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 and Long-term Safety Extension Treatment With Seltorexant

Depressive Disorder, Major Clinical Trial

Official title:

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 and an Open-labeled Long-term Safety Extension Treatment With Seltorexant

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04533529
• Other study ID #: CR108804
• Secondary ID: 2020-000337-4042
• Status: Completed
• Phase: Phase 3
• Start date: September 16, 2020
• Est. completion date: April 30, 2024

Study information

• Verified date: June 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 an selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) in double-blind treatment phase and to assess the long-term safety and tolerability of seltorexant as adjunctive therapy to an antidepressant in participants with major depressive disorder (MDD) in open-label treatment phase.

Description:

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 adjunctive treatment of major depressive disorder with insomnia symptoms (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 4 phases: a screening phase (up to 30 days), a double-blind (DB) treatment phase (43 days), open label (OL) treatment phase (1-year), and a post treatment follow-up phase (7 to 14 days after end of treatment). The total study duration for each participant will be up to 64 weeks. Efficacy, safety, pharmacokinetics, and biomarkers will be assessed at specified time points during this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 588
• Est. completion date: April 30, 2024
• Est. primary completion date: April 25, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 74 Years

Eligibility

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 length of the current depressive episode must be less than or equal to (<=) 24 months prior to randomization

• 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 beyond insomnia present, and overall good tolerability, as assessed by the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (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

• Body mass index (BMI) between 18 and 40 kilograms per meter square (kg/m^2), inclusive (BMI = weight/height^2)

• Participant must be medically stable on the basis of the following performed at screening: 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, a) severe renal insufficiency (creatinine clearance [CrCl] <30 milliliter per minute [mL/min]); b) clinically significant or unstable cardiovascular, respiratory, gastrointestinal, neurologic, hematologic, rheumatologic, immunologic or endocrine disorders; c) uncontrolled Type 1 or Type 2 diabetes mellitus

• Has a current or recent history of homicidal ideation or serious suicidal ideation within the past 3 months, 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 Columbia Suicide Severity Rating Scale (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

• 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 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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major

Intervention

Drug:
• Seltorexant
Seltorexant tablet will be administered orally once daily.
• Placebo
Matching placebo tablet will be administered orally once daily.

