NRX-101 for Treatment-Resistant Bipolar Depression in Patients At Risk for Self-Harm

NRX-101_006 EAP

There is no currently-approved pharmacotherapy for patients with Treatment-Resistant Bipolar Depression and Suicidal Ideation or behavior. The purpose of this Expanded Access Treatment Protocol is to make NRX-101 available to patients who have depression and suicidal ideation despite treatment with currently approved medication and to gather information on safety and efficacy in a real-world data environment. Participants will be treated by their own practicing psychiatrist and will agree to periodic psychometric evaluations to assess depression, suicidal ideation, and side effects.

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Inclusion Criteria: 1. 18 to 65 years of age, inclusive, at Screening 2. Able to understand and provide written and dated informed consent prior to screening 3. Deemed likely to comply with the study protocol, including communication of adverse events (AEs) and other clinically important information, including adherence to the text messaging component of the trial. 4. Will follow medical directions for psychiatric care, as appropriate, per the standard of care. 5. Resides in a stable living situation. A stable living situation will be defined as a minimum of 3 months at the same address with a reasonable expectation that the situation will continue such that the patient's ability to participate in the study will not be affected. Please note that housing in a shelter of any kind will not be deemed stable housing. 6. Must have been under the care of a licensed qualified psychiatric prescriber for a minimum of 6 months prior to screening and be able and willing to provide documentation of treatment history and current and past psychiatric medication. 7. Has an identified reliable informant/care partner, that is willing to provide information and/or supportive care as necessary. 8. Diagnosed with bipolar disorder (BD) I or II according to the criteria defined in the DSM-5. The diagnosis of BD will be made by a psychiatrist or other qualified licensed psychiatric provider able to render a diagnosis and be supported by the MINI 7.0.2. 9. Confirmed active suicidal ideation (without the intention to act) as evidenced by an answer of 'Yes' on item 3 and/or 4 and not requiring hospitalization at Screening and an answer of 'No' on item 5 of the C-SSRS within 4-weeks of Screening 10. A total score greater than or equal to 20 on the 10 items of the MADRS 11. No co-morbidities, as ascertained by medical history clinical laboratory evaluations, and electrocardiogram (ECG) which might interfere with compliance or the ability to assess efficacy or safety. 12. If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following criteria, and agrees to continue use of the same method of birth control for the duration of study participation: 1. Non-childbearing potential: physiologically incapable of becoming pregnant (i.e. permanently sterilized \[status post-hysterectomy, bilateral tubal ligation\] or post-menopausal with last menses at least one year prior to screening); or 2. Childbearing potential, and meets the following criteria: i. Use of any form of hormonal birth control for at least 2 months prior to Screening, on hormone replacement therapy that started prior to 12 months of amenorrhea, using an intrauterine device (IUD) for at least 1 month prior to Screening, in a monogamous relationship with a partner who has had a vasectomy, or sexually abstinent. ii. Negative urine pregnancy test at Screening, confirmed by a second negative urinary pregnancy test at Day 1, prior to receiving any study treatment 13. Body mass index (BMI) between 18-40 kg/m2. 14. If receiving concurrent psychotherapy, the type and frequency of the therapy (e.g., weekly or monthly) has been stable for at least 3 months prior to Screening and is expected to remain stable for the duration of study participation 15. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines, maximum 2mg/daily, or trazodone) will be allowed if the therapy has been stable for at least 4-weeks prior to screening and if it is expected to remain stable during the course of the patient's participation in the study. Participants can also continue treatment with benzodiazepines maximum dose 2mg/daily used for anxiety if therapy has been stable relative to dose and schedule for at least 4-weeks prior to screening and if it is expected to remain stable during the course of the patient's participation in the study. If receiving concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines, or trazodone), the therapy has been stable for at least 4 weeks prior to Screening and is expected to remain stable for the duration of study participation. 16. If receiving benzodiazepines for anxiety, the dose and frequency have been stable for at least 4 weeks prior to Screening and is expected to remain stable for the duration of study participation 17. If women are receiving hormone replacement therapy or estrogen replacement, the therapy has been stable for at least 3 months prior to Screening and is expected to remain stable for the duration of study participation Exclusion Criteria: * 1. Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study. 2. Female who is pregnant or breastfeeding. 3. Female with a positive pregnancy test at Screening or prior to randomization. 4. Current DSM-5 diagnosis of moderate or severe substance use or abuse disorder or a diagnosis of dependence (except marijuana or tobacco use disorder only) within the 12 months prior to Screening. (Note: Substance abuse cannot be the precipitant for study entry.) 5. A lifetime history of 1. phencyclidine (PCP)/ketamine drug abuse, or 2. failed use of ketamine for depression or suicidality. 6. History of schizophrenia or schizoaffective disorder, or any history of psychotic symptoms when not in an acute bipolar mood episode. 7. History of anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified (NOS), or other specified feeding and eating disorders (OSFED) within 5 years of Screening. 8. Has dementia, delirium, amnestic, or any other cognitive disorder. 9. Current major psychiatric disorder, diagnosed at Screening with the MINI 7.0.2 which is the primary focus of treatment, with bipolar disorder as the secondary focus of treatment, within the past 6 months. 10. Estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 using the Cockcroft-Gault formula 11. A clinically significant abnormality on the Screening physical examination that may affect safety or study participation, or that may confound interpretation of study results according to the study clinician. 12. Current episode of: a. Myocardial infarction within 1 year of Screening. b. Diagnosis of angina pectoris. c. Prolonged QTc interval, as measured by Fridericia's correction formula (QTcF) ≥450 msec at Screening for males or ≥ 470 msec for females on 2 of 3 measurements at least 15 minutes apart prior to randomization on Day 1. 13. Diagnosis of chronic lung disease, excluding asthma. 14. Lifetime history of any of the following: surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's Disease, Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention that, according to the clinician, is deemed associated with significant injury to, or malfunction of, the CNS. 15. History of significant head trauma within the past two years. 16. Diabetes mellitus fulfilling any of the following criteria: 1. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \>8.0 % at Screening. 2. Admitted to the hospital for treatment of diabetes mellitus or diabetes mellitus-related illness in the past 12 weeks. 3. Not under physician care for diabetes mellitus. 4. Not on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks prior to Screening. 5. Not on the same dose of oral thiazolidinediones (glitazones) for the 8 weeks prior to Screening. 17. Any current or past history of any physical condition which, in the opinion of the investigator, may put the patient at risk or interfere with study results interpretation. 18. Diagnosis of HIV/AIDS 19. Diagnosis of Hepatitis C 20. On exclusionary concomitant psychotropic and non-psychotropic medications (see Appendix 1). 21. Prescribed more than one agent in each of the following categories at randomization: <!-- --> 1. Approved SSRIs 2. Approved serotonin and norepinephrine reuptake inhibitors (SNRIs) 3. Approved tetracyclic antidepressants (TeCAs) 4. Approved Mood stabilizers (e.g. lithium, valproic acid, and lamotrigine) Note: Any/all 5hT2A medications will be discontinued at study entry. Participants currently on Lurasidone will be randomized to either standard of care or NRXx-101 at the indicated starting dose 22. Currently prescribed oxcarbazepine or carbamazepine 23. Exclusionary laboratory values or any other clinically significant abnormal laboratory result (as determined by the investigator and Medical Monitor) at Screening. 24. Known allergies to lurasidone or Latuda®, cycloserine or Seromycin®, or the following excipients: mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and/or hydroxypropylmethylcellulose (HPMC). 25. Participation in any clinical trial with an investigational drug or device within the past month or planned concurrent study participation. 26. Study site personnel and/or persons employed by NRx Pharma, Inc., the Contract Research Organization (CRO), the investigator, or study site (i.e., permanent, temporary contract worker, or designee responsible for the conduct of the study), or an immediate family member (i.e., spouse, parent, child, or sibling \[biological or legally adopted\]) of such persons. 27. Positive urine toxicity screening for use of any cocaine, opiates and non-prescribed amphetamine and non-prescribed barbiturates (Note: Cannabinoids or Marijuana use is not exclusionary unless it meets the DSM-5 criteria for abuse disorder or dependence) 28. Signs and symptoms of active or residual COVID-19, or unresolved symptoms of COVID-19 that impact health, e.g. requirements for oxygen supplementation, etc. Discharge from an inpatient hospitalization for more than 48 hours for COVID-19 within the past 28 days.

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2023-03-24