<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02974010</url>
  </required_header>
  <id_info>
    <org_study_id>NRX 101-001</org_study_id>
    <nct_id>NCT02974010</nct_id>
  </id_info>
  <brief_title>Sequential Therapy for the Treatment of Severe Bipolar Depression.</brief_title>
  <acronym>STABIL-B</acronym>
  <official_title>Sequential Therapy (NRX-100 Followed by NRX-101) for the Treatment of Acute Suicidal Ideation and Behavior in Bipolar Depression: the STABIL-B Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NeuroRx, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Target Health Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>NeuroRx, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of&#xD;
      d-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar&#xD;
      Depression with Acute Suicidal Ideation (C-SSRS level 4 or 5) or Behavior (ASIB) in following&#xD;
      initial stabilization. Patients with Severe Bipolar Depression and ASIB will be recruited in&#xD;
      both inpatient and outpatient settings and, following informed consent, will be given an&#xD;
      intravenous infusion of ketamine 0.5mg/kg over 40 minutes. Those who exhibit a satisfactory&#xD;
      clinical response to ketamine will be randomly allocated to NRX-101 or to lurasidone alone&#xD;
      (the comparator group). This study is conducted as a feasibility study for a pivotal phase&#xD;
      2b/3 clinical trial and the primary outcomes for this phase 2 study were blood levels of&#xD;
      NRX-101, in order to confirm pharmaco-kinetics with remission from depression, as measured by&#xD;
      BISS-derived MADRS and relapse as secondary outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of&#xD;
      D-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar&#xD;
      Depression with Acute Suicidal Ideation or Behavior (ASIB) in adults with Bipolar Depression&#xD;
      following initial stabilization with ketamine. In recent years, intravenous and intranasal&#xD;
      ketamine have demonstrated rapid and potent effects in achieving remission from both&#xD;
      depression and suicidal ideation in both bipolar depression and major depressive disorder.&#xD;
      However ketamine is will understood to induce hallucination and other dissociative side&#xD;
      effects, to be addictive and have high abuse potential, and to have potential neurotoxic&#xD;
      effects. Moreover, ketamine can only be administered in a monitored hospital or clinic&#xD;
      setting. NRX-101 was developed with the objective of seeking a safe, non-hallucinogenic,&#xD;
      non-addictive, oral medication that might maintain the effects of ketamine in patients with&#xD;
      severe depression and acute suicidal ideation and which might be considered as initial&#xD;
      therapy for patients with depression and non-acute suicidal ideation. The D-cycloserine&#xD;
      component of NRX-101 is believed to act by inhibiting the brain's NMDA receptor and raising&#xD;
      levels of glutamate/glutamine (Glx) in the anterior cingulate cortex. Increased Glx, as&#xD;
      measured by magnetic resonance spectroscopy, has been associated with clinical improvement&#xD;
      following electroconvulsive therapy (ECT) and following administration of IV ketamine.&#xD;
&#xD;
      The proposed oral combination product is intended to be administered as part of a sequential&#xD;
      therapy consisting of the following 2 components:&#xD;
&#xD;
        1. an initial, one-time intravenous (iv) infusion of ketamine (0.5 mg/kg administered over&#xD;
           40 min), followed one day later by&#xD;
&#xD;
        2. twice daily oral capsules of NRX 101 (DCS + lurasidone), dosing of which is initiated 1&#xD;
           day after ketamine administration, titrated over 5 days to a maintenance dose and&#xD;
           continued for up to 6 weeks. Each NRX-101 oral capsule contains DCS (237.5 or 175.0 mg)&#xD;
           and lurasidone (8.25, 16.5, or 33.0 mg). It is anticipated that subjects entering the&#xD;
           study will be receiving concurrent disorder-directed treatment with other approved&#xD;
           medications. This treatment regime will be maintained upon entry into the study.&#xD;
           However, any use of lurasidone, quetiapine, or olanzapine will be stopped at study&#xD;
           entry, so as to avoid either duplication with study drug (groups 1 and 2) or undermining&#xD;
           of the control group.&#xD;
&#xD;
      The clinical efficacy goal is to provide extended relief from symptoms associated with&#xD;
      Severed Bipolar Depression and ASIB in adults with Bipolar Disorder, after initial&#xD;
      stabilization with iv ketamine in a clinic, emergency department, or inpatient setting.&#xD;
&#xD;
      The proposed NRX-101 product takes advantage of a unique synergistic confluence of combining&#xD;
      two active pharmaceutical ingredients (DCS and lurasidone) that respectively inhibit the NMDA&#xD;
      and the D2/5-HT2A receptors in the brain. NMDA receptor antagonists, most notably ketamine,&#xD;