Locations

Country	Name	City	State
Brazil	CPN - Centro de Pesquisa em Neurociências Ltda	Belo Horizonte
Brazil	CCB Centro Cardiologico de Brasilia Ltda - CCB Cardiologia	Brasilia
Brazil	Instituto de Neurologia de Curitiba	Curitiba
Brazil	Universidade Federal do Ceara Hospital Universitario Walter Cantidio	Fortaleza
Brazil	Instituto Mederi de Pesquisa e Saude	Passo Fundo
Brazil	Ruschel Medicina e Pesquisa Clínica Ltda	Rio de Janeiro
Brazil	Instituto Bairral de Psiquiatria	Sao Paulo
Brazil	SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo	Sao Paulo
Bulgaria	Mental Health Center Prof. Dr. Ivan Temkov	Bourgas
Bulgaria	Ambulatory for Individual Practice for Specialized Medical Care in Psychiatry Dr. Ivo Natsov ET	Cherven bryag
Bulgaria	State Psychiatric Hospital Kardzhali	Kardzhali
Bulgaria	Medical center Spectar - Plovdiv EOOD	Plovdiv
Bulgaria	UMHAT 'Sv. Georgi' EAD	Plovdiv
Bulgaria	MHC - Sofia, EOOD	Slivnitsa
Bulgaria	DCC 'Sv. Vrach and Sv. Sv. Kuzma and Damyan', OOD	Sofia
Bulgaria	Medical Center Intermedica, OOD	Sofia
Bulgaria	Medical Center St. Naum	Sofia
Bulgaria	Medical center - VAS OOD	Targovishte
Bulgaria	Mental Health Center - Vratsa EOOD	Vratsa
Colombia	Centro de Investigaciones y Proyectos en Neurociencias CIPNA	Barranquilla
Colombia	HOMO - ESE Hospital Mental de Antioquia	Bello
Colombia	Centro de Investigaciones del Sistema Nervioso Grupo Cisne Ltda.	Bogota
Colombia	Fundacion Centro de Investigacion Clinica CIC	Medellin
Colombia	Psynapsis Salud Mental S.A.	Pereira
Czechia	BRAIN-SOULTHERAPY s.r.o.	Kladno
Czechia	Neuroterapie KH s r o	Kutna Hora
Czechia	A-Shine s.r.o.	Plzen
Czechia	Clintrial s r o	Praha 10
Czechia	Medical Services Prague s.r.o.	Praha 6
Mexico	Iecsi S.C.	Monterrey
Mexico	CRI Centro Regiomontano de Investigacion SC	Nuevo Leon
Mexico	Bind Investigaciones S.C.	San Luis Potosi
Russian Federation	Psychoneurological dispensary 1	Saint Petersburg
Russian Federation	City Psychiatric Hospital of St. Nikolay Chudotvorets	Saint-Petersburg
Russian Federation	Bekhterev Psychoneurological Research Institute	St Petersburg
Russian Federation	Psychoneurological Dispensary of Frunzensky District	St-Petersburg
Russian Federation	SPb SBIH 'City Psychoneurological Dispensary # 7 (With Inpatient Facilities)'	St. Petersburg
Russian Federation	St-Petersburg Bekhterev Psychoneurological Research Institute	St. Petersburg
Russian Federation	Stavropol Region Psychiatric Hospital #2	Stavropol
Russian Federation	Yaroslavl Region Clinical Psychiatric Hospital	Yaroslavl
South Africa	Farmovs Pty Ltd	Bloemfontein
South Africa	Iatros International	Bloemfontein
South Africa	Cape Town Clinical Research Centre	Cape Town
South Africa	Flexivest 14 Research	Cape Town
South Africa	DJW Research	Krugersdorp
South Africa	Stanza Clinical Research Centre : Mamelodi	Mamelodi East
South Africa	Synexus Watermeyer	Pretoria
South Africa	Somerset West Clinical Research Unit	Strand
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Institucion Hosp Hestia Palau	Barcelona
Spain	Hosp. Univ. de Basurto	Bilbao
Spain	Hosp. Univ. La Paz	Madrid
Spain	Hosp. Univ. Ramon Y Cajal	Madrid
Spain	Centro Salud Mental La Corredoria	Oviedo
Spain	Clinica Univ. de Navarra	Pamplona
Spain	Corporacio Sanitari Parc Tauli	Sabadell
Spain	Centro de salud San Juan - IBSAL	Salamanca
Spain	Hosp. Prov. de Zamora	Zamora
Sweden	Affecta Pskyiatrimottagning	Halmstad
Sweden	PharmaSite Helsingborg	Helsingborg
Sweden	ProbarE i Lund AB	Lund
Sweden	PharmaSite	Malmo
Sweden	Läkarmottagningen	Skovde
Sweden	ProbarE i Solna	Stockholm
Taiwan	Chang-Gung Memorial Hospital-Keelung	Keelung
Taiwan	Cheng Hsin General Hospital	Taipei
Taiwan	Mackay Memorial Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Taipei Medical University	Taipei City
Taiwan	Chang Gung Memorial Hospital- Linkou	Taoyuan County
United States	Lehigh Center for Clinical Research	Allentown	Pennsylvania
United States	Advanced Research Center Inc	Anaheim	California
United States	Haidar Almhana Nieding	Avon Lake	Ohio
United States	Hassman Research Institute, LLC.	Berlin	New Jersey
United States	Neurobehavioral Medicine Group	Bloomfield Hills	Michigan
United States	Synexus	Cerritos	California
United States	Alpine Research Organization	Clinton	Utah
United States	The Ohio State University	Columbus	Ohio
United States	Connecticut Clinical Trials LLC	Cromwell	Connecticut
United States	Relaro Medical Trials	Dallas	Texas
United States	Revive Research Institute	Elgin	Illinois
United States	University of Connecticut Health Center	Farmington	Connecticut
United States	North Texas Clinical Trials	Fort Worth	Texas
United States	Sarkis Clinical Trials	Gainesville	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	Red Oak Psychiatry Associates	Houston	Texas
United States	Irvine Clinical Research	Irvine	California
United States	Clinical NeuroScience Solutions Inc	Jacksonville	Florida
