A Study to Evaluate the Efficacy and Safety of JNJ-42847922 as Adjunctive Therapy to Antidepressants in Adult Participants With Major Depressive Disorder 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 dose-response relationship of 2 doses of JNJ-42847922 before interim analysis, and potentially 3 doses based on interim analysis results, compared to placebo as adjunctive therapy to an antidepressant drug in improving depressive symptoms in participants with Major Depressive Disorder (MDD) who have had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI); and to assess the safety and tolerability of JNJ-42847922 compared to placebo as adjunctive therapy to an antidepressant in participants with MDD.

Detailed Description
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The study will investigate the antidepressant effects of a range of doses of JNJ-42847922 (seltorexant) (versus placebo), as adjunctive treatment to antidepressant drugs for treatment of MDD, and will assess the safety and tolerability of JNJ-42847922. The study will be conducted in 3 phases: a screening phase (up to 4 weeks), a double-blind treatment phase (6 weeks), and a post-treatment follow-up phase (2 weeks). Efficacy, safety, pharmacokinetic, and biomarker evaluations will be performed in the study at defined timepoints. The duration of the study will be up to approximately 12 weeks (84 days).

Official Title
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A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Adaptive Dose-Finding Study to Evaluate the Efficacy and Safety of JNJ-42847922 as Adjunctive Therapy to Antidepressants in Adult Subjects With Major Depressive Disorder Who Have Responded Inadequately to Antidepressant Therapy

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: Placebo
* Drug: JNJ-42847922


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women of non-childbearing potential (WONCBP), aged 18 to 70 years (inclusive). A WONCBP is defined as: a).Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. b). Permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy. c). If reproductive status is questionable, additional evaluation should be considered 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). In addition their major depressive episode must be deemed valid using the SCID Screening Questionnaire (SSQ) interview administered by remote, independent raters. The length of the current depressive episode must be less than or equal to (<=) 18 months Have had an inadequate response to at least 1 but no more than 3 antidepressants, administered at an adequate dose and duration in the current episode of depression, as measured by the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ). An inadequate response is defined as less than (<)50 percent (%) reduction in depressive symptom severity, as assessed by the MGH-ATRQ. An adequate trial is defined as an antidepressant treatment for at least 4 weeks at or above the minimum therapeutic dose specified in the MGH-ATRQ, for any particular antidepressant. The inadequate response must include the participant's current antidepressant treatment Participants receiving monotherapy treatment for depressive symptoms with one of the following selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants, in any formulation: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine at a stable dose (at or above the minimum therapeutic dose level) for at least 4 weeks, and for no greater than 12 months, at screening. Modification of an effective preexisting therapy should not be made for the explicit purpose of entering a subject into the study Have a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater than or equal to (>=)25 (performed by independent, centralized remote raters) at screening and must not demonstrate a clinically significant improvement (that is, an improvement of greater than [>]20% on their MADRS total score) from the screening to baseline visit Must be otherwise healthy on the basis of physical examination, medical history, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests performed at screening. If the results of the clinical laboratory tests are outside the normal reference ranges, the participant could 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 Exclusion Criteria: Has a history of, or current signs and symptoms of, severe renal insufficiency (creatinine clearance <30 milliliter per minute [mL/min]); moderate to severe hepatic insufficiency (Child-Pugh Score 7-9), significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic (including narcolepsy), hematologic, rheumatologic, immunologic or endocrine disorders (including uncontrolled hypo- or hyperthyroidism or diabetes, or