      have been shown in many studies to rapidly reduce depressive and suicidal ideation. However,&#xD;
      numerous studies have demonstrated the potential of NMDA antagonists to cause hallucination&#xD;
      and other dissociative side effects. Similarly, D2/5HT2A receptor antagonists, such as&#xD;
      lurasidone have demonstrated antidepressant effects in bipolar depression, but have&#xD;
      demonstrated a propensity to cause akathisia in some patients. The goals of combining these&#xD;
      drugs into a single course of treatment is to maximize the beneficial effects of the specific&#xD;
      subcomponents while overcoming potential treatment-limiting side effects associated with&#xD;
      those subcomponents.&#xD;
&#xD;
      Beneficial effects of the proposed dosage regimen include 1) well-documented pharmacodynamic&#xD;
      effects of ketamine in treating both persistent depressive symptoms and suicidal ideation in&#xD;
      bipolar disorder (McCloud, 2015; Naughton, 2014; Newport, 2015; Price, 2014), 2)&#xD;
      well-documented pharmacodynamic effects of oral DCS against persistent symptoms of depression&#xD;
      (Heresco-Levy, 2013) and 3) the FDA-approved efficacy of lurasidone in treatment-resistant&#xD;
      depression (Sunovion Pharmaceuticals, 2013). Due to the synergistic effects, the proposed&#xD;
      NRX-101 combination capsule is also expected to avoid or minimize the significant undesired&#xD;
      adverse effects associated with the usage of these drugs as single agents (eg, negative&#xD;
      consequences of repeated use of ketamine (JHP Pharmaceuticals, 2012), potential&#xD;
      psychotomimetic effects of long-term treatment with DCS alone (Kantrowitz, 2010) and&#xD;
      potential akathisia and susceptibility for increased suicidality associated with lurasidone&#xD;
      alone (Sunovion Pharmaceuticals, 2013).&#xD;
&#xD;
      The risk of ASIB is higher in bipolar depression than other psychiatric disorder and the&#xD;
      majority of currently available antidepressants are contraindicated for patients with bipolar&#xD;
      depression. NeuroRx believes that the proposed NRX-101 treatment regimen (ketamine&#xD;
      administration followed by NRX-101) will demonstrate superiority over ketamine followed by&#xD;
      lurasidone in maintaining remission from depression and in delaying the time to documented&#xD;
      relapse from depression and suicidality in bipolar disorder, providing a new treatment option&#xD;
      for patients with Severe Bipolar Depression and ASIB.&#xD;
&#xD;
      There is currently no FDA-approved product for the treatment of ASIB. NeuroRx proposes that&#xD;
      NRX-101 will fulfill an urgent medical need for safe and effective treatment for ASIB.&#xD;
&#xD;
      Patients with Severe Bipolar Depression and ASIB will be recruited in inpatient settings and,&#xD;
      following informed consent, will be given an intravenous infusion of either ketamine 0.5mg/kg&#xD;
      over 40 minutes or normal saline (placebo). Those who exhibit a satisfactory clinical&#xD;
      response to ketamine will be randomly allocated to NRX-101 or to lurasidone along (the&#xD;
      comparator group). The primary outcome variable for this phase 2 study will be blood level&#xD;
      (pharmacokinetic) exposure of NRX-101 and its D-cycloserine component with remission from&#xD;
      depression, as measured on the MADRS scale and relapse as secondary endpoints. Relapse is&#xD;
      defined as return of either depression or suicidality OR the need to alter therapy, which&#xD;
      might include re-hospitalization, additional antidepressant medication, or electroconvulsive&#xD;
      therapy (ECT).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 15, 2018</start_date>
  <completion_date type="Actual">November 20, 2019</completion_date>
  <primary_completion_date type="Actual">August 31, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>BDM Score (BISS-derived MADRS) Change From Baseline at Day 42</measure>
    <time_frame>Day 42</time_frame>
    <description>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.&#xD;
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</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Bipolar Depression</condition>
  <condition>Suicidal Ideas</condition>
  <condition>Suicidal Ideation</condition>
  <condition>Suicide, Attempted</condition>
  <arm_group>
    <arm_group_label>NRX-101</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>NRX-101 is a fixed dose combination of d-cycloserine and lurasidone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lurasidone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NRX-101 Oral Capsule</intervention_name>
    <description>Prospective Randomized Factorial Design Study as per arm/group descriptions</description>
    <arm_group_label>NRX-101</arm_group_label>
    <other_name>D-cycloserine + Lurasidone Fixed Dose Combination</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lurasidone Oral Capsule</intervention_name>
    <description>Prospective Randomized Factorial Design Study as per arm/group descriptions</description>
