suicidal Ideation and Behavior

Intervention / Treatment
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* Drug: NRX-101
* Drug: Lurasidone HCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with bipolar disorder by a qualified rater according to the criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and supported by the Mini International Neuropsychiatric Interview (MINI) 7.0.2. Confirmed active suicidal ideation (without the intention to act) as evidenced by an answer of 'Yes' on item 3 and/or item 4 and not requiring hospitalization at Screening and an answer of No on item 5 of the C-SSRS. A total score greater than or equal to 30 on the 10 items of the MADRS. Subject has no co-morbidities as ascertained by medical history, physical examination (including measurement of vital signs), clinical laboratory evaluations, and electrocardiogram (ECG) Exclusion Criteria: Subject has current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or tobacco use disorder) within the 12 months prior to Screening. Subject has a lifetime history of: phencyclidine (PCP)/ketamine drug abuse, or failed use of ketamine for depression or suicidality. Subject has schizophrenia or schizoaffective disorder, or any history of psychotic symptoms when not in an acute bipolar mood episode. Subject has a current major psychiatric disorder, diagnosed at Screening Subject has been prescribed more than one agent in each of the following categories at randomization: Approved SSRIs Approved serotonin and norepinephrine reuptake inhibitors (SNRIs) Approved tetracyclic antidepressants (TeCAs) Approved Mood stabilizers (e.g., lithium, valproic acid, and lamotrigine) Subject has signs and symptoms of active or residual COVID-19, or unresolved symptoms of COVID-19 that impact health

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NRX-101<br>Following study enrollment and randomization, subjects will receive twice daily NRX-101 | Drug: NRX-101<br>* NRX-101, a fixed dose combination of D-cycloserine+lurasidone will be given twice a day by mouth<br>|
| Active Comparator: Lurasidone<br>Following study enrollment, subjects will receive twice daily lurasidone | Drug: Lurasidone HCl<br>* Lurasidone HCl will be given twice a day by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in MADRS-10 over 42 Days | Mean change from baseline to endpoint (Day 42/exit) in total MADRS score, a 10-item clinician-rated scale, with each item rated on a 0-6 severity scale (0 Minimum, 60 maximum), where higher scores indicate a worse outcome | Six weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change from baseline in CGI-SS | Mean change from baseline to exit (Day 42/exit) in CGI-SS score | Six Weeks | 
| Time to Treatment Failure | Time to relapse, where relapse is defined as experiencing a return of suicidality in the Columbia Suicide Severity Rating Scale (C-SSRS) of >=4)), or a return to baseline levels of depression following an improvement of 25% or greater on the MADRS score, or the need to implement a new treatment plan. The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. A lower score on the C-SSRS indicates a better outcome (min=0, max=5) | 6 weeks |