insulin-dependent diabetes mellitus). Participants with non-insulin dependent diabetes mellitus who are well-controlled (hemoglobin A1C [HbA1C] <=7.5% and fasting glucose <126 milligram per deciliter [mg/dL] at screening) could 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 Has signs and symptoms of Cushing's Disease, Addison's Disease, primary amenorrhea, or other evidence of significant medical disorders of the hypothalamic-pituitary-adrenal (HPA) axis Has a history of lack of response to 3 or more adequate antidepressant treatments, 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 4 weeks) Has history or current diagnosis of a psychotic disorder, bipolar disorder, mental retardation, autism spectrum disorder, or borderline personality disorder, somatoform disorders, chronic fatigue syndrome or fibromyalgia Has any significant primary sleep disorder, including but not limited to obstructive sleep apnea, restless leg syndrome, or parasomnias

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive 2 placebo capsules matching JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6). | Drug: Placebo<br>* Participants will receive 2 placebo capsules matching JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6).<br>|
| Experimental: JNJ-42847922<br>Participants will receive 2 capsules of JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6). | Drug: JNJ-42847922<br>* Participants will receive 2 capsules of JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6).<br>* Other names: Seltorexant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | 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 range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. | Baseline to Week 6 | 
| Percentage of Participants With Treatment-emergent Adverse Events as a Measure of Safety and Tolerability | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between the initial administration of study drug and 2 days after the last administration of study drug. | Up to Week 8 | 
| Percentage of Participants With Clinically Significant Laboratory Abnormalities | Percentage of participants with clinically significant laboratory abnormalities were reported which included Gamma-glutamyl transferase (GGT), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), Creatine Kinase (CK), Lactate Dehydrogenase (LDH), Albumin , bicarbonate, bilirubin, calcium, chloride, cholesterol, creatinine, direct bilirubin, glucose, high density lipoprotein (HDL) cholesterol, hemoglobin A1C, low density lipoprotein (LDL) cholesterol, phosphate, potassium, protein, sodium, triglycerides, urate, and urea nitrogen. | Up to Week 8 | 
| Change From Baseline in Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) at Day 8 | Change from baseline in vital signs (SBP and DBP) at Day 8 was reported. | Baseline and Day 8 | 
| Change From Baseline in Vital Signs (SBP and DBP) at Day 22 | Change from baseline in vital signs (SBP and DBP) at Day 22 was reported. | Baseline and Day 22 | 
| Change From Baseline in Vital Signs (SBP and DBP) at Day 42 | Change from baseline in vital signs (SBP and DBP) at Day 42 was reported. | Baseline and Day 42 | 
| Change From Baseline in Vital Signs (SBP and DBP) at Endpoint (Week 6) | Change from baseline in vital signs (SBP and DBP) at endpoint was reported. | Baseline and Endpoint (Week 6) | 
| Change From Baseline in Vital Sign (Pulse Rate [PR]) at Day 8 | Change from baseline in vital sign (PR) at Day 8 was reported. | Baseline and Day 8 | 
| Change From Baseline in Vital Sign (PR) at Day 22 | Change from baseline in vital sign (PR) at Day 22 was reported. | Baseline and Day 22 | 
| Change From Baseline in Vital Sign (PR) at Day 42 | Change from baseline in vital sign (PR) at Day 42 was reported. | Baseline and Day 42 | 
| Change From Baseline in Vital Sign (PR) at Endpoint (Week 6) | Change from baseline in vital sign (PR) at endpoint (Week 6) was reported. | Baseline and Endpoint (Week 6) | 
| Change From Baseline in Vital Sign (Temperature) at Day 8 | Change from baseline in vital Sign (temperature) at Day 8 was reported. | Baseline and Day 8 | 
| Change From Baseline in Vital Sign (Temperature) at Day 22 | Change from baseline in vital Sign (temperature) at Day 22 was reported. | Baseline and Day 22 | 
| Change From Baseline in Vital Sign (Temperature) at Day 42 | Change from baseline in vital Sign (temperature) at Day 42 was reported. | Baseline and Day 42 | 
| Change From Baseline in Vital Sign (Temperature) at Endpoint (Week 6) | Change from baseline in vital Sign (temperature) at endpoint (Week 6) was reported. | Baseline and Endpoint (Week 6) | 
| Change From Baseline in Physical Examination (Waist Circumference) at Day 42 | Change from baseline in physical examination (waist circumference) was reported. | Baseline and Day 42 | 