    <arm_group_label>Lurasidone</arm_group_label>
    <other_name>Lurasidone Fixed Dose Combination</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketamine Intravenous Infusion</intervention_name>
    <description>Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
    <arm_group_label>Lurasidone</arm_group_label>
    <arm_group_label>NRX-101</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Saline Solution Intravenous Infusion</intervention_name>
    <description>Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
    <arm_group_label>Lurasidone</arm_group_label>
    <arm_group_label>NRX-101</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:A subject will be eligible for inclusion in this study only if all of&#xD;
        the following criteria apply:&#xD;
&#xD;
          1. Male or female, 18 to 65 years of age, inclusive, at screening.&#xD;
&#xD;
          2. Able to read, understand, and provide written, dated informed consent prior to&#xD;
             screening. Participants will be deemed likely to comply with study protocol and&#xD;
             communicate with study personnel about AEs and other clinically important information.&#xD;
&#xD;
          3. Diagnosed with Bipolar Disorder (BD) according to the criteria defined in the DSM-5.&#xD;
             The diagnosis of BD will be made by a site psychiatrist and supported by the MINI&#xD;
             7.0.2. The diagnosis will be confirmed by remote, independent raters, via&#xD;
             teleconference between the screen visit and the baseline visit.&#xD;
&#xD;
          4. Suicidal ideation or behavior of sufficient severity to meet the requirements for a&#xD;
             score of 4, or 5 on the C-SSRS (suicide attempt, interrupted attempt, aborted attempt,&#xD;
             preparatory actions toward imminent suicidal behaviors, active method, intent +/-&#xD;
             plan).&#xD;
&#xD;
          5. A score equal to or greater than 20 on the MADRS items of the BISS.&#xD;
&#xD;
          6. In good general health, in the opinion of the investigator, as ascertained by medical&#xD;
             history, physical examination (PE) (including measurement of seated vital signs),&#xD;
             clinical laboratory evaluations, and electrocardiogram (ECG).&#xD;
&#xD;
          7. If female, a status of non-childbearing potential or use of an acceptable form of&#xD;
             birth control per the following specific criteria:&#xD;
&#xD;
             a. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant,&#xD;
             i.e., permanently sterilized [status post hysterectomy, bilateral tubal ligation], or&#xD;
             is post-menopausal with her last menses at least one year prior to screening); or&#xD;
&#xD;
               -  Childbearing potential, and meets the following criteria:&#xD;
&#xD;
                    -  Childbearing potential, including women using any form of hormonal birth&#xD;
                       control, on hormone replacement therapy started prior to 12 months of&#xD;
                       amenorrhea, using an intrauterine device (IUD), having a monogamous&#xD;
                       relationship with a partner who has had a vasectomy, or is sexually&#xD;
                       abstinent.&#xD;
&#xD;
                    -  Negative urinary pregnancy test at screening, confirmed by a negative&#xD;
                       urinary pregnancy test at randomization prior to receiving study treatment.&#xD;
&#xD;
                    -  Willing and able to continuously use one of the following methods of birth&#xD;
                       control during the course of the study, defined as those which result in a&#xD;
                       low failure rate (i.e., less than 1% per year) when used consistently and&#xD;
                       correctly: implants, injectable or patch hormonal contraception, oral&#xD;
                       contraceptives, IUD, double-barrier contraception, sexual abstinence. The&#xD;
                       form of birth control will be documented at screening and baseline.&#xD;
&#xD;
          8. Body mass index between 18-35 kg/m2.&#xD;
&#xD;
          9. Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive&#xD;
             behavioral, insight-oriented) and frequency (e.g., weekly or monthly) of the therapy&#xD;
             has been stable for at least three months prior to screening and if the type and&#xD;
             frequency of the therapy is expected to remain stable during the course of the&#xD;
             subject's participation in the study.&#xD;
&#xD;
         10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines&#xD;
             or trazodone) will be allowed if the therapy has been stable for at least 4 weeks&#xD;
             prior to screening and if it is expected to remain stable during the course of the&#xD;
             subject's participation in the study. Subjects can also continue treatment with&#xD;
             benzodiazepines used for sleep or anxiety if therapy has been stable for at least 4&#xD;
