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The purpose of this study is to evaluate the efficacy of aticaprant compared with placebo as adjunctive therapy to an antidepressant in improving depressive symptoms in adult participants with major depressive disorder (MDD) with moderate-to-severe anhedonia (ANH+) who have had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy

Depressive Disorder, Major

Major Depressive Disorder With Anxious Distress

Depressive Disorder

Depression

Mood disorders

Brain and Nervous System Conditions

Anhedonia

Depression is a common and serious psychiatric disorder which is a leading cause of disability worldwide and is associated with elevated mortality and suicide risk. Aticaprant (JNJ-67953964) is a once daily, highly selective kappa opioid receptor (KOR) antagonist, with demonstrated selectivity over mu opioid receptor (MOR) and delta opioid receptor (DOR) being developed for adjunctive treatment of major depressive disorder (MDD) with moderate-to-severe anhedonia (ANH+). The study consists of a screening phase (up to 30 days prior to randomization), double-blind treatment phase (43 days), and follow-up phase (up to 14 days). The total duration of the study will be up to 87 days. Safety evaluations including adverse events, physical examinations, urine drug test, alcohol breath tests, and clinical laboratory tests will be assessed at specific time points during this study.

Placebo

Aticaprant

A Randomized, Double-blind, Multicenter, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy

The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition. Negative change in MADRS total score indicates improvement.

The DARS is a 17-item self-report questionnaire that is designed to assess anhedonia in MDD across the 4 domains: hobbies, social activities, food/drink, and sensory experience. The DARS scale measures desire, motivation, effort, and consummatory pleasure. The DARS is rated on a 5-point Likert scale (0=not at all, 1=slightly, 2=moderately, 3=mostly, 4=very much) and responses are summed to generate the total score (ranges from 0 to 68). A lower total score is indicative of greater anhedonia. Positive changes in DARS total score indicate improvement.

Change from baseline over time in MADRS total score is reported. The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition. Negative change in MADRS total score indicates improvement.

Percentage of participants who achieved response on depressive symptoms scale based on MADRS total score at Day 43 are reported. Responders are defined as participants with a >=50 percent (%) improvement in the MADRS total score from baseline to a given timepoint. The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition.

Percentage of participants with remission of depressive symptoms based on MADRS total score at Day 43 is reported. Participant is defined as a remitter at a given time point if the MADRS total score is less than or equal to (<=)10 at that time point. The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The scale consists of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score is the sum of scores from individual question items, which ranges from 0 to 60; higher scores represent a more severe condition.

Change from baseline to Day 43 in PHQ-9 total score is reported. 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) 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. 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). Negative changes in PHQ-9 total score indicate improvement.

Change from baseline over time in DARS total score is reported. The DARS is a 17-item self-report questionnaire that is designed to assess anhedonia in MDD across the 4 domains: hobbies, social activities, food/drink, and sensory experience. The DARS scale measures desire, motivation, effort, and consummatory pleasure. The DARS is rated on a 5-point Likert scale (0=not at all, 1=slightly, 2=moderately, 3=mostly, 4=very much) and responses are summed to generate the total score (range of 0 to 68). A lower total score is indicative of greater anhedonia. Positive changes in DARS total score indicate improvement.

Change from baseline over time in the PHQ-9 anhedonia-specific item (PHQ-9, item 1 is little interest or pleasure in doing things) is reported. 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) 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. 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). Negative changes in PHQ-9 total score indicate improvement.

Percentage of participants with a score <2 in the PHQ-9 anhedonia-specific item (PHQ-9, item 1 is little interest or pleasure in doing things) at Day 43 is reported. 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) 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. 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).

Change from baseline over time in the PROMIS-APS 8a is reported. This 8-item measure assesses participants' ability to participate in social roles and activities. The items measures the degree of involvement in social roles, activities, and responsibilities, including work, family, friends, and leisure. Each item is rated on a 5-point ordinal scale including 1=always, 2=usually, 3=sometimes, 4=rarely and 5=never, with higher scores indicating better social functioning. The total scores of PROMIS-APS 8a ranges from 8 to 40 and is transformed using a T-score metric with a mean of 50 and a standard deviation of 10. T-score ranges from 25.9 to 65.4, a higher score indicates better social functioning. Positive change in score indicates improvement.

The WPAI:D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI yields four types of scores: (a) Absenteeism (work time missed); (b) Presenteeism (impairment at work / reduced on-the-job effectiveness); (c) Work productivity loss (overall work impairment / absenteeism plus presenteeism); (d) Activity Impairment. The first three scores are derived only for respondents who were working (should be missing for non-working), but the last score is applicable for all respondents. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity. Negative changes in score indicates less impairment and greater productivity.

Percentage of participants with TEAEs during DB treatment phase are reported. A TEAE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. A TEAE does not necessarily have a causal relationship with the intervention. TEAEs included both serious and non serious adverse events. TEAEs were defined as AEs with onset during the DB Treatment Phase, or AEs that are a consequence of a pre-existing condition that has worsened since baseline (Day 1).

An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention.

Participants will receive aticaprant tablets orally once daily for 42 days during double-blind treatment phase in addition to the current antidepressant selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) therapy. Participants who will complete the double-blind treatment phase (Day 43) may be eligible to participate in a separate 52-week open-label long-term safety study (67953964MDD3003).

