NRX-101 Expanded Access

-

Eligible for inclusion in this EAP only if all the following criteria apply:

1. 18 years of age or older
2. Able to understand the study procedures and risks and able to provide written and dated informed consent before any protocol-specific procedure.
3. In the investigator's judgment, likely to comply with the Expanded Access Protocol, including transcranial magnetic stimulation visits, NRX-101 dosing instructions, scheduled assessments, and prompt communication of adverse events and other clinically important information.
4. Under the care of a board-certified psychiatrist or other qualified psychiatric prescriber who has completed protocol-specific training, is registered as an investigator for this Expanded Access Protocol, and agrees to direct and document the patient's psychiatric care according to standard of care.
5. Diagnosed with treatment resistant depression (TRD) according to the criteria defined in the DSM-5. This diagnosis must be made by a psychiatrist or other qualified licensed psychiatric provider.
6. History of inadequate response, intolerance, or loss of effect to at least one prior adequate pharmacologic treatment for the current depressive episode with a medication indicated for treatment-resistant depression in the investigator's judgment.
7. Planned course of theta burst transcranial magnetic stimulation as part of standard clinical care for the current depressive episode, to be delivered at a site with appropriate experience and safety procedures for transcranial magnetic stimulation.
8. No uncontrolled or unstable medical condition that, in the investigator's judgment, creates an unacceptable risk with theta burst transcranial magnetic stimulation in combination with NRX-101 or prevents adequate assessment of safety.

9. If heterosexual 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 treatment with NRX-101:

   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 urinary pregnancy test at Screening, confirmed by a second negative urinary pregnancy test at Day 1, prior to receiving treatment with NRX-101.

10. Sufficient stability of residence and contact information to allow appropriate follow up and emergency contact during participation in the Expanded Access Protocol, in the investigator's judgment.
11. The patient is not participating in and cannot reasonably enroll in the concurrent Phase IIb trial NRX101-011, because the patient does not meet at least one inclusion criterion for NRX101-011, meets at least one exclusion criterion for NRX101-011, or faces distance, transportation, schedule, or other practical barriers that prevent trial participation despite interest. The investigator must document the specific reason in the source record.

Exclusion Criteria:

1. Heterosexual 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 (positive pregnancy test at Screening) or breastfeeding.
3. Active suicidality (without the intention to act) as evidenced by a score of >3 on the Columbia Suicide Severity Rating Scale.
4. Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or tobacco use disorder) within the 12 months prior to Screening. (Note: Substance use disorder cannot be the precipitant for study entry).
5. Current DSM-5 diagnosis of alcohol use disorder
6. A lifetime history of phencyclidine (PCP)/ketamine drug abuse
7. History of schizophrenia or schizoaffective disorder
8. History of anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified (NOS), or other specified feeding and eating disorders (OSFED) within 3 years of Screening.
9. Has dementia, delirium, amnestic, or any other cognitive disorder.
10. Renal impairment defined as estimated glomerular filtration rate (eGFR) \< 60 mL/min, calculated using the 2021 CKD-EPI creatinine equation (race-free).
11. Clinically significant hepatic impairment. Clinically significant hepatic impairment is defined as a history of chronic liver disease (e.g., cirrhosis, chronic hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis) or evidence at Screening of acute liver disease or impaired liver function (e.g., ALT or AST >3 × ULN, total bilirubin >2 × ULN) or in the opinion of the Investigator.
12. 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.
13. Risk factors for neurocardiogenic syncope including history of syncope/ presyncope related to noxious stimuli, anxiety, micturation, or posture.
14. Co-morbidities as ascertained by medical history, physical examination (including measurement of vital signs), clinical laboratory evaluations, and electrocardiogram (ECG) which might interfere with compliance or the ability to assess efficacy or safety.

15. Diagnosis of moderate to severe heart disease or current episode of:

    1. Myocardial infarction within 1 year of Screening.
    2. Diagnosis of angina pectoris.
    3. 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.
16. Diagnosis of chronic lung disease, excluding asthma.
17. Lifetime history of any of the following: neurologic conditions with structural cerebral damage, traumatic brain injury, multiple sclerosis, surgical procedures involving the brain or meninges, meningoencephalitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's Disease, Parkinson's Disease), mental retardation, stroke (ischemic or hemorrhagic), intracranial abscess, or any other disease/procedure/accident/intervention that, according to the clinician, is deemed associated with significant injury to, or malfunction of, the CNS.
18. History of epilepsy, personal history of seizure, family history of epilepsy or seizure in a first degree relative.
19. Diagnosis of parenchymal or leptomeningeal cancer.

20. Diabetes mellitus fulfilling any of the following criteria:

    1. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.0 percent 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.
21. 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.
22. On exclusionary concomitant psychotropic and non-psychotropic medications (see Section 9.5)

23. 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).
24. Currently prescribed oxcarbazepine or carbamazepine.
25. Exclusionary laboratory values or any other clinically significant abnormal laboratory result at Screening. Within normal limits (WNL) will be determined based on lab values of the local lab used.
26. Known allergies to lurasidone or Latuda®, cycloserine or Seromycin®, or the following excipients: mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and/or hydroxypropylmethylcellulose (HPMC).
27. Participation in any clinical trial with an investigational drug or device within the past 3 months or planned concurrent study participation.
28. 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.
29. Positive urine toxicity screening for use of any cocaine, opiates, non-prescribed amphetamines, or non-prescribed barbiturates. (Note: cannabinoids or marijuana use is not exclusionary, unless patient meets the DSM-5 criteria for cannabis withdrawal).
30. Patients with pacemakers and/or any implants including metal in the head except the mouth (cochlear implant, implanted brain stimulators, aneurysm clips)
31. Individuals with an intracranial lesion or increased intracranial pressure