             weeks prior to screening and if it is expected to remain stable during the course of&#xD;
             the subject's participation in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        A subject will not be eligible for inclusion in this study if any of the following criteria&#xD;
        apply:&#xD;
&#xD;
          1. Female of childbearing potential who is not willing to use one of the specified forms&#xD;
             of birth control during the study.&#xD;
&#xD;
          2. Female that is pregnant or breastfeeding.&#xD;
&#xD;
          3. Female with a positive pregnancy test at screening or baseline.&#xD;
&#xD;
          4. Current diagnosis of a substance use disorder (abuse or dependence, as defined by&#xD;
             DSM-5, with the exception of nicotine dependence), at screening or within 6 months&#xD;
             prior to screening.&#xD;
&#xD;
          5. Current Axis I disorder, diagnosed at screening with the use of the MINI 7.0.2, that&#xD;
             is the primary focus of treatment and BD the secondary focus of treatment for the past&#xD;
             6 months or more.&#xD;
&#xD;
          6. History of schizophrenia or schizoaffective disorders, or any history of psychotic&#xD;
             symptoms.&#xD;
&#xD;
          7. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise&#xD;
             specified, within 5 years of screening.&#xD;
&#xD;
          8. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their&#xD;
             BD or has been predominant to their BD at any time within 6 months prior to screening.&#xD;
&#xD;
          9. Has dementia, delirium, amnestic, or any other cognitive disorder.&#xD;
&#xD;
         10. Has a clinically significant abnormality on the screening physical examination that&#xD;
             might affect safety, study participation, or confound interpretation of study results&#xD;
             according to the study clinician.&#xD;
&#xD;
         11. Participation in any clinical trial with an investigational drug or device within the&#xD;
             past month or concurrent to study participation.&#xD;
&#xD;
         12. Current episode of:&#xD;
&#xD;
               -  Hypertension, Stage 1 as defined by a systolic blood pressure ≥140 mmHg or&#xD;
                  diastolic blood pressure ≥90 mmHg at screening on two of three measurements at&#xD;
                  least 15 minutes apart.&#xD;
&#xD;
               -  Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or&#xD;
                  diastolic blood pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5&#xD;
                  hours prior to ketamine infusion on two of three measurements at least 15 minutes&#xD;
                  apart.&#xD;
&#xD;
               -  Recent myocardial infarction (within one year) or a history of myocardial&#xD;
                  infarction.&#xD;
&#xD;
               -  Syncopal event within the past year.&#xD;
&#xD;
               -  Congestive heart failure (CHF) New York Heart Association Criteria &gt;Stage 2&#xD;
&#xD;
               -  Angina pectoris.&#xD;
&#xD;
               -  Heart rate &lt;50 or &gt;105 beats per minute at screening or randomization (Baseline&#xD;
                  Visit).&#xD;
&#xD;
               -  QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline&#xD;
                  Visit).&#xD;
&#xD;
         13. Current history of hypertension, or on antihypertensives for the purpose of lowering&#xD;
             blood pressure, with either an increase in antihypertensive dose or increase in the&#xD;
             number of antihypertensive drugs used to treat hypertension over the last 2 months.&#xD;
&#xD;
         14. Chronic lung disease excluding asthma.&#xD;
&#xD;
         15. Lifetime history of surgical procedures involving the brain or meninges, encephalitis,&#xD;
             meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or&#xD;
             Parkinson's Disease), epilepsy, mental retardation, or any other&#xD;
             disease/procedure/accident/intervention which, according to the screening clinician,&#xD;
             is deemed associated with significant injury to or malfunction of the CNS, or history&#xD;
             of significant head trauma within the past 2 years.&#xD;
&#xD;
         16. Presents with any of the following lab abnormalities:&#xD;
&#xD;
               -  Subjects with diabetes mellitus fulfilling any of the following criteria:&#xD;
&#xD;
                    -  Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) &gt;8.5%&#xD;
                       at screening.&#xD;
&#xD;
                    -  Admitted to hospital for treatment of diabetes mellitus or diabetes&#xD;
                       mellitus-related illness in the past 12 weeks.&#xD;
&#xD;
                    -  Not under physician care for diabetes mellitus.&#xD;
&#xD;
                    -  Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for&#xD;
                       the 4 weeks prior to screening. For thiazolidinediones (glitazones) this&#xD;
                       period should not be less than 8 weeks.&#xD;
&#xD;
