Sequential Therapy for the Treatment of Severe Bipolar Depression.
Condition: Bipolar Depression; Suicidal Ideas; Suicidal Ideation; Suicide, Attempted
MeSH terms: Depression; Depressive Disorder; Suicide; Bipolar Disorder; Suicidal Ideation; Suicide, Attempted
Intervention: NRX-101 Oral Capsule; Lurasidone Oral Capsule; Ketamine Intravenous Infusion; Saline Solution Intravenous Infusion
Intervention description: Prospective Randomized Factorial Design Study as per arm/group descriptions; Prospective Randomized Factorial Design Study as per arm/group descriptions; Randomized administration of Ketamine or Placebo in a 3 to 1 ratio; Randomized administration of Ketamine or Placebo in a 3 to 1 ratio
Intervention MeSH terms: Cycloserine; Ketamine; Lurasidone Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: d-cycloserine; lurasidone; ketamine; randomized controlled trial

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.
    

Eligibility criteria:

        Inclusion Criteria:A subject will be eligible for inclusion in this study only if all of
        the following criteria apply:

          1. Male or female, 18 to 65 years of age, inclusive, at screening.

          2. 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.

          3. 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.

          4. 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).

          5. A score equal to or greater than 20 on the MADRS items of the BISS.

          6. 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).

          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
             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.

          8. Body mass index between 18-35 kg/m2.

          9. 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.

         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 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.

        Exclusion Criteria:

        A subject will not be eligible for inclusion in this study if any of the following criteria
        apply:

          1. Female of childbearing potential who is not willing to use one of the specified forms
             of birth control during the study.

          2. Female that is pregnant or breastfeeding.

          3. Female with a positive pregnancy test at screening or baseline.

          4. 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.

          5. 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.

          6. History of schizophrenia or schizoaffective disorders, or any history of psychotic
             symptoms.

          7. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise
             specified, within 5 years of screening.

          8. 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.

          9. Has dementia, delirium, amnestic, or any other cognitive disorder.

         10. 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.

         11. Participation in any clinical trial with an investigational drug or device within the
             past month or concurrent to study participation.

         12. 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.

               -  Syncopal event within the past year.

               -  Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2

               -  Angina pectoris.

               -  Heart rate <50 or >105 beats per minute at screening or randomization (Baseline
                  Visit).

               -  QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline
                  Visit).

         13. Current 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 2 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 which, 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 2 years.

         16. Presents with any of the following lab abnormalities:

               -  Subjects with diabetes mellitus fulfilling any of the following criteria:

                    -  Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5%
                       at screening.

                    -  Admitted to hospital for treatment of diabetes mellitus or diabetes
                       mellitus-related illness in the past 12 weeks.

                    -  Not under physician care for diabetes mellitus.

                    -  Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for
                       the 4 weeks prior to screening. For thiazolidinediones (glitazones) this
                       period should not be less than 8 weeks.

               -  Any other clinically significant abnormal laboratory result (determined as such
                  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. Positive screening urine test for drugs of abuse at screening: cocaine, amphetamines,
             barbiturates, opiates.

         19. Subjects with exclusionary laboratory values, or requiring treatment with exclusionary
             concomitant medications as defined in the study manual

         20. Subjects on exclusionary concomitant psychotropic medications.

         21. Subjects with a lifetime history of illicit PCP/ketamine drug use or previous failed
             use of ketamine for depression.

         22. Liver Function Tests higher than 2.5 times upper limit of normal as defined in the
             study manual.

         23. Known allergies to Lurasidone or Latuda, Cycloserine or Seromycin, Mannitol,
             Croscarmellose Sodium, Magnesium Stearate, Silicon Dioxide, and/or HPMC
             (hydroxypropylmethylcellulose)

             -