NRX-101 for Maintenance of Remission From Severe Bipolar Depression in Patients With Suicidal Ideation

NMDA antagonist drugs have increasingly been demonstrated to reduce symptoms of depression and suicidal ideation. NeuroRx has developed a sequential therapy consisting of IV NRX-100 (ketamine HCL) for rapid stabilization of symptoms of depression and suicidal ideation followed by oral NRX-101 (fixed dose combination of D-cycloserine and lurasidone) for maintenance of stabilization from symptoms of depression and suicidal ideation. NRX-101 has been awarded Fast Track and Breakthrough Therapy Designation by the US Food and Drug Administration. The SevereBD study will test the hypothesis that NRX-101 is superior to lurasidone alone in maintaining remission from symptoms of depression (primary endpoint), clinical relapse (declared secondary endpoint), and suicidal ideation or behavior (declared secondary endpoint) over a six week period of twice-daily oral dosing.

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 or Behavior (ASIB) in adults with Bipolar Depression following initial stabilization with ketamine. NRX-101 has been awarded Fast Track and Breakthrough Therapy Designation by the US Food and Drug Administration.

In recent years, intravenous and intranasal ketamine have demonstrated rapid and potent effects in achieving remission from both depression and suicidal ideation in both bipolar depression and major depressive disorder. However ketamine is will understood to induce hallucination and other dissociative side effects, to be addictive and have high abuse potential, and to have potential neurotoxic effects. Moreover, ketamine can only be administered in a monitored hospital or clinic setting. NRX-101 was developed with the objective of seeking a safe, non-hallucinogenic, non-addictive, oral medication that might maintain the effects of ketamine in patients with severe depression and acute suicidal ideation and which might be considered as initial therapy for patients with depression and non-acute suicidal ideation. The D-cycloserine component of NRX-101 is believed to act by inhibiting the brain's NMDA receptor and raising levels of glutamate/glutamine (Glx) in the anterior cingulate cortex. Increased Glx, as measured by magnetic resonance spectroscopy, has been associated with clinical improvement following electroconvulsive therapy (ECT) and following administration of IV ketamine.

Primary Objective:

To test the hypothesis that following successful response to a single infusion of ketamine (NRX-100), treatment with NRX-101 is superior to lurasidone in maintaining improvement in symptoms of depression as measured by the MADRS-10 total score.

Secondary Objectives:

Key secondary: To test the hypothesis that following response to a single infusion of NRX-100, daily oral NRX-101 is superior to lurasidone in delaying time to relapse of suicidality or depression in patients with Severe Bipolar Depression and Acute Suicidal Ideation and Behavior (ASIB). Avoiding relapse will be defined as being relapse-free, without experiencing a 50% or greater return to pre-infusion baseline levels of depression, or suicidality, or the need to implement a new treatment plan.

* To demonstrate that following NRX-100 response, treatment with NRX-101 are less likely to suffer from akathisia than those treated with lurasidone.
* To demonstrate that following NRX-100 response, other efficacy advantages observed in NRX-100 responders are more favorable for NRX-101 vs. lurasidone
* To demonstrate safety and tolerability of NRX-101 vs. lurasidone.
* To demonstrate that following successful NRX-100 response, NRX-101 diminishes the length of stay for index hospitalization vs. lurasidone.

Methodology: A multi-center, randomized, stratified, double-blind, adaptive trial conducted under a Special Protocol Agreement with the FDA that enrolls patients demonstrating successful response in NCT03396601. Randomization will be 2:1 favoring NRX-101 (n=48) vs. lurasidone alone (n=24).