               -  Any other clinically significant abnormal laboratory result (determined as such&#xD;
                  by the investigator and medical monitor) at the time of the screening.&#xD;
&#xD;
         17. Any current or past history of any physical condition which in the investigator's&#xD;
             opinion might put the subject at risk or interfere with study results interpretation.&#xD;
&#xD;
         18. Positive screening urine test for drugs of abuse at screening: cocaine, amphetamines,&#xD;
             barbiturates, opiates.&#xD;
&#xD;
         19. Subjects with exclusionary laboratory values, or requiring treatment with exclusionary&#xD;
             concomitant medications as defined in the study manual&#xD;
&#xD;
         20. Subjects on exclusionary concomitant psychotropic medications.&#xD;
&#xD;
         21. Subjects with a lifetime history of illicit PCP/ketamine drug use or previous failed&#xD;
             use of ketamine for depression.&#xD;
&#xD;
         22. Liver Function Tests higher than 2.5 times upper limit of normal as defined in the&#xD;
             study manual.&#xD;
&#xD;
         23. Known allergies to Lurasidone or Latuda, Cycloserine or Seromycin, Mannitol,&#xD;
             Croscarmellose Sodium, Magnesium Stearate, Silicon Dioxide, and/or HPMC&#xD;
             (hydroxypropylmethylcellulose)&#xD;
&#xD;
             -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrew Nierenberg, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Daniel C Javitt, MD</last_name>
    <role>Study Director</role>
    <affiliation>NeuroRx, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site, Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site, Fort Lauderdale</name>
      <address>
        <city>Fort Lauderdale</city>
        <state>Florida</state>
        <zip>33024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site, Charlotte</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site, Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>November 22, 2016</study_first_submitted>
  <study_first_submitted_qc>November 25, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2016</study_first_posted>
  <results_first_submitted>December 13, 2020</results_first_submitted>
  <results_first_submitted_qc>May 1, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">May 25, 2021</results_first_posted>
  <last_update_submitted>May 1, 2021</last_update_submitted>
  <last_update_submitted_qc>May 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 25, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>d-cycloserine</keyword>
  <keyword>lurasidone</keyword>
  <keyword>ketamine</keyword>
  <keyword>randomized controlled trial</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Suicide</mesh_term>
    <mesh_term>Bipolar Disorder</mesh_term>
    <mesh_term>Suicidal Ideation</mesh_term>
    <mesh_term>Suicide, Attempted</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cycloserine</mesh_term>
    <mesh_term>Ketamine</mesh_term>
    <mesh_term>Lurasidone Hydrochloride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 17, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT02974010/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Ketamine Followed by NRX-101</title>
          <description>NRX-101 is a fixed dose combination of d-cycloserine and lurasidone&#xD;
NRX-101 Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="P2">
          <title>Ketamine Followed by Lurasidone</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="P3">
          <title>Saline Followed by NRX-101</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="P4">
          <title>Saline Followed by Lurasidone</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Completed day 42 but did not return for day 70</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Ketamine Followed by NRX-101</title>
          <description>NRX-101 is a fixed-dose combination of d-cycloserine and lurasidone&#xD;
NRX-101 Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="B2">
          <title>Ketamine Followed by Lurasidone</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="B3">
          <title>Saline Followed by NRX-101</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="B4">
          <title>Saline Followed by Lurasidone</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="12"/>
            <count group_id="B2" value="5"/>
            <count group_id="B3" value="4"/>
            <count group_id="B4" value="1"/>
            <count group_id="B5" value="22"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33.9" spread="10.5"/>
                    <measurement group_id="B2" value="49" spread="8.9"/>
                    <measurement group_id="B3" value="41" spread="8.9"/>
                    <measurement group_id="B4" value="54" spread="0"/>
                    <measurement group_id="B5" value="39.5" spread="11.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Columbia Suicide Severity Rating Scale (CSSRS)</title>
