Sequential Therapy for the Treatment of Severe Bipolar Depression.

NCT02974010 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: NRX 101-001
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 4

Brief Summary

NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of d-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar Depression with Acute Suicidal Ideation (C-SSRS level 4 or 5) or Behavior (ASIB) in following initial stabilization. Patients with Severe Bipolar Depression and ASIB will be recruited in both inpatient and outpatient settings and, following informed consent, will be given an intravenous infusion of ketamine 0.5mg/kg over 40 minutes. Those who exhibit a satisfactory clinical response to ketamine will be randomly allocated to NRX-101 or to lurasidone alone (the comparator group). This study is conducted as a feasibility study for a pivotal phase 2b/3 clinical trial and the primary outcomes for this phase 2 study were blood levels of NRX-101, in order to confirm pharmaco-kinetics with remission from depression, as measured by BISS-derived MADRS and relapse as secondary outcomes.

Conditions

Bipolar Depression; Suicidal Ideas; Suicidal Ideation; Suicide, Attempted

Keywords

d-cycloserine; lurasidone; ketamine; randomized controlled trial

Outcome Measures

Primary Outcomes (1)

• BDM Score (BISS-derived MADRS) Change From Baseline at Day 42

  The study will measure the difference on BISS-derived MADRS score between NRX-101 and lurasidone (comparator) groups. The Bipolar Inventory of Symptom Scale (BISS) is a validated 42-item clinician-rated scale (21 items each for the depression and mania subscales) in which each item is rated on a 0-4 severity scale where higher values indicate worse severity. BISS-derived MADRS (BDM): MADRS is a 10-item clinician-rated scale, with each item rated on a 0-6 severity scale, where a higher number indicates worse severity. Responses to each question are equally weighted and summed. The BDM has a minimum score of 0 and a maximum of 40, where higher scores indicate a worse severity, therefore decreases in average BDM are considered a better outcome. Data are presented as mean change from baseline (end of stage 1, Day 1) using LOCF

  Day 42

Study Arms (2)

NRX-101

EXPERIMENTAL

NRX-101 is a fixed dose combination of d-cycloserine and lurasidone

Drug: NRX-101 Oral Capsule; Drug: Ketamine Intravenous Infusion; Drug: Saline Solution Intravenous Infusion

Lurasidone

ACTIVE COMPARATOR

Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101

Drug: Lurasidone Oral Capsule; Drug: Ketamine Intravenous Infusion; Drug: Saline Solution Intravenous Infusion

Interventions

NRX-101 Oral Capsule DRUG

Prospective Randomized Factorial Design Study as per arm/group descriptions

Also known as: D-cycloserine + Lurasidone Fixed Dose Combination

NRX-101

Lurasidone Oral Capsule DRUG

Prospective Randomized Factorial Design Study as per arm/group descriptions

Also known as: Lurasidone Fixed Dose Combination

Lurasidone

Ketamine Intravenous Infusion DRUG

Randomized administration of Ketamine or Placebo in a 3 to 1 ratio

Lurasidone; NRX-101

Saline Solution Intravenous Infusion DRUG

Randomized administration of Ketamine or Placebo in a 3 to 1 ratio

Lurasidone; NRX-101

Eligibility Criteria

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

You may qualify if:

• Male or female, 18 to 65 years of age, inclusive, at screening.
• Able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about AEs and other clinically important information.
• Diagnosed with Bipolar Disorder (BD) according to the criteria defined in the DSM-5. The diagnosis of BD will be made by a site psychiatrist and supported by the MINI 7.0.2. The diagnosis will be confirmed by remote, independent raters, via teleconference between the screen visit and the baseline visit.
• Suicidal ideation or behavior of sufficient severity to meet the requirements for a score of 4, or 5 on the C-SSRS (suicide attempt, interrupted attempt, aborted attempt, preparatory actions toward imminent suicidal behaviors, active method, intent +/- plan).
• A score equal to or greater than 20 on the MADRS items of the BISS.
• In good general health, in the opinion of the investigator, as ascertained by medical history, physical examination (PE) (including measurement of seated vital signs), clinical laboratory evaluations, and electrocardiogram (ECG).
• If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:
• a. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized \[status post hysterectomy, bilateral tubal ligation\], or is post-menopausal with her last menses at least one year prior to screening); or
• Childbearing potential, and meets the following criteria:
• Childbearing potential, including women using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent.
• Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy test at randomization prior to receiving study treatment.
• Willing and able to continuously use one of the following methods of birth control during the course of the study, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly: implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence. The form of birth control will be documented at screening and baseline.
• Body mass index between 18-35 kg/m2.
• Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, insight-oriented) and frequency (e.g., weekly or monthly) of the therapy has been stable for at least three months prior to screening and if the type and frequency of the therapy is expected to remain stable during the course of the subject's participation in the study.
• Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines or trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study. Subjects can also continue treatment with benzodiazepines used for sleep or anxiety if therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study.

You may not qualify if:

• Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
• Female that is pregnant or breastfeeding.
• Female with a positive pregnancy test at screening or baseline.
• Current diagnosis of a substance use disorder (abuse or dependence, as defined by DSM-5, with the exception of nicotine dependence), at screening or within 6 months prior to screening.
• Current Axis I disorder, diagnosed at screening with the use of the MINI 7.0.2, that is the primary focus of treatment and BD the secondary focus of treatment for the past 6 months or more.
• History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms.
• History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within 5 years of screening.
• Any Axis I or Axis II Disorder, which at screening is clinically predominant to their BD or has been predominant to their BD at any time within 6 months prior to screening.
• Has dementia, delirium, amnestic, or any other cognitive disorder.
• Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results according to the study clinician.
• Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation.
• Current episode of:
• Hypertension, Stage 1 as defined by a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg at screening on two of three measurements at least 15 minutes apart.
• Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5 hours prior to ketamine infusion on two of three measurements at least 15 minutes apart.
• Recent myocardial infarction (within one year) or a history of myocardial infarction.

Sponsors & Collaborators

• NeuroRx, Inc.: lead
• Massachusetts General Hospital: collaborator
• Target Health Inc.: collaborator

Study Sites (4)

Research Site, Birmingham

Birmingham, Alabama, 35294, United States

Location

Research Site, Fort Lauderdale

Fort Lauderdale, Florida, 33024, United States

Location

Research Site, Charlotte

Charlotte, North Carolina, 28211, United States

Location

Research Site, Houston

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Nierenberg A, Lavin P, Javitt DC, Shelton R, Sapko MT, Mathew S, Besthof RE, Javitt JC. NRX-101 (D-cycloserine plus lurasidone) vs. lurasidone for the maintenance of initial stabilization after ketamine in patients with severe bipolar depression with acute suicidal ideation and behavior: a randomized prospective phase 2 trial. Int J Bipolar Disord. 2023 Aug 13;11(1):28. doi: 10.1186/s40345-023-00308-5.

  PMID: 37573534 DERIVED

MeSH Terms

Conditions

Bipolar Disorder; Suicidal Ideation; Suicide, Attempted

Interventions

Cycloserine; Lurasidone Hydrochloride

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders; Suicide; Self-Injurious Behavior; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins; Thiazoles; Sulfur Compounds; Organic Chemicals; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Martin Brecher
• Organization: NeuroRx

mbrecher@neurorxpharma.com

+1 484 254 6134

Study Officials

• Andrew Nierenberg, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

• Daniel C Javitt, MD

  NeuroRx, Inc.

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2016
• First Posted: November 28, 2016
• Study Start: January 15, 2018
• Primary Completion: August 31, 2018
• Study Completion: November 20, 2019
• Last Updated: May 25, 2021
• Results First Posted: May 25, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)