| Change From Baseline in Physical Examination (Body Weight) at Day 42 | Change from baseline in physical examination (body weight) was reported. | Baseline and Day 42 | 
| Change From Baseline in Physical Examination (Body Mass Index [BMI]) at Day 42 | Change from baseline in physical examination (BMI) was reported. | Baseline and Day 42 | 
| Percentage of Participants With Treatment-emergent Abnormal Electrocardiogram (ECG) Values Outside Pre-defined Limits | Percentage of participants with treatment-emergent abnormal ECG values (Heart rate less than or equal to [<=] 50 or greater than or equal to [>=] 100 beats per minute [bpm], PR interval <=120 or >=200 milliseconds [msec], QRS interval <=60 or >=120 msec, and QT interval <=200 or >=500 msec) outside pre-defined limits were reported. | Up to Week 6 | 
| Percentage of Participants With Most Severe Post-baseline Potentially Suicide-Related Category Using Columbia Suicide Severity Rating Scale (C-SSRS) | C-SSRS is a clinician-rated instrument that reports severity of both suicidal ideation and behavior. Suicidal ideation was classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). Suicidal behavior is classified on a 5-item scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), and 4 (actual attempt). More than 1 classification can be selected provided they represent separate episodes. Minimum total score 0, maximum total score 5; higher total scores indicate more suicidal ideation and/or suicidal behavior. If no events qualify for score of 1 to 10, score of 0 was assigned (0= no event that can be assessed on the basis of C-SSRS). Higher scores indicate greater severity. | Up to Week 8 | 
| Change From Baseline in Sexual Functioning as Measured by Arizona Sexual Experiences Scale (ASEX) Score at Day 42 | Effect on sexual functioning was assessed using the ASEX score. The ASEX is a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Each of the 5 items is rated on a 6-point scale, ranging from 1 to 6. The 5 items are summed to create a total score, ranging from 5 to 30, with the higher scores indicating more sexual dysfunction. | Baseline and Day 42 | 
| Physician Withdrawal Checklist-20 (PWC-20) Total Score at Day 43 | Intensity of discontinuation symptoms was assessed (for example: underlying depression; anxiety-nervousness; dysphoric mood/depression; difficulty concentrating; weakness; fatigue-lethargy-lack of energy; irritability), using the Physician Withdrawal Checklist (PWC-20) administered by a trained clinician/rater. Symptoms are rated on a scale 0 (No symptom present) and 3 (severe symptoms). Total scores range from 0 to 24 calculated by adding the scores of following 8 items: Nausea-Vomiting, Diarrhea, Poor Coordination, Diaphoresis, Tremor-Tremulousness, Dizziness-Lightheadedness, Increased Acuity Sound Smell Touch, Paresthesias. Higher scores indicating more severe symptoms. | Day 43 | 
| Physician Withdrawal Checklist-20 (PWC-20) Total Score From Day 49 to Day 56 | Intensity of discontinuation symptoms was assessed (for example: underlying depression; anxiety-nervousness; dysphoric mood/depression; difficulty concentrating; weakness; fatigue-lethargy-lack of energy; irritability), using the Physician Withdrawal Checklist (PWC-20) administered by a trained clinician/rater. Symptoms are rated on a scale 0 (No symptom present) and 3 (severe symptoms). Total scores range from 0 to 24 calculated by adding the scores of following 8 items: Nausea-Vomiting, Diarrhea, Poor Coordination, Diaphoresis, Tremor-Tremulousness, Dizziness-Lightheadedness, Increased Acuity Sound Smell Touch, Paresthesias. Higher scores indicating more severe symptoms. | Day 49 to Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the MADRS Total Score by Baseline Insomnia Severity Index (ISI) Score at Day 42 | 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 range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. The ISI has 7 questions, each rated on a 5-point Likert scale ranging from 0 to 4. The total score is calculated as the sum of the 7 items ranging from 0 to 28. Higher scores represent a more severe condition. | Baseline and Day 42 | 
| Change From Baseline in ISI Total Score at DB Endpoint (Up to Week 6) | The ISI is a commonly used, 7-item psychometrically validated measure used to rate insomnia. Each item is scored 0 (no problem) to 4 (very big problem) with total between 0-28 which is calculated by adding the scores of all 7 items (absence of insomnia [0-7]; sub-threshold insomnia [8-14]; moderate insomnia [15-21]; and severe insomnia [22-28]). The change in ISI total score from baseline at DB endpoint was evaluated. Negative change in score indicates improvement. | Baseline and DB Endpoint (Up to Week 6) | 