          <description>Columbia Suicide Severity Rating Scale (C-SSRS): C-SSRS is a well validated, 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. . It contains a 1-to-5 rating scale for suicidal ideation of increasing severity (from a &quot;wish list to die&quot; to an &quot;active thought of killing oneself with plan and intent&quot;).</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>CSSRS = 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CSSRS = 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CSSRS =3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CSSRS =4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CSSRS = 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>BDM Score (BISS-derived MADRS) Change From Baseline at Day 42</title>
        <description>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.&#xD;
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</description>
        <time_frame>Day 42</time_frame>
        <population>Last Observation Carrier Forward</population>
        <group_list>
          <group group_id="O1">
            <title>Ketamine Followed by NRX-101</title>
            <description>NRX-101 is a fixed-dose combination of d-cycloserine and lurasidone&#xD;
NRX-101 Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
          </group>
          <group group_id="O2">
            <title>Ketamine Followed by Lurasidone</title>
            <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
          </group>
          <group group_id="O3">
            <title>Saline Followed by NRX-101</title>
            <description>Saline (stage 1) followed by NRX-101 (stage 2)</description>
          </group>
          <group group_id="O4">
            <title>Saline Followed by Lurasidone</title>
            <description>Saline (stage 1) followed by lurasidone (stage 2)</description>
          </group>
        </group_list>
        <measure>
          <title>BDM Score (BISS-derived MADRS) Change From Baseline at Day 42</title>
          <description>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.&#xD;
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</description>
          <population>Last Observation Carrier Forward</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.3" spread="1.95"/>
                    <measurement group_id="O2" value="2.4" spread="2.95"/>
                    <measurement group_id="O3" value="-1.06" spread="3.81"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.0" spread="1.91"/>
                    <measurement group_id="O2" value="4.8" spread="2.95"/>
                    <measurement group_id="O3" value="-0.5" spread="3.74"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 14</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.2" spread="1.91"/>
                    <measurement group_id="O2" value="11.4" spread="2.95"/>
                    <measurement group_id="O3" value="0.31" spread="4.0"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 21</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.5" spread="1.91"/>
                    <measurement group_id="O2" value="10.0" spread="2.95"/>
                    <measurement group_id="O3" value="1.0" spread="5.72"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 28</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.5" spread="1.91"/>
                    <measurement group_id="O2" value="11.2" spread="2.95"/>
                    <measurement group_id="O3" value="1.69" spread="7.34"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 35</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.8" spread="1.91"/>
                    <measurement group_id="O2" value="10.8" spread="2.95"/>
                    <measurement group_id="O3" value="1.75" spread="8.43"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 42</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" spread="1.91"/>
                    <measurement group_id="O2" value="11.0" spread="2.95"/>
                    <measurement group_id="O3" value="0.38" spread="5.77"/>
                    <measurement group_id="O4" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.03</p_value>
            <p_value_desc>BDM LS difference overall</p_value_desc>
            <method>Mixed Models Analysis</method>
            <method_desc>BDM LS difference overall</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Study Duration (6 weeks)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Ketamine Followed by NRX-101</title>
          <description>NRX-101 is a fixed-dose combination of d-cycloserine and lurasidone&#xD;
NRX-101 Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="E2">
          <title>Ketamine Followed by Lurasidone</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="E3">
          <title>Saline Followed by NRX-101</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
        <group group_id="E4">
          <title>Saline Followed by Lurasidone</title>
          <description>Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101&#xD;
Lurasidone Oral Capsule: Prospective Randomized Factorial Design Study as per arm/group descriptions&#xD;
Ketamine Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio&#xD;
