Adult subjects, ≥18 years of age, with a primary diagnosis of MDD who have had an IR to ≥1 oral antidepressant medication (including the subject’s current antidepressant treatment) in the current episode of depression.

Primary: • To evaluate the efficacy of NBI‑1065845 compared with placebo as an adjunctive treatment in delaying relapse of depressive symptoms (maintenance of effect) in subjects with MDD who have a stable response after open-label treatment with NBI‑1065845. Secondary: • To evaluate the efficacy of NBI‑1065845 compared with placebo as an adjunctive treatment on functional impairment and associated disability and on overall severity of depressive illness in subjects with MDD who have a stable response after open-label treatment with NBI‑1065845. • To evaluate the safety and tolerability of NBI‑1065845 as an adjunctive treatment in subjects with MDD.

tablet

NBI-1065845

110

1 mg per tablet

The primary endpoint for this study will be the time from randomization to relapse.

Subjects must meet all of the following inclusion criteria:
1. Completed informed consent.
2. ≥18 years of age at the time of signing the informed consent.
3. A body mass index (BMI) of 18 to 42 kg/m2, inclusive (BMI is defined as the subject's
weight in kilograms divided by the square of the subject's height in meters).
4. The subject has a primary diagnosis of recurrent MDD (moderate or severe) or persistent
depressive disorder meeting the Diagnostic and Statistical Manual of Mental Disorders,
5th Edition (DSM-5) criteria or relevant International Statistical Classification of Diseases
and Related Health Problems, 10th Revision (ICD-10) criteria codes for 296.32 (F33.1),
296.33 (F33.2), 296.35 (F33.41), or 300.4 (F34.1). The diagnosis must be confirmed using
the Mini-International Neuropsychiatric Interview (MINI) in a face-to-face evaluation.
5. The subject must be receiving ≥1 oral antidepressant treatment(s) (listed in Appendix B) and
must:
• Have been taking their current antidepressant medication(s) for ≥8 weeks prior to
screening, AND
• Be willing to continue the same treatment at the same dose and frequency of
administration throughout participation in the study, AND
• Antidepressant treatment(s) must be confirmed by records/documentation consistent
with site or local practice (eg, medical, prescription, or pharmacy records, or health
insurance data).
6. Subject must have an IR (≤50% improvement) to 1 to 5 (inclusive) oral antidepressant
treatments (including the subject’s current antidepressant treatment) that were administered
as adequate courses (dose, duration, adherence) in the current episode of depression, as
assessed using the Massachusetts General Hospital - Antidepressant Treatment Response
Questionnaire (MGH-ATRQ).
7. Total Hamilton Depression Rating Scale-17 Item (HAM-D17) score ≥22 at screening and at
study baseline (Day 1).
8. The subject’s current major depressive episode, depression symptom severity, and
antidepressant treatment response in the current depressive episode must be confirmed by the
“State versus Trait, Assessability, Face Validity, Ecological Validity, Rule of Three P’s”
(SAFER) Interview and final agreement with the Sponsor or Sponsor designee.
9. All subjects who are receiving psychotherapy (including cognitive behavioral therapy [CBT])
can continue receiving psychotherapy; however, CBT must have been ongoing for the last
3 months prior to Day 1. New psychotherapy may not be initiated during this study.
10. The subject is euthyroid. An abnormally high or low thyroid-stimulating hormone (TSH)
level may be corroborated by a free thyroxine (T4) level in addition to a comprehensive
history and physical examination to rule out a thyroid disorder. Subjects maintained on
thyroid medication must be on stable dosage for a period of ≥3 months prior to the screening
visit.
11. Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening and a
negative urine pregnancy test at Day 1, for females of childbearing potential.
12. Female subjects of childbearing potential must agree to use acceptable methods of
contraception as listed below consistently from screening until the final study visit or 30 days
after the last dose of study treatment, whichever is longer.
Women are considered to not be of childbearing potential if they are either postmenopausal
(defined as no menses for 12 months without an alternative medical cause and confirmed by
elevated follicle stimulating hormone (FSH) consistent with a postmenopausal range) or if
they have undergone permanent sterilization procedure, such as hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy.
Acceptable methods of contraception include the following:
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
• Combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation, which may be oral, intravaginal, or transdermal at least
3 months prior to screening
• Progestogen-only hormonal contraception associated with inhibition of ovulation,
which may be oral, injected, or implanted at least 3 months prior to screening
• Bilateral tubal ligation
• Total abstinence from heterosexual intercourse (periodic abstinence is not acceptable)
• Sexual partner(s) who had been vasectomized for at least 3 months prior to screening
with medically confirmed successful procedure
• Progesterone only where inhibition of ovulation is not the primary mode of action
• Male or female condom with or without spermicide
• Cap, diaphragm, or sponge with spermicide
13. Willing and able to comply with all study procedures and restrictions in the opinion of the
investigator.