| Percentage of Participants With Response on Depressive Symptoms Scale Based on MADRS Total Score | Responders are defined as participants with a >=50 percent (%) improvement in the MADRS total score from baseline to a given timepoint. 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 range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. Participants with missing values at a given time point were imputed as non-responders. | Day 42 | 
| Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score | Participants with a MADRS total score of less than or equal to (<=) 8, <=10, and <=12 at a given time point were considered as remitters. 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 range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. Participants with missing values at a given time point were imputed as non-responders. | Day 42 | 
| Change From Baseline in Structured Interview Guide for the Hamilton Anxiety Rating Scale (HAM-A) Total Score at Day 42 | HAM-A is a 14-item scale designed to measure anxiety in individuals. Each question reflects a symptom of anxiety and physical as well as mental symptoms are represented. Each of the 14-items in the scale is scored on a 5-point scale, ranging from 0 (a complete lack of that symptom) to 4 (a very severe show of anxiety with that symptom). The total score ranges from 0 to 56 which is calculated by adding the scores of all 14 items, where 0-13 indicates normal range, 14-17 indicates mild severity, 18 -24: mild to moderate severity, 25 -30: moderate to severe, and >=31: severe. Higher score indicates worsening. Negative change in score indicates improvement. | Baseline and Day 42 | 
| Percentage of Participants With Response on Anxiety Symptoms Scale Based on HAM-A Total Score | Participants with a >=50 percent improvement in the HAM-A total score from baseline at a given timepoint were considered as responders. HAM-A is a 14-item scale designed to measure anxiety in individuals. Each question reflects a symptom of anxiety and physical as well as mental symptoms are represented. Each of the 14-items in the scale is scored on a 5-point scale, ranging from 0 (a complete lack of that symptom) to 4 (a very severe show of anxiety with that symptom). The total score ranges from 0 to 56 which is calculated by adding the scores of all 14 items, where 0-13 indicates normal range, 14-17 indicates mild severity, 18 -24: mild to moderate severity, 25 -30: moderate to severe, and >=31: severe. Higher score indicates worsening. Participants with missing values at a given time point were imputed as non-responders. | Day 42 | 
| Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at DB Endpoint (Up to Week 6) | The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S is a 7-point global assessment scale that measures the clinician's impression of the severity of illness exhibited by a participant, rating according to: 1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=among the most extremely ill participants. Higher scores indicate worsening. Negative change in score indicates improvement. | Baseline and DB Endpoint (Up to Week 6) | 
| Change From Baseline in the Sheehan Disability Scale (SDS) Score at Day 42 | The SDS is a 5-item questionnaire which has been widely used and accepted for assessment of functional impairment and associated disability. The first 3 items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The scores for the first 3 items are summed to create a total score of 0-30, where a higher score indicates greater impairment. It also has 1 item on days lost from school or work and 1 item on days when underproductive. Negative change in score indicates improvement. | Baseline and Day 42 | 
| Change From Baseline in the MADRS Total Score at Day 42 in Participants With Major Depressive Disorder (MDD) With Anxious Distress Versus Participants With MDD Without Anxious Distress | 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 range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. Negative change in score indicates improvement. | Baseline and Day 42 | 
| Change From Baseline in Salivary Cortisol Levels, Measured Upon Awakening at Days 8, 22 and 42 | Exposure on the hypothalamic-pituitary-adrenal (HPA) axis in participants with MDD was evaluated by assessing change in salivary cortisol levels. | Baseline, Days 8, 22 and 42 | 
| Plasma Concentrations of Seltorexant and Its Metabolites (M12 and M16) | Plasma concentrations of Seltorexant and its metabolites (M12 and M16) over time were reported. | Day 1: Between 0.25 hours (h) to 1.5 hour, 2 to 4 hours, and 6 to 8 hours post-dose; Day 8 (morning): 6 to 12 hours post evening dose of Day 7 | 
