Depression with Difficulty Sleeping

1. Male or female, aged 18 to 74 years (inclusive). Note: Participants should be at least 18 years of age or older as per the legal age of consent in the jurisdiction in which the study is taking place.

2. Criterion modified per Amendment 42.1 Meet DSM-5 diagnostic criteria for MDD, without psychotic features (DSM-5 296.22, 296.23, 296.32, or 296.33), based upon clinical assessment and confirmed by the SCID-CT diagnosed with first depressive episode prior to age 60.The length of the current depressive episode must be ≤24 months. The sleep item of the MDD symptoms (Item 4 of the SCID-CT) should be positive for IS prior to randomization.

3. Criterion modified per Amendment 43.1 Have had an inadequate response to at least 1 but no more than 2 antidepressants (see the inclusion criterion 4 below), administered at an adequate dose and duration in the current episode of depression. The current antidepressant cannot be the first antidepressant treatment for the first lifetime episode of depression. An inadequate response is defined as <50% reduction but with some improvement (i.e., improvement >0%) in depressive symptom severity with residual symptoms present other than insomnia, and overall good tolerability, as assessed by the MGH-ATRQ (see Section 4.1). An adequate trial is defined as a stable antidepressant treatment for at least 6weeks on a stable dose (and no greater than 18 months in the current episode) at or above the minimum therapeutic dose specified in the MGH-ATRQ and must include the participant’s current antidepressant treatment. Note: Participants with no improvement on the current SSRI/SNRI should not be enrolled in the study. If a participant has received 2 SSRI/SNRI treatments of sufficient dose and duration in the current episode, and has shown <25% improvement to both, then the participant would not qualify based on exclusion criterion 9.

4. Criterion modified per Amendment 3

4.1. Criterion modified per Amendment 4

4.2 Is receiving and tolerating well any one of the following SSRI or SNRI for depressive symptoms at screening,  in any formulation and available in the participating country: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine at a stable dose (at or above therapeutic dose level) for at least 6 weeks, and for no greater than 18months in the current episode.

Note: The above SSRI/SNRI needs to be approved for the treatment of MDD according to the local label of the country where the clinical site is located.

Note: Dose and duration of treatment should be documented in the source documents by the investigator based on available evidence such as using the medical or pharmacy records. The investigator will use this information to complete the MGH-ATRQ.

Note: Participants using fluvoxamine as baseline SSRI and have normal renal and hepatic function may enter the study. See renal and hepatic function restrictions in Section 6.5(Concomitant Therapy).

5. Criterion modified per Amendment 3

5.1. Criterion modified per Amendment 4

5.2 Have a HDRS-17 total score ≥20at the first screening interview, must not demonstrate a clinically significant improvement (i.e., an improvement of >20% on their HDRS-17 total score) from the first to the second independent HDRS-17 rating, and must have a HDRS-17 total score ≥18 at the second screening interview.

6. Have a patient version ISI total score ≥15 as well as a clinician version of the ISI total score ≥15at the second screening visit.

7. Criterion modified per Amendment 4

7.1 Body mass index (BMI) between 18 and 40kg/m2, inclusive (BMI=weight/height2).

8. Must be an outpatient at screening.

9. Participant must be medically stable on the basis of the following: physical examination, vital signs (including blood pressure), and 12-lead ECG performed at screening and baseline. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined by the investigator and recorded in the participant’s source documents and initialed by the investigator.

10. Participant must be medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology,  or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study.  This determination must be recorded in the participant’s source documents and initialed by the investigator.

11. Must sign an ICF indicating that he or she understands the purpose of, and procedures required for the study and be willing to participate in the study.

12. A woman of childbearing potential must have a negative highly sensitive serum (β human chorionic gonadotropin [β-hCG]) pregnancy test at screening and a negative urine pregnancy test predose on Day 1 of the DB phase prior to randomization.

13. Criterion modified per Amendment 4

13.1 Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies.

a. Before entering the study, a woman must be either:

·  Postmenopausal

A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In women who are <40 years old and have amenorrhea, FSH should be performed to determine post-menopausal status, based on the reference range of central laboratory. In women who are ≥40 years old and have amenorrhea for less than 12 months, FSH test may be performed at investigator judgment to assist in determining their post-menopausal status. In women who are ≥40 years old and have amenorrhea for ≥12 months, FSH is not required..

·  Permanently sterile

Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy. No FSH testing is required.

b. Of childbearing potential and

·  Practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) (see Section 10.5,   Appendix 5, Contraceptive and Barrier Guidance and Collection of Pregnancy Information). The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.

Examples of highly effective contraceptives include:

−User independent methods:

implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)

−User-dependent methods:

combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable

Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for participants in clinical studies

·  Agrees to remain on a highly effective method throughout the study and for at least 1 month after the last dose of study drug.

