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
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Depressive Disorder, Major
- Sponsor
- Janssen Research & Development, LLC
- Enrollment
- 287
- Locations
- 100
- Primary Endpoint
- Percentage of Participants With Clinically Significant Laboratory Abnormalities
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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
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).
Investigators
Eligibility Criteria
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
Arms & Interventions
Placebo
Participants will receive 2 placebo capsules matching JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6).
Intervention: Placebo
JNJ-42847922
Participants will receive 2 capsules of JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6).
Intervention: JNJ-42847922
Outcomes
Primary Outcomes
Percentage of Participants With Clinically Significant Laboratory Abnormalities
Time Frame: Up to Week 8
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.
Change From Baseline in Vital Sign (PR) at Endpoint (Week 6)
Time Frame: Baseline and Endpoint (Week 6)
Change from baseline in vital sign (PR) at endpoint (Week 6) was reported.
Change From Baseline in Vital Sign (Temperature) at Day 8
Time Frame: Baseline and Day 8
Change from baseline in vital Sign (temperature) at Day 8 was reported.
Change From Baseline in Vital Signs (SBP and DBP) at Day 22
Time Frame: Baseline and Day 22
Change from baseline in vital signs (SBP and DBP) at Day 22 was reported.
Change From Baseline in Vital Sign (Pulse Rate [PR]) at Day 8
Time Frame: Baseline and Day 8
Change from baseline in vital sign (PR) at Day 8 was reported.
Change From Baseline in Physical Examination (Body Weight) at Day 42
Time Frame: Baseline and Day 42
Change from baseline in physical examination (body weight) was reported.
Physician Withdrawal Checklist-20 (PWC-20) Total Score at Day 43
Time Frame: 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.
Change From Baseline in Physical Examination (Body Mass Index [BMI]) at Day 42
Time Frame: Baseline and Day 42
Change from baseline in physical examination (BMI) was reported.
Physician Withdrawal Checklist-20 (PWC-20) Total Score From Day 49 to Day 56
Time Frame: 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.
Change From Baseline to Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
Time Frame: Baseline to Week 6
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.
Percentage of Participants With Treatment-emergent Adverse Events as a Measure of Safety and Tolerability
Time Frame: Up to Week 8
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.
Change From Baseline in Vital Signs (SBP and DBP) at Day 42
Time Frame: Baseline and Day 42
Change from baseline in vital signs (SBP and DBP) at Day 42 was reported.
Percentage of Participants With Most Severe Post-baseline Potentially Suicide-Related Category Using Columbia Suicide Severity Rating Scale (C-SSRS)
Time Frame: Up to Week 8
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.
Change From Baseline in Sexual Functioning as Measured by Arizona Sexual Experiences Scale (ASEX) Score at Day 42
Time Frame: Baseline and 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.
Change From Baseline in Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) at Day 8
Time Frame: Baseline and Day 8
Change from baseline in vital signs (SBP and DBP) at Day 8 was reported.
Change From Baseline in Vital Signs (SBP and DBP) at Endpoint (Week 6)
Time Frame: Baseline and Endpoint (Week 6)
Change from baseline in vital signs (SBP and DBP) at endpoint was reported.
Change From Baseline in Vital Sign (PR) at Day 22
Time Frame: Baseline and Day 22
Change from baseline in vital sign (PR) at Day 22 was reported.
Change From Baseline in Vital Sign (PR) at Day 42
Time Frame: Baseline and Day 42
Change from baseline in vital sign (PR) at Day 42 was reported.
Change From Baseline in Vital Sign (Temperature) at Day 22
Time Frame: Baseline and Day 22
Change from baseline in vital Sign (temperature) at Day 22 was reported.
Change From Baseline in Vital Sign (Temperature) at Day 42
Time Frame: Baseline and Day 42
Change from baseline in vital Sign (temperature) at Day 42 was reported.
Change From Baseline in Vital Sign (Temperature) at Endpoint (Week 6)
Time Frame: Baseline and Endpoint (Week 6)
Change from baseline in vital Sign (temperature) at endpoint (Week 6) was reported.
Change From Baseline in Physical Examination (Waist Circumference) at Day 42
Time Frame: Baseline and Day 42
Change from baseline in physical examination (waist circumference) was reported.
Percentage of Participants With Treatment-emergent Abnormal Electrocardiogram (ECG) Values Outside Pre-defined Limits
Time Frame: Up to Week 6
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.
Secondary Outcomes
- Change From Baseline in ISI Total Score at DB Endpoint (Up to Week 6)(Baseline and DB Endpoint (Up to Week 6))
- Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score(Day 42)
- Change From Baseline in Structured Interview Guide for the Hamilton Anxiety Rating Scale (HAM-A) Total Score at Day 42(Baseline and Day 42)
- Percentage of Participants With Response on Depressive Symptoms Scale Based on MADRS Total Score(Day 42)
- Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at DB Endpoint (Up to Week 6)(Baseline and DB Endpoint (Up to Week 6))
- 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(Baseline and Day 42)
- Change From Baseline in the MADRS Total Score by Baseline Insomnia Severity Index (ISI) Score at Day 42(Baseline and Day 42)
- Change From Baseline in Salivary Cortisol Levels, Measured Upon Awakening at Days 8, 22 and 42(Baseline, Days 8, 22 and 42)
- Plasma Concentrations of Seltorexant and Its Metabolites (M12 and M16)(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)(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)(Baseline and DB Endpoint (Up to Week 6))
- Percentage of Participants With Response on Anxiety Symptoms Scale Based on HAM-A Total Score(Day 42)
- Change From Baseline in Anhedonia Using the Snaith-Hamilton Pleasure Scale (SHAPS) Score at DB Endpoint (Up to Week 6)(Baseline and DB Endpoint (Up to Week 6))
- Change From Baseline in the Sheehan Disability Scale (SDS) Score at Day 42(Baseline and Day 42)
- Change From Baseline in Severity of Depression Using the Patient Global Impression-Severity (PGI-S) Score at DB Endpoint (Up to Week 6)(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)(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)(Baseline and 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)(Baseline and DB 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)(Baseline and DB Endpoint (Up to Week 6))