| Change From Baseline in Depressive Symptoms Using the Patient Health Questionnaire 9-Item (PHQ-9) at DB Endpoint (Up to Week 6) | The PHQ-9 is a 9-item, Patient Reported Outcome (PRO) 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 participants item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate (10-14), Moderately Severe (15-19) and Severe (20-27). | Baseline and DB Endpoint (Up to Week 6) | 
| Change From Baseline in Anhedonia Using the Snaith-Hamilton Pleasure Scale (SHAPS) Score at DB Endpoint (Up to Week 6) | The SHAPS is a 14-item, self-report instrument to assess hedonic capacity in adults with MDD. Each of the items has a set of 4 response categories-Definitely Agree (=1), Agree (=2), Disagree (=3), and Definitely Disagree (=4). A total score is created with either of the Disagree responses receiving a score of 1 and either of the Agree responses receiving a score of 0. The participants item responses are summed to provide a total score ranging from 0 to 14. A higher total SHAPS score indicates higher levels of current anhedonia. | Baseline and DB Endpoint (Up to Week 6) | 
| Change From Baseline in Sleep Disturbance Using the Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) Short Form at DB Endpoint (Up to Week 6) | The PROMIS-SD Short Form subscale consists of a static 8 item questionnaire. It assesses the concepts of sleep initiation (2 items), quality of sleep (3 items), early morning feelings (2 items) and worrying about sleep (1 item). Responses to each of the 8 items range from 1 to 5, and the range of possible summed raw scores is 8 to 40. Higher scores on the PROMIS-SD indicate more of the concept measured (disturbed sleep). Negative change in score indicates improvement. | Baseline and DB Endpoint (Up to Week 6) | 
| Change From Baseline in Fatigue Using the Patient Reported Outcome Measurement Information System-Fatigue (PROMIS-F) Short Form Subscale Score at DB Endpoint (Up to Week 6) | The PROMIS-Fatigue Short Form subscale consists of a static 8 item questionnaire. It assesses a range of symptoms from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles. Ratings are done on a 5-item Likert scale ranging from 0 (not at all) to 5 (very much) or 0 (never) to 5(always) depending upon the question answered. Higher scores on the PROMIS-F indicate more of the concept measured (fatigue). Negative change in score indicates improvement. | Baseline and DB Endpoint (Up to Week 6) | 
| Change From Baseline in Severity of Depression Using the Patient Global Impression-Severity (PGI-S) Score at DB Endpoint (Up to Week 6) | The PGI-S is a self-report scale to measure severity of illness (1=none, 2=mild, 3=moderate, 4=severe). Higher score indicates more illness severity. Negative change in score indicates improvement. | Baseline and DB Endpoint (Up to Week 6) | 
| Change From Baseline in European Quality of Life 5 Dimensions (EQ-5D-5L) Heath State Index Total Score at DB Endpoint (Up to Week 6) | EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). The responses to 5 EQ-5D-5L dimensions were scored using a utility-weighted algorithm to derive an EQ-5D-5L health status index score between 0 (death) to 100 (full health). | Baseline and DB Endpoint (Up to Week 6) | 
| Change From Baseline in EQ-5D-5L Visual Analog Scale (VAS) Total Score at Endpoint (Up to Week 6) | The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). EQ-5D-5L (describing and valuing health-related quality of life) descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe the participant's current health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. Higher scores representing a better health state. An increase in the EQ-5D-5L total score indicates improvement. EQ-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). | Baseline and Endpoint (up to Week 6) | 
| Change From Baseline in Work Productivity and Limitations Using the Work Limitations Questionnaire (WLQ) Short Form Score at DB Endpoint (Up to Week 6) | The WLQ is to assess the on-the-job impact of chronic health problems and/or treatment (work limitations) in adults. It is a 8-item questionnaire self-report rating scale developed to measure the on-the-job impact of chronic health problems and/or treatment (work limitations). It comprises five dimensions of limitations: handling time, physical, mental-interpersonal, productivity loss and output demands. Participants respond to each item with options ranging from 'Almost all of the time' to 'none of the time', or 'Does not apply to my job'. Each dimension of limitations have a scale score ranging from 0 to 100 with lower score indicating low level of work limitations. | Baseline and DB Endpoint (Up to Week 6) |