NRX-101 for Bipolar Depression With Subacute Suicidal Ideation

A Randomized, Double-Blind Controlled Comparison of NRX-101 to Lurasidone for Adults With Bipolar Depression and Subacute Suicidal Ideation or Behavior

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Bipolar Depression; Suicidal Ideation and Behavior
• Intervention / Treatment: Drug: NRX-101; Drug: Lurasidone HCl

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2; Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Marisa Gorovitz, MSW; Phone Number: 484-268-1656; Email: mgorovitz@nrxpharma.com
• Study Contact Backup: Name: Heather A Lothamer, RN, PhD; Phone Number: 484-268-1654; Email: clinicaltrials@nrxpharma.com

Study Locations

• United States
  • California
    • Culver City, California, United States, 90320
      • Science 37
  • Florida
    • Miami Lakes, Florida, United States, 33014
      • San Marcus Research Clinic, Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • ACMR
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta, LLC
    • Savannah, Georgia, United States, 31405
      • iResearch Savannah
  • Maryland
    • Gaithersburg, Maryland, United States, 20877
      • CBH Health
  • Nebraska
    • Omaha, Nebraska, United States, 68144
      • Omaha Insomnia and Psychiatric Services
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurologic Institute
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Peace Health Medical Group
  • Texas
    • Austin, Texas, United States, 78712
      • University of Texas Health Austin
    • Austin, Texas, United States, 78746
      • Roots Behavioral Health
    • Fort Worth, Texas, United States, 76104
      • JPS Health
    • Houston, Texas, United States, 77055
      • Houston Mind and Brain
    • Richmond, Texas, United States, 77407
      • Health Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: NeuroRx, Inc.
• Collaborators: Prevail Infoworks, Inc
• Investigators: Study Director: Martin Brecher, MD, NRx Pharma; Study Chair: Andrew A Nierenberg, MD, Harvard Medical School (HMS and HSDM); Study Chair: Jonathan C Javitt, MD, MPH, NRx Pharmaceuticals

Publications and helpful links

Helpful Links

• STABIL-B Study Results

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2022
• Primary Completion (Estimated): February 28, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: January 4, 2018
• First Submitted That Met QC Criteria: January 9, 2018
• First Posted (Actual): January 10, 2018

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Self-Injurious Behavior; Suicide; Depression; Depressive Disorder; Bipolar Disorder; Suicidal Ideation; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Adrenergic alpha-Antagonists; Adrenergic alpha-2 Receptor Antagonists; Lurasidone Hydrochloride
• Other Study ID Numbers: NRX101_003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be shared under an approved confidentiality agreement within one year of drug approval
• IPD Sharing Time Frame: Within one year of drug approval
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No