Saline Solution Intravenous Infusion: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (20.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>angina pectoris</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>palpitations</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>tinnitus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>tinnitus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Diplopia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>vision blurred</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>abdominal distention</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>fatigue</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>vulvovaginal candidiasis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>thermal burn</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>wound</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>weight increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>muscle spasms</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>coordination abnormal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>dysmetropsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>hypoasthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>akathisia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>hypersomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>lethargy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>sedation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>somnolence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Dissociation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>euphoric mood</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>restlessness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>anorgasmia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>depressed mood</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>depression</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>restlessness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>suicidal ideation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>acute kidney injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>ejaculation delayed</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>dry skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>hypertension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Martin Brecher</name_or_title>
      <organization>NeuroRx</organization>
      <phone>+1 484 254 6134</phone>
      <email>mbrecher@neurorxpharma.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02974010
org study id: NRX 101-001
nct id: NCT02974010
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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. 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.

      The proposed oral combination product is intended to be administered as part of a sequential
      therapy consisting of the following 2 components:

        1. an initial, one-time intravenous (iv) infusion of ketamine (0.5 mg/kg administered over
           40 min), followed one day later by

        2. twice daily oral capsules of NRX 101 (DCS + lurasidone), dosing of which is initiated 1
           day after ketamine administration, titrated over 5 days to a maintenance dose and
           continued for up to 6 weeks. Each NRX-101 oral capsule contains DCS (237.5 or 175.0 mg)
           and lurasidone (8.25, 16.5, or 33.0 mg). It is anticipated that subjects entering the
           study will be receiving concurrent disorder-directed treatment with other approved
           medications. This treatment regime will be maintained upon entry into the study.
           However, any use of lurasidone, quetiapine, or olanzapine will be stopped at study
           entry, so as to avoid either duplication with study drug (groups 1 and 2) or undermining
           of the control group.

      The clinical efficacy goal is to provide extended relief from symptoms associated with
      Severed Bipolar Depression and ASIB in adults with Bipolar Disorder, after initial
      stabilization with iv ketamine in a clinic, emergency department, or inpatient setting.

      The proposed NRX-101 product takes advantage of a unique synergistic confluence of combining
      two active pharmaceutical ingredients (DCS and lurasidone) that respectively inhibit the NMDA
      and the D2/5-HT2A receptors in the brain. NMDA receptor antagonists, most notably ketamine,
      have been shown in many studies to rapidly reduce depressive and suicidal ideation. However,
      numerous studies have demonstrated the potential of NMDA antagonists to cause hallucination
      and other dissociative side effects. Similarly, D2/5HT2A receptor antagonists, such as
      lurasidone have demonstrated antidepressant effects in bipolar depression, but have
      demonstrated a propensity to cause akathisia in some patients. The goals of combining these
      drugs into a single course of treatment is to maximize the beneficial effects of the specific
      subcomponents while overcoming potential treatment-limiting side effects associated with
      those subcomponents.