Eligibility Criteria:
Inclusion Criteria:

* A subject will be eligible for inclusion in this study based on successful response to infusion under NCT03396601 and the following criteria:

  1. 18 to 65 years of age, inclusive, at screening.
  2. 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.
  3. Resides in a stable living situation, in the opinion of the investigator
  4. Has an identified reliable informant, in the opinion of the investigator
  5. 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.
  6. In good general health, as ascertained by medical history, physical examination (including measurement of seated vital signs), clinical laboratory evaluations, and electrocardiogram
  7. 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 post-menopausal with last menses at least one year prior to screening); or b. 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.
  8. Body mass index between 18-35kg/m2.
  9. Concurrent psychotherapy will be allowed if the type and frequency of the therapy (e.g., weekly or monthly) has been stable for at least three months prior to screening and is expected to remain stable for the duration of the study.
  10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines, or trazodone) will be allowed if the therapy has been stable for at least four 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 anxiety if therapy has been stable for at least four weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study.

      Exclusion Criteria:

      A subject will not be eligible for inclusion in this study if any of the following criteria apply:

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  1. Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
  2. Female who is pregnant or breastfeeding.
  3. Female with a positive pregnancy test at screening or before oral dosing of investigational product.
  4. 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.
  5. Subjects with a lifetime history of PCP/ketamine drug use, or failed use of ketamine for depression.
  6. History of schizophrenia or schizoaffective disorder, or any history of psychotic symptoms when not in an acute bipolar mood episode.
  7. History of anorexia nervosa, bulimia nervosa, or eating disorder NOS (OSFED) within five years of screening.
  8. Has dementia, delirium, amnestic, or any other cognitive disorder.
  9. 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.
  10. 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.
  11. 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.
  12. Current episode of:

      1. Untreated hypertension, (Stage 1 or greater) 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. If untreated due to missing medication dose/s this is not exclusionary.
      2. 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).
      3. Recent myocardial infarction (within one year).
      4. Syncopal event within the past year.
      5. Congestive heart failure (CHF) New York Heart Association Criteria \>Stage 2.
      6. Angina pectoris.
      7. Heart rate \<50 or \>105 beats per minute at screening, pre-ketamine infusion (Day 0) or at randomization (Day 1).
      8. QTcF ≥450 msec at screening for men, ≥ 470 msec for women, pre-ketamine infusion (Day 0), or at randomization (Day 1), on two of three measurements at least 15 minutes apart.
  13. History of hypertension, or on antihypertensives for the purpose of lowering blood pressure, with either an increase in antihypertensive dose or increase in the number of antihypertensive drugs used to treat hypertension over the last two months.
  14. Chronic lung disease, excluding asthma.
  15. Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention that, according to the screening clinician, is deemed associated with significant injury to or malfunction of the CNS; or history of significant head trauma within the past two years.
  16. Presents with any of the following lab abnormalities:

      a. Subjects with diabetes mellitus fulfilling any of the following criteria: i. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \>8.0 % at screening.

      ii. Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus-related illness in the past 12 weeks.

      iii. Not under physician care for diabetes mellitus. iv. Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the four weeks prior to screening. For thiazolidinediones (glitazones) this period should not be less than eight weeks.

      b. Any other clinically significant abnormal laboratory result (as determined by the investigator and medical monitor) at the time of the screening.
  17. Any current or past history of any physical condition which, in the investigator's opinion, might put the subject at risk or interfere with study results interpretation.
  18. Subjects on exclusionary concomitant psychotropic medications (see Appendix 1) as defined in the study manual.
  19. At randomization, subjects prescribed more than one agent in each category;

      1. Approved antidepressants (e.g., SSRIs, SNRIs, TeCAs, fluoxetine), but not 5-HT-2a antagonists (lurasidone, aripiprazole, olanzapine, quetiapine)
      2. Mood stabilizers (e.g., lithium, carbamazepine, valproic acid)
  20. Subjects with exclusionary laboratory values (see Table 2).
  21. Known allergies to lurasidone or Latuda, cycloserine or Seromycin, or the excipients mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and/or HPMC (hydroxypropylmethylcellulose).
  22. Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation.
  23. Study site personnel and/or persons employed by NeuroRx, Inc. or Target Health or by the investigator or study site (i.e., permanent, temporary contract worker, or designee responsible for the conduct of the study), or an immediate family member (i.e., spouse or parent, child, or sibling \[biological or legally adopted\]) of such persons.