Participants will receive matching placebo orally once daily for 42 days during double-blind treatment phase in addition to their current antidepressant (SSRI/SNRI) therapy. Participants who will complete the double-blind treatment phase (Day 43) may be eligible to participate in a separate 52-week open-label long-term safety study (67953964MDD3003).

The purpose of this study is to evaluate the efficacy of aticaprant compared with placebo as
      adjunctive therapy to an antidepressant in improving depressive symptoms in adult
      participants with major depressive disorder (MDD) with moderate-to-severe anhedonia (ANH+)
      who have had an inadequate response to current antidepressant therapy with a selective
      serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

Depression is a common and serious psychiatric disorder which is a leading cause of
      disability worldwide and is associated with elevated mortality and suicide risk. Aticaprant
      (JNJ-67953964) is a once daily, highly selective kappa opioid receptor (KOR) antagonist, with
      demonstrated selectivity over mu opioid receptor (MOR) and delta opioid receptor (DOR) being
      developed for adjunctive treatment of major depressive disorder (MDD) with moderate-to-severe
      anhedonia (ANH+). The study consists of a screening phase (up to 30 days prior to
      randomization), double-blind treatment phase (43 days), and follow-up phase (up to 14 days).
      The total duration of the study will be up to 87 days. Safety evaluations including adverse
      events, physical examinations, urine drug test, alcohol breath tests, and clinical laboratory
      tests will be assessed at specific time points during this study.

SW Biomedical Research, LLC

University of Arizona

Advanced Research Center Inc

Proscience Research Group

Behavioral Research Specialists, LLC

Asclepes Research

Excell Research Inc

Syrentis Clinical Research

Viking Clinical Research Ltd.

University of Connecticut Health Center

Innovative Research of West Florida, Incorporated

Vertex Research Group, Inc

Gulfcoast Medical Research Center

New Life Medical Research Center, Inc.

Amedica Research Institute, Inc.

Convenient Medical Center

Galiz Research

Meridian International Research

University of Miami

Pharmax Research Clinic Inc

A Plus Research

Medical Research Group of Central Florida

USF, Department of Psychiatry and Behavioral Neurosciences

Research Network America

Chicago Research Center

University of Kansas Medical Center Research Institute

Clinical Trials of America

ActivMed Practices & Research

Psychiatric Care and Research Center (PCRC)

Bioscience Research LLC

Fieve Clinical Research, Inc.

Finger Lakes Clinical Research

Patient Priority Clinical Sites, LLC

University of Cincinnati Medical Center

Midwest Clinical Research Center

Charak Center for Health and Wellness

Suburban Research Associates

University of Pennsylvania - Perelman School of Medicine

West Houston Clinical Research Service

North Texas Clinical Trials

Bay Area Clinical Services

Clinical Trial Network - Houston

Alpine Research Organization

University of Virginia

Northwest Clinical Research Center

Anima

C.H.U. Brugmann

Vitaz

Ambulatory for Individual Practice for Specialized Medical Care in Psychiatry Dr. Ivo Natsov ET

Ambulatory Group practice for specialized help in psychiary Philipopolis ODD

Medical Center Mentalcare OOD

Mental Health Center - Rousse

Medical Center St. Naum

Mental Health Center - Veliko Tarnovo EOOD

Narodni ustav dusevniho zdravi

A-Shine s.r.o.

Praglandia, s.r.o.

Clintrial s.r.o.

AD71 s.r.o.

NeuropsychiatrieHK, s.r.o.

Psychiatricka ordinace

Dr.Mathe es Tarsa Bt

AUSL LE di Lecce

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria alle Scotte

Mlynowamed Specjalistyczny Psychiatryczny Gabinet Lekarski Joanna Lazarczyk

Specjalistyczna Indywidualna Praktyka Lekarska

Specjalistyczny Gabinet Psychiatryczny Kowalkowski Gerard

Hospital de Braga

Hosp. Univ. La Paz

Hosp. Regional Univ. de Malaga

Hosp. Alvaro Cunqueiro

ProbarE i Lund AB

ProbarE i Stockholm AB

Studieenheten Akademiskt Specialistcentrum Stockholm

Change from baseline in MADRS total score to Day 43 will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which 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.

Change from baseline in DARS total score to Day 43 will be reported. DARS is a 17-item self-report questionnaire that is designed to assess anhedonia in major depressive disorder (MDD), and particularly to increase scale generalizability while maintaining specificity. Respondents provide their own examples of rewarding experiences across the domains of hobbies, social activities, food/drink, and sensory experience. Participants answer a set of standardized questions about desire, motivation, effort, and consummatory pleasure with a recall period of "right now" for the examples provided. The instrument is scored as a total sum of all items (range 0-68) with higher scores reflecting increased motivation, effort and pleasure (that is, less anhedonia).

Change from baseline in MADRS total score over time will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which 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.

Percentage of responders on depressive symptoms scale, defined as a greater than or equal to (>=) 50 percent (%) improvement in MADRS total score from baseline to Day 43 will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which 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.

Percentage of participants with remission of depressive symptoms, defined as a MADRS total score less than or equal to (<=) 10 at Day 43 will be reported. The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which 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.

Change from baseline in PHQ-9 total score to Day 43 will be reported. The 9-item PHQ-9 scale scores each of the 9 symptom domains of the diagnostic and statistical manual of mental disorders-5th edition (DSM-5) MDD criteria and