Note: If the childbearing potential status changes after start of the study or the risk of pregnancy changes (e.g., a woman who is not heterosexually active becomes active) a female participant or female partner of a male participant must begin a highly effective method of contraception, as described throughout the inclusion criteria. If reproductive status is questionable, additional evaluation should be considered.

14. A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of at least 1 month after receiving the last dose of study drug.

15. During the study and for a minimum of 1 spermatogenesis cycle (defined as approximately 3 months) after receiving the last dose of study drug, a man

·  who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository)  and his female partner must use a highly effective method of contraception.

·  who is sexually active with a woman who is pregnant must use a condom.

·  must agree not to donate sperm.

16. Criterion deleted per Amendment 3

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Criterion modified per Amendment 3

Criterion modified per Amendment 4

1.2. Has a recent (last 3 months) history of, or current signs and symptoms of,

–  severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min).

–  clinically significant or unstable cardiovascular, respiratory,  gastrointestinal, neurologic, hematologic, rheumatologic, immunologic, or endocrine disorders.

–  uncontrolled Type 1 or Type 2 diabetes mellitus. Note: Participants with Type 1 or Type 2 diabetes mellitus who are controlled (hemoglobin A1C≤8.5% and glucose ≤150mg/dL at screening) may be eligible to participate if otherwise medically healthy, and if on a stable regimen of glucose-lowering medications for at least 2 months prior to screening.

2. Has a history of narcolepsy or seizures (except childhood seizures)

3. Has clinically significant hepatic disease as defined by:

–  ≥2x Upper Limit of Normal (ULN) increase of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at screening (one retest is permitted)

–  significant liver disease including cirrhosis, ascites, active hepatitis etc. (fatty liver disease and Gilbert’s syndrome will be allowed if it does not meet above criteria).

4. Has taken a strong inhibitor of CYP3A4 or CYP2C9 or moderate/strong inducer of CYP3A4 or CYP2C9 or a dual inhibitor/inducer of CYP3A4 and CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study. See Section 10.6, Appendix 6: for examples of strong inhibitors or moderate/strong inducers of CYP3A4 and CYP2C9 or dual inhibitors/inducers of CYP3A4 and CYP2C9.

5. Has taken a moderate inhibitor of CYP3A4 or CYP2C9 within 14 days before the first study drug administration on Day 1 or will require treatment during the study and has:

–  limited renal (CrCl <60 mL/min) or

–  hepatic disease (AST/ALT >1.5X ULN and bilirubin >1.5X ULN).See Section 10.6, Appendix6: for examples of moderate CYP3A4 or CYP2C9 inhibitors.

6. Has current signs/symptoms of hypothyroidism or hyperthyroidism. For participants with a history of thyroid disease and for participants who, regardless of thyroid history have the thyroid stimulating hormone (TSH) value out of range, a free thyroxine (FT4) test will be conducted. If the FT4 value is abnormal and considered to be clinically significant (after discussion with the sponsor’s study responsible physician/scientist or designee) the participant is not eligible. Participants with a pre-existing history of thyroid disease/disorder who are treated with thyroid hormones need to be on a stable dosage for 3 months prior to the start of the screening phase. Participants taking thyroid supplementation for antidepressant purposes are not allowed in the study.

7. Has Cushing’s Disease, Addison’s Disease, primary amenorrhea, or other evidence of significant medical disorders of the HPA axis.

8. Criterion modified per Amendment 3

8.1. Has a  current or recent history of  homicidal ideation or serious suicidal ideation within the past 3months, corresponding to a positive response on item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) for ideation on the C-SSRS, or a history of suicidal behavior within the past 6 months, as validated by the C-SSRS at screening or Day 1.Participants with prior suicidal behavior in the past year, or prior serious suicidal ideation/plan within the past 6 months, should be carefully screened.  For current suicidal ideation, only participants with non-serious items (1-3 of the suicidal ideation section of the C-SSRS) may be included at the discretion of the investigator.

9. Has a history of treatment-resistant MDD, defined as a lack of response to 2 or more adequate antidepressant treatments in the current episode, as indicated by no or minimal (<25% improvement in symptoms) when treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at least 6weeks).

10. Has a history or evidence of clinically meaningful noncompliance with current antidepressant therapy.

11. Has a primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, social anxiety disorder, or specific phobia which has been the primary focus of psychiatric treatment within the past 2 years. These are allowed as secondary diagnoses if MDD is the primary focus of treatment according to the investigator.

12. Criterion modified per Amendment 3

12.1. Current active DSM-5 diagnosis of obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, bulimia nervosa or fibromyalgia. These disorders need to be in remission for at least 1 year for the participant to be enrolled.

