NRX101 Glx Biomarker Validation Study

NCT03402152 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: NRX101_004
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Subnormal level of Glutamate+Glutamine (Glx) in the Anterior Cingulate Cortex (ACC) of the brain has been associated with depression and PTSD. Similarly, interventions that increase the level of Glx in the brain, specifically electroconvulsive therapy (ECT) and intravenous ketamine infusion have been associated with a rapid decrease in depression and suicidal ideation. This effect has been demonstrated in a dose-dependent manner in randomized clinical assessments. D-cycloserine, a glycine site modulator of NMDA receptor function has been demonstrated to increase Glx in the ACC of normal volunteers. The purpose of this study is to determine whether NRX-101, an experimental drug containing a fixed dose combination of D-cycloserine and lurasidone (1) raises Glx by a greater amount than either placebo or lurasidone alone in patients with bipolar depression, and (2) whether that elevation in Glx is correlated with a decrease in depression.

Conditions

Bipolar Depression; Suicidal Ideation

Keywords

Biomarker

Outcome Measures

Primary Outcomes (1)

• Glx

  Mean change in Glx Area Under the Curve (AUC) measured in 15 minute increments over 2 hours at following experimental drug vs. comparator

  Immediate

Secondary Outcomes (3)

• Depression

  4 weeks

• Suicidal ideation (1)

  4 weeks

• Suicidal ideation (2)

  6 hours

Study Arms (2)

NRX-101 vs. Placebo

EXPERIMENTAL

Following study enrollment and randomization, subjects will undergo two treatment sessions, 3 days apart. Each treatment session will be conducted while the subject is undergoing Magnetic Resonance Spectroscopy to measure Glx in the ACC. In one treatment session the subject will receive oral placebo and in the other treatment session the subject will receive oral NRX-101. Following the second treatment session, the subject will participate in a four week open study of NRX-101, at the end of which a third session of Magnetic Resonance Spectroscopy will be conducted.

Drug: NRX-101; Drug: Placebo

NRX-101 vs. lurasidone HCl

EXPERIMENTAL

Following study enrollment and randomization, subjects will undergo two treatment sessions, 3 days apart. Each treatment session will be conducted while the subject is undergoing Magnetic Resonance Spectroscopy to measure Glx in the ACC. In one treatment session the subject will receive oral lurasidone and in the other treatment session the subject will receive oral NRX-101. Following the second treatment session, the subject will participate in a four week open study of NRX-101, at the end of which a third session of Magnetic Resonance Spectroscopy will be conducted.

Drug: NRX-101; Drug: Lurasidone HCl

Interventions

NRX-101 DRUG

NRX-101, a fixed dose combination of D-cycloserine+lurasidone will be given twice a day by mouth

NRX-101 vs. Placebo; NRX-101 vs. lurasidone HCl

Lurasidone HCl DRUG

Lurasidone HCl will be given twice a day by mouth

NRX-101 vs. lurasidone HCl

Placebo DRUG

Placebo oral capsule

NRX-101 vs. Placebo

Eligibility Criteria

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

You may qualify if:

• to 65 years of age, inclusive, at screening.
• Able to understand and provide written and dated informed consent prior to screening. Deemed likely to comply with study protocol and communicate AEs and other clinically important information, and agree to be hospitalized to complete screening and initiate experimental treatment.
• Resides in a stable living situation, in the opinion of the investigator
• Has an identified reliable informant, in the opinion of the investigator
• Diagnosed with bipolar disorder (BD) according to the criteria defined in the DSM-5. The diagnosis of BD will be made by a psychiatrist and supported by the MINI 7.0.2.
• Suicidal ideation or behavior as evidenced by an answer of "Yes" to item 2 or item 3 on the C-SSRS.
• A score of greater than or equal to 20 on the MADRS.
• In good general health, as ascertained by medical history, physical examination (including measurement of seated vital signs), clinical laboratory evaluations, and electrocardiogram
• If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:
• Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized \[status post hysterectomy, bilateral tubal ligation\], or post-menopausal with last menses at least one year prior to screening); or
• Childbearing potential, and meets the following criteria:
• i. 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 sexually abstinent.
• ii. Negative urinary pregnancy test at screening, confirmed by a second negative urinary pregnancy test at randomization prior to receiving study treatment.
• iii. 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 pre-ketamine baseline.
• Body mass index between 18-35kg/m2.

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 who is pregnant or breastfeeding.
• Female with a positive pregnancy test at screening or before oral dosing of investigational product.
• Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or tobacco use disorder) within the 12 months prior to screening. Substance abuse cannot be the precipitant of entry to treatment.
• Subjects with a lifetime history of PCP/ketamine drug use, or failed use of ketamine for depression.
• History of schizophrenia or schizoaffective disorder, or any history of psychotic symptoms when not in an acute bipolar mood episode.
• History of anorexia nervosa, bulimia nervosa, or eating disorder NOS (OSFED) within five years of screening.
• Has dementia, delirium, amnestic, or any other cognitive disorder.
• Any major psychiatric disorder, including a personality disorder, which is clinically predominant to BD at screening, or has been the primary focus of treatment predominant to BD at any time within six months prior to screening.
• Current major psychiatric disorder, diagnosed at screening with the MINI 7.0.2, that is the primary focus of treatment, with BD as the secondary focus of treatment, within the past six months.
• A clinically significant abnormality on the screening physical examination that might affect safety or study participation, or that might confound interpretation of study results according to the study clinician.
• Current episode of:
• Hypertension, Stage 2, as defined by a systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥99 mmHg within 1.5 hours prior to ketamine infusion on two of three measurements at least 15 minutes apart at the pre-ketamine assessment (on Day 0 at Visit 1).
• Recent myocardial infarction (within one year).
• Syncopal event within the past year.

Sponsors & Collaborators

• NeuroRx, Inc.: lead
• Target Health Inc.: collaborator

Study Sites (1)

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

Related Publications (2)

• Dong Z, Grunebaum MF, Lan MJ, Wagner V, Choo TH, Milak MS, Sobeih T, Mann JJ, Kantrowitz JT. Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study. Front Psychiatry. 2021 Jun 2;12:653026. doi: 10.3389/fpsyt.2021.653026. eCollection 2021.

  PMID: 34149476 RESULT

• Milak MS, Rashid R, Dong Z, Kegeles LS, Grunebaum MF, Ogden RT, Lin X, Mulhern ST, Suckow RF, Cooper TB, Keilp JG, Mao X, Shungu DC, Mann JJ. Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial. JAMA Netw Open. 2020 Aug 3;3(8):e2013211. doi: 10.1001/jamanetworkopen.2020.13211.

  PMID: 32785636 RESULT

Related Links

• FDA Biomarker Letter of Support
• Listing of FDA biomarker qualification programs

MeSH Terms

Conditions

Bipolar Disorder; Suicidal Ideation

Interventions

Lurasidone Hydrochloride

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Joshua T Kantrowicz, MD

  New York State Psychiatric Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: Participants and Care Providers will be masked with regard to medication administered.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2018
• First Posted: January 18, 2018
• Study Start: November 1, 2018
• Primary Completion: January 1, 2021
• Study Completion: June 1, 2021
• Last Updated: August 9, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)