      Beneficial effects of the proposed dosage regimen include 1) well-documented pharmacodynamic
      effects of ketamine in treating both persistent depressive symptoms and suicidal ideation in
      bipolar disorder (McCloud, 2015; Naughton, 2014; Newport, 2015; Price, 2014), 2)
      well-documented pharmacodynamic effects of oral DCS against persistent symptoms of depression
      (Heresco-Levy, 2013) and 3) the FDA-approved efficacy of lurasidone in treatment-resistant
      depression (Sunovion Pharmaceuticals, 2013). Due to the synergistic effects, the proposed
      NRX-101 combination capsule is also expected to avoid or minimize the significant undesired
      adverse effects associated with the usage of these drugs as single agents (eg, negative
      consequences of repeated use of ketamine (JHP Pharmaceuticals, 2012), potential
      psychotomimetic effects of long-term treatment with DCS alone (Kantrowitz, 2010) and
      potential akathisia and susceptibility for increased suicidality associated with lurasidone
      alone (Sunovion Pharmaceuticals, 2013).

      The risk of ASIB is higher in bipolar depression than other psychiatric disorder and the
      majority of currently available antidepressants are contraindicated for patients with bipolar
      depression. NeuroRx believes that the proposed NRX-101 treatment regimen (ketamine
      administration followed by NRX-101) will demonstrate superiority over ketamine followed by
      lurasidone in maintaining remission from depression and in delaying the time to documented
      relapse from depression and suicidality in bipolar disorder, providing a new treatment option
      for patients with Severe Bipolar Depression and ASIB.

      There is currently no FDA-approved product for the treatment of ASIB. NeuroRx proposes that
      NRX-101 will fulfill an urgent medical need for safe and effective treatment for ASIB.

      Patients with Severe Bipolar Depression and ASIB will be recruited in inpatient settings and,
      following informed consent, will be given an intravenous infusion of either ketamine 0.5mg/kg
      over 40 minutes or normal saline (placebo). Those who exhibit a satisfactory clinical
      response to ketamine will be randomly allocated to NRX-101 or to lurasidone along (the
      comparator group). The primary outcome variable for this phase 2 study will be blood level
      (pharmacokinetic) exposure of NRX-101 and its D-cycloserine component with remission from
      depression, as measured on the MADRS scale and relapse as secondary endpoints. Relapse is
      defined as return of either depression or suicidality OR the need to alter therapy, which
      might include re-hospitalization, additional antidepressant medication, or electroconvulsive
      therapy (ECT).
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: BDM Score (BISS-derived MADRS) Change From Baseline at Day 42
time frame: Day 42
description: 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
arm group label: NRX-101
arm group type: Experimental
description: NRX-101 is a fixed dose combination of d-cycloserine and lurasidone
arm group label: Lurasidone
arm group type: Active Comparator
description: Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101
intervention type: Drug
intervention name: NRX-101 Oral Capsule
description: Prospective Randomized Factorial Design Study as per arm/group descriptions
arm group label: NRX-101
other name: D-cycloserine + Lurasidone Fixed Dose Combination
intervention type: Drug
intervention name: Lurasidone Oral Capsule
description: Prospective Randomized Factorial Design Study as per arm/group descriptions
arm group label: Lurasidone
other name: Lurasidone Fixed Dose Combination
intervention type: Drug
intervention name: Ketamine Intravenous Infusion
description: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio
arm group label: Lurasidone
arm group label: NRX-101
intervention type: Drug
intervention name: Saline Solution Intravenous Infusion
description: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio
arm group label: Lurasidone
arm group label: NRX-101
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Andrew Nierenberg, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Daniel C Javitt, MD
role: Study Director
affiliation: NeuroRx, Inc.
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Suicide
mesh term: Bipolar Disorder
mesh term: Suicidal Ideation
mesh term: Suicide, Attempted
mesh term: Cycloserine
mesh term: Ketamine
mesh term: Lurasidone Hydrochloride
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 