13. Criterion modified per Amendment 3

13.1. Has history or current diagnosis of a psychotic disorder, bipolar disorder, intellectual disability, autism spectrum disorder, borderline personality disorder, somatoform disorders.

14. Has any significant primary sleep disorder, including but not limited to obstructive sleep apnea, restless leg syndrome, or parasomnias. Participants with insomnia disorder are allowed.

15. Criterion modified per Amendment 3

15.1. Has a history of moderate to severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening or positive test result(s) for alcohol and/or drugs of abuse (e.g., opiates [including methadone], cocaine, amphetamines, methamphetamines, cannabinoids, cannabidiol [CBD], barbiturates, 3,4-Methylenedioxymethamphetamine [MDMA]) at screening or at baseline.

Note: One retest during screening is allowed at investigator’s judgment. Tobacco and caffeine use are not exclusionary.

16. Taking, at screening, benzodiazepines at high dosages greater than the equivalent of 30 mg diazepam or 3 mg of lorazepam at long duration which might result in benzodiazepine withdrawal syndrome. Participants must have a negative benzodiazepine test at baseline and be free of signs of the benzodiazepine abstinence syndrome. (See Section10.8, Appendix 8: Benzodiazepine Equivalence Table).

17. Had a clinically significant acute illness, per investigator judgment, within 7 days before the first dose of study drug.

18. Has a known malignancy or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor’s study responsible physician/scientist or designee, is considered cured with minimal risk of recurrence).

19. Criterion modified per Amendment 4

19.1 Has clinically significant ECG abnormalities at screening or Day1 prior to randomization that may jeopardize the participants’ safety or the integrity of the study, in the Investigator’s judgment, defined as:–  During screening and/or Day 1, a QT interval corrected according to Fridericia’s formula (QTcF): ≥450 msec (males); ≥470 msec (females). Note: If the QTcF is prolonged on the initial ECG at a given time point, the average QTcF of 3 ECGs, recorded 4 minutes apart, must not be ≥450 msec for males and ≥470 msec for females.–  Evidence of 2nd and 3rd degree atrioventricular block.–  Features of new ischemia–  Other clinically important arrhythmia or cardiac abnormalities.

20. Criterion modified per Amendment 3

20.1. Has within the last 5 years received any prior antidepressant treatment with ketamine/esketamine, electroconvulsive therapy, vagal nerve stimulation, or a deep brain stimulation device.

Note: Participants who previously had taken up to 2 doses of ketamine/esketamine and did not continue (e.g., did not benefit from the treatment or experienced tolerability issues) can be considered for enrollment.

21. Ongoing psychological treatments (e.g., Cognitive Behavior Therapy, Interpersonal Psychotherapy, Psychodynamic Psychotherapy etc.), initiated within 6 weeks prior to start of screening. Note: a participant who has been receiving ongoing psychological treatment for a period of greater than 6 weeks is eligible, if the investigator deems the psychological treatment to be of stable duration and frequency.

22. Has received experimental therapies (psychological, pharmacologic or noninvasive) within 30 days before screening or if greater than 2  experimental therapies in the past year.

23. Has known allergies, hypersensitivity, intolerance, or any contraindication to seltorexant and local label for quetiapine XRor its excipients (refer to Investigator’s Brochure22for seltorexant and local label for quetiapine XR).

24. Criterion modified per Amendment 424.1 Has had exposure to quetiapine >50mg/day (immediate release or XR) in the current episode of MDDor ≥30-day total exposure to a dose of quetiapine >100 mg/day (immediate release or XR) in the last 3 years prior to screening (per patient report or other information).Participants who have had more than 30 days of antipsychotic use (other than quetiapine) in the current episode of MDD will also be excluded.

25. Has had a >7-day exposure or poor tolerability to seltorexant in previous studies (per patient report or other information).

26. Has a history of tardive dyskinesia or neuroleptic malignant syndrome.

27. Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an equivalent amount of blood within 30 days before the first dose of study drug.

28. Has cognitive impairment per investigator judgment that would render the informed consent invalid or limit the ability of the participant to comply with the study requirements. Participant has neurodegenerative disorder (e.g., Alzheimer’s disease, vascular dementia, Parkinson’s disease with clinical evidence of cognitive impairment) or evidence of mild cognitive impairment (MCI). Participants of age ≥65 years has a MMSE <25 or <23 for those participants with less than high school equivalent education.

29. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

30. Has taken any disallowed therapies as noted in Section 6.5, Concomitant Therapy.

31. Is pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or within 1 month after the last dose of study drug.

32. Plans to father a child while enrolled in this study or within 3 months after the last dose of study drug.

33. Has had major surgery, (e.g., requiring general anesthesia) within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.

Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate.

34. Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.