A Study of Seltorexant as Adjunctive Therapy to Antidepressants in Adult and Elderly Participants With Major Depressive Disorder With Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy of Seltorexant compared with placebo as adjunctive therapy to an antidepressant in improving depressive symptoms in participants with major depressive disorder with insomnia symptoms (MDDIS) who have had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

Detailed Description
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Major depressive disorder (MDD) is a common, serious, recurrent disorder. Seltorexant (JNJ-42847922) is a potent and selective antagonist of the human orexin-2 receptor (OX2R) that is being developed for the adjunctive treatment of MDDIS. The hypothesis for this study is that adjunctive treatment with seltorexant is superior to placebo in treating depressive symptoms, as measured by change in Montgomery Asberg Depression Rating Scale (MADRS) total score from baseline to Day 43 in adult and elderly participants with MDDIS who have had an inadequate response to treatment with a SSRI/SNRI. The study will be conducted in 3 phases: a screening phase (up to 30 days), a double-blind (DB) treatment phase (43 days), and a post treatment follow-up phase (7 to 14 days after DB treatment phase). Total duration of study is up to 12 weeks. Efficacy, safety, pharmacokinetics, and biomarkers will be assessed at specified time points during this study.

Official Title
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A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients With Major Depressive Disorder With Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: Seltorexant
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet diagnostic and statistical manual of mental disorders-5th edition (DSM-5) diagnostic criteria for major depressive disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the structured clinical interview for DSM-5 Axis I disorders-clinical trials version (SCID-CT) diagnosed with first depressive episode prior to age 60. The duration of the current depressive episode must be less than or equal to (<=) 24 months Have had an inadequate response to at least 1 but no more than 2 antidepressants, 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 less than (<) 50 percent (%) reduction but with some improvement (that is, improvement greater than [>] 0%) in depressive symptom severity with residual symptoms other than insomnia present, and overall good tolerability, as assessed by the MGH-ATRQ Is receiving and tolerating well any one of the following selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (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 therapeutic dose level) for at least 6 weeks, and for no greater than 18 months in the current episode Have a hamilton depression rating scale (HDRS)-17 total score greater than or equal to (>=) 20 at the first screening interview, must not demonstrate a clinically significant improvement (that is [ie], 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 Have a patient version of the Insomnia Severity Index (ISI) total score >=15 as well as a clinician version of the ISI total score >=15 at the second screening visit Body mass index (BMI) between 18 and 40 kilogram per meter square (kg/m^2) inclusive (BMI=weight/height^2) Participant must be medically stable on the basis of clinical laboratory tests performed at screening Participant must be medically stable on the basis of the following: physical examination (including a brief neurological examination), vital signs (including blood pressure), and 12-lead electrocardiogram (ECG) performed at screening and baseline Exclusion Criteria: Has a recent (last 3 months) history of, or current signs and symptoms of, severe renal insufficiency (creatinine clearance [CrCl] < 30 milliliter per minute [mL/min]); clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic, hematologic, rheumatologic, immunologic or endocrine disorders and uncontrolled Type 1 or Type 2 diabetes mellitus Has clinically significant hepatic disease as defined by >=2*Upper Limit of Normal (ULN) increase of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at screening 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 massachusetts general hospital-antidepressant treatment response questionnaire [MGH-ATRQ]) and duration (at least 6 weeks). Has history or current diagnosis of a psychotic disorder, bipolar disorder, intellectual disability, autism spectrum disorder, borderline personality disorder, or somatoform disorders 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 Has a history of moderate to severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Seltorexant<br>Participants will receive Seltorexant orally once daily from Day 1 to Day 42 (until the end of Week 6). | Drug: Seltorexant<br>* Participants will receive Seltorexant tablets.<br>|
| Placebo Comparator: Placebo<br>Participants will receive matching placebo tablets orally once daily from Day 1 to Day 42 (until the end of Week 6). | Drug: Placebo<br>* Participants will receive matching placebo tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score to Day 43 | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Baseline to Day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the MADRS Without Sleep Item (MADRS-WOSI) Total Score to Day 43 | MADRS-WOSI considered 9 of the 10 MADRS items, excluding reduced sleep item. The total score ranged from 0 to 54, with higher scores corresponding to greater symptom severity. | Baseline to Day 43 | 
| Change from Baseline in Sleep Disturbance Using the Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) Short Form 8a T-score to Day 43 | The PROMIS-Sleep Disturbance (PROMIS-SD) is used to assess self-reported perceptions of sleep quality, sleep depth and restoration associated with sleep. The full PROMIS-SD includes 27 items with each item based on a 7-day recall period and assessed on a 5 level Likert-type scale. The 8-item short form will be used in this study, in which responses are scored 1 to 5 for each item. A higher score on 5 of the 8 items reflects a worse outcome, whereas a higher score on 3 items reflects an improved outcome; therefore, the directionality of the 8 item scores are first synchronized prior to calculation of the total raw score. To find the total raw score for a short form with all questions answered, sum the values of the response to each question. For example, for the adult 8-item form, the lowest possible raw score is 8; the highest possible raw score is 40. Higher overall score indicates more sleep disturbance. | Baseline to Day 43 | 
| Change from Baseline in the MADRS-6 Total Score to Day 43 | The MADRS-6 scale is a clinician-administered questionnaire used to measure the severity of MDD symptoms. The MADRS-6 scale is a subset of the MADRS-10 scale, comprised of the following individual questionnaire items: Apparent Sadness, Reported Sadness, Inner Tension, Lassitude, Inability to Feel, and Pessimistic Thoughts. Scores range from 0 (no apparent symptoms) to 36 (most severe symptoms). | Baseline to Day 43 | 
| Percentage of Participants with Response on Depressive Symptoms Scale Based on Montgomery-Asberg Depression Rating Scale (MADRS) total score from Baseline to Day 43 | Responders are defined as participants with greater than or equal to (>=) 50 percent (%) improvement in the MADRS total score from baseline to Day 43. | Baseline to Day 43 | 
| Change from Baseline in Patient Health Questionnaire, 9-Item (PHQ-9) Total Score to Day 43 | The PHQ-9 is a 9-item, participant reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the diagnostic and statistical manual of mental disorders-5th edition (DSM-5) major depressive disorder (MDD) criteria. Each item is rated on a 4 point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. | Baseline to Day 43 |