Subjects will be excluded from the study if they meet any of the following criteria:
Psychiatric Criteria:
1. A current or prior psychiatric disorder diagnosis in the last 1 year that was the primary focus
of treatment other than MDD (assessed by the MINI); a comorbid personality disorder that
has been evident outside of depressive episodes or that may interfere with participation in the
study; or a diagnosis of neurodegenerative disorders (including but not limited to dementias),
eating disorder, schizophrenia, schizoaffective disorder, bipolar disorder, MDD with
psychotic features or mixed features, intellectual disability, or mental disorders due to a
general medical condition as defined in DSM-5.
2. Are considered by the investigator to be at imminent risk of suicide or injury to self or others:
• Have a significant risk of suicidal or violent behavior, or attempted suicide in the
1 year prior to screening.
• Subjects with any suicidal ideation of type 4 (active suicidal ideation with some intent
to act, without specific plan) or type 5 (active suicidal ideation with specific plan and
intent) in the past 6 months before screening based on the C-SSRS.
• According to the investigator's clinical judgment should be excluded.
3. Subject has moderate-to-severe substance use disorder diagnosis per DSM-5 with the
exception of caffeine, nicotine, and cannabis (see below) or has a known drug dependence
within 12 months of the start of screening:
• The subject has a positive urine drug screen (UDS) at screening or Day 1 for
disallowed substances (eg, alcohol, barbiturates, phencyclidine, cocaine, opiates,
amphetamines, methadone, or unprescribed benzodiazepines).
• The subject is taking a daily dose of a prescription benzodiazepine greater than the
equivalent of 4 mg/day of lorazepam (Appendix C).
Note: Subjects testing positive for cannabinoids at screening may be eligible for participation
in the study if all of the following criteria are met:
• The subject does not meet the diagnostic criteria for moderate or severe substance use
disorder within the 12 months before screening based on the MINI.
• Based on the investigator’s clinical assessment, the subject’s cannabis use is limited
to ≤3 times per week and is not expected to interfere with their ability to adhere to
study procedures.
• Cannabis is legal per local law.
Treatment-Related Criteria:
4. Are currently taking long-acting injectable antipsychotic medications or any of the prohibited
medications (except quetiapine when used for sleep, up to 50 mg/day) as specified in
Table 2.
5. Prior IR to adequate course of antidepressant treatment with ketamine or esketamine per the
MGH-ATRQ.
6. The subject’s depressive symptoms have previously demonstrated nonresponse to an
adequate course of treatment with electroconvulsive therapy (ECT) in the current major
depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT.
7. Participation in other interventional investigational studies (excluding vaccine clinical
studies):
• Used or plans to use any active investigational drug in the context of a clinical study
within the preceding 60 days or <5 half-lives prior to the screening visit, whichever is
longer, or
• Has participated in more than 2 investigational drug studies in the 12 months prior to
the screening visit, or
• Is currently participating in another interventional clinical study (for subjects in the
US, per registry database query), or
• Has participated in a clinical study for a psychiatric condition that is exclusionary per
this protocol.
This criterion must be reconfirmed prior to the first dose of study treatment on Day 1 (with
the exception of registry database query, which only needs to be completed at screening).
8. Has affirmed ingested grapefruit juice, grapefruit products, Seville oranges, Seville orange
products, pomegranate products, or star fruit products within 7 days before Day 1.
Other Medical Criteria:
9. Pregnant (ie, positive pregnancy test at screening or baseline), lactating, or plans to become
pregnant during the study.
10. An unstable medical condition or unstable chronic disease (including history of neurological
[including cognitive impairment, myasthenia gravis], hepatic, renal, cardiovascular,
gastrointestinal, pulmonary, autoimmune, or endocrine disease that may affect study
participation or results) within 3 months before Day 1, or malignancy within 6 months before
Day 1.
11. Any laboratory abnormality suggestive of clinically significant, poorly or unmanaged,
undiagnosed disease.
12. History of epilepsy, seizures, or convulsions (except uncomplicated febrile convulsions with
no sequelae), or
• Any active or unstable medical condition or an abnormality that may increase risk of
seizure, lower the seizure threshold, or may put them at risk due to their participation
in this study, as judged by the investigator, or
• Any first degree relative with a history of seizure or active seizure disorder, except
for uncomplicated febrile convulsions with no sequelae.
13. History of neurological abnormalities including brain injury (including traumatic injury),
perinatal cerebropathy, and postnatal brain damage, blood-brain barrier abnormality, and
cavernous angioma.
14. Have a diagnosis of AIDS at screening.
15. Any of the following cardiovascular conditions or measures:
• QT interval corrected for heart rate using Fridericia’s correction (QTcF) >450 msec
(males) or >470 msec (females) at screening or Day 1
• Long QT syndrome or is under the treatment with Class 1A (eg, quinidine,
procainamide) or Class 3 (eg, amiodarone, sotalol) antiarrhythmic drugs
16. Have 1 or more clinical laboratory test values outside of the reference range, based on blood
samples taken at the screening visit that are of potential risk to the subject’s safety as
determined by the investigator, or have at the screening visit:
• Serum creatinine >1.5 × the upper limit of normal (ULN) for males and >1.2 × ULN
for females
• Aspartate aminotransferase (AST) >3 × ULN
• Alanine aminotransferase (ALT) >3 × ULN
• Total bilirubin >1.5 × ULN unless due to a documented diagnosis of Gilbert's
syndrome
• Albumin ≤3.5 g/dL
17. Have any of the following laboratory abnormalities at screening:
• Hemoglobin <10 g/dL
• White blood cell (WBC) count <3.0 × 103/mm3
• Platelet count <100,000/mm3
• Absolute neutrophil count <1.0 × 103/mm3
18. Have a hemoglobin A1c (HbA1c) >7.5% suggestive of uncontrolled diabetes mellitus at
screening
Other Criteria:
19. Affirmed significant blood loss or donation (≥550 mL) within 8 weeks before Day 1.
20. Any reason that makes the subject unsuitable for participation in this study (eg, subject is
homeless, known to have difficulty complying with treatment or medical procedures, known
to provide inaccurate medical information, or known to attempt participation in clinical trials
inappropriately) per the investigator, Medical Monitor, and/or Sponsor.
21. Employee, or immediate relative of an employee, of the Sponsor, any of its affiliates or
partners, or the study center.