United States	Synexus Clinical Research US Inc	Jamaica	New York
United States	Joliet Center for Clinical Research	Joliet	Illinois
United States	Omega Clinical Trials LLC	La Habra	California
United States	Altea Research Institute	Las Vegas	Nevada
United States	Synergy East	Lemon Grove	California
United States	Premier Psychiatric Research Institute, LLC	Lincoln	Nebraska
United States	Semel Institute for Neuroscience and Human Behavior	Los Angeles	California
United States	Lindner Center of Hope	Mason	Ohio
United States	Medical Research Center of Miami II Inc	Miami	Florida
United States	Pharmax Research Clinic Inc	Miami	Florida
United States	Phoenix Medical Research, Inc.	Miami	Florida
United States	Galiz Research	Miami Springs	Florida
United States	Catalina Research Institute	Montclair	California
United States	Bioscience Research LLC	Mount Kisco	New York
United States	Baber Research Group	Naperville	Illinois
United States	Bravo Health Care Center	North Bay Village	Florida
United States	American Medical Research, Inc.	Oak Brook	Illinois
United States	Pacific Research Partners	Oakland	California
United States	North County Clinical Research	Oceanside	California
United States	Oklahoma Clinical Research Center	Oklahoma City	Oklahoma
United States	APG Research LLC	Orlando	Florida
United States	Combined Research Orlando	Orlando	Florida
United States	Nova Psychiatry INC	Orlando	Florida
United States	University of Pennsylvania - Perelman School of Medicine	Philadelphia	Pennsylvania
United States	Green Mountain Research Institute	Rutland	Vermont
United States	Midwest Research Group - St. Charles Psychiatric Associates	Saint Charles	Missouri
United States	Mid-America Clinical Research, LLC	Saint Louis	Missouri
United States	PsychCare Consultants Research	Saint Louis	Missouri
United States	Syrentis Clinical Research	Santa Ana	California
United States	Louisiana Clinical Research	Shreveport	Louisiana
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Viking Pharmaceutical Trials Inc. dba Viking Clinical Research	Temecula	California
United States	Adams Clinical	Watertown	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Brazil,  Bulgaria,  Colombia,  Czechia,  Mexico,  Russian Federation,  South Africa,  Spain,  Sweden,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Double-blind (DB) Treatment Phase: Change From Baseline 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 of 60. Higher scores represent a more severe condition.	Baseline, Day 43
Primary	Open-Label (OL) Treatment Phase: Number of Participants with Adverse Events (AEs) including AEs of Special Interest (AESI) as a Measure of Safety and Tolerability	Number of participants with AE including AE of special interest as a measure of safety and tolerability will be reported. An AE is any untoward medical occurrence in a clinical study participant administered a investigational or non-investigational medicinal product. An AE does not necessarily have a causal relationship with the treatment. AESI will comprise of cataplexy, sleep paralysis, complex, sleep-related behaviors/parasomnias, sleep terrors, bruxism, sleep sex, sleep related eating disorder, catathrenia, fall and motor vehicle accident.	1 year
Primary	OL Treatment Phase: Change From Baseline in Blood Pressure	Change from baseline in blood pressure will be reported.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change From Baseline in Pulse Rate	Change from baseline in pulse rate will be reported.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change From Baseline in Weight	Change from baseline in weight as a part of physical examination will be reported.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change From Baseline in Body Mass Index (BMI)	Change from baseline in BMI as a part of physical examination will be reported.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change From Baseline in Suicidality Assessment Using the Columbia Suicide Severity Rating Scale (C-SSRS)	Change from baseline in suicidality assessment using C-SSRS will be reported. C-SSRS is a clinician rated assessment of suicidal behavior and/or intent. Scale consists of 28 items in 4 sections: suicide behavior, actual attempts, suicidal ideation, and intensity of ideation. Suicidal ideation consists of 5 'yes/no' items: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, active suicidal ideation with specific plan and intent. Only items with yes responses are listed. Worsening of suicidal ideation indicates an increase in severity of suicidal ideation from baseline. Suicidal behavior consists of 5 'yes/no' items: preparatory acts or behavior, aborted attempt, actual attempt, completed suicide.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Physician Withdrawal Checklist (PWC-20) Scores	Withdrawal symptoms assessment using the PWC-20 will be reported. The PWC-20 is a simple and accurate method used to assess potential withdrawal symptoms following cessation of treatment. The PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms. Each individual item score ranges from 0 (not present) to 3 (severe), where higher scores = more affected condition.	End of Treatment/Early withdrawal to end of the Follow-up visit (up to 14 days)
Primary	OL Treatment Phase: Number of Participants with Laboratory Abnormalities	Number of participants with laboratory abnormalities related to hematology, serum chemistry, coagulation, liver function tests and urinalysis will be reported.	Up to 1 year
Primary	OL Treatment Phase: Change From Baseline in QTc Interval	Change from baseline in QT interval corrected for heart rate (QTc interval) using Fridericia method will be measured by electrocardiogram (ECG).	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change from Baseline in Heart Rate (HR)	Change from baseline in HR will be measured by ECG.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change from Baseline in QRS Interval	Change from baseline in QRS interval will be measured by ECG.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change from Baseline in PR Interval	Change from baseline in PR interval will be measured by ECG.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Change From Baseline in QT Interval	Change from baseline in QT interval will be measured by ECG.	Baseline (Day 43), up to 1 year
Primary	OL Treatment Phase: Participant-reported Sexual Functioning Using Arizona Sexual Experiences Scale (ASEX) Score	The ASEX is a patient-reported 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. The total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction.	Up to 1 year
Secondary	DB Treatment Phase: Change From Baseline in the MADRS Without Sleep Item (MADRS-WOSI) Total Score	Change from Baseline in MADRS-WOSI will be reported. MADRS-WOSI is defined as the full MADRS without the sleep item. The total score ranges from 0 to 54, with higher scores corresponding to greater symptom severity.	Baseline and Day 43
Secondary	DB Treatment Phase: Change From Baseline in Sleep Disturbance Using the Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) Short Form 8a T-score	The 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 and Day 43
Secondary	DB Treatment Phase: Change From Baseline in the MADRS-6 Total Score	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, comprises 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 and Day 43
Secondary	DB Treatment Phase: Percentage of Participants with Response on Depressive Symptoms Scale Based on Montgomery-Asberg Depression Rating Scale (MADRS)	Percentage of participants with response on depressive symptoms scale based on MADRS will be reported. Responders are defined as percentage of participants with greater than or equal to (>=) 50 percent (%) improvement in the MADRS total score from baseline to Day 43.	Day 43
Secondary	DB Treatment Phase: Change From Baseline in Patient Health Questionnaire, 9-Item (PHQ-9) Total Score	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 and Day 43
Secondary	DB Treatment Phase: Number of Participants with Adverse Events (AEs) including AEs of Special Interest (AESI) as a Measure of Safety and Tolerability	Number of participants with AE including AE of special interest as a measure of safety and tolerability will be reported. An AE is any untoward medical occurrence in a clinical study participant administered a investigational or non-investigational medicinal product. An AE does not necessarily have a causal relationship with the treatment. AESI include: Cataplexy, Sleep paralysis, complex, sleep-related behaviors/parasomnias such as: confusional arousal, somnambulism, sleep terror, bruxism, sleep sex, sleep-related eating disorder, sleep behavior disorder, catathrenia.	Up to Day 50 to 57 (every two weeks)
Secondary	OL Treatment Phase: Change From Baseline Over Time 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 of 60. Higher scores represent a more severe condition.	Baseline (Day 43), up to 1 year
Secondary	OL Treatment Phase: Change From Baseline Over Time in the Clinical Global Impression-Severity (CGI S) Score	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.	Baseline (Day 43), up to 1 year
Secondary	OL Treatment Phase: Change from Baseline Over Time in the MADRS-WOSI Total Score	Change from Baseline in MADRS-WOSI will be reported. MADRS-WOSI is defined as the full MADRS without the sleep item. The total score ranges from 0 to 54, with higher scores corresponding to greater symptom severity.	Baseline (of OL phase), up to 1 year
Secondary	OL Treatment Phase: Change From Baseline Over Time in Sleep Disturbance Using the PROMIS SD Short Form 8a T-score	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 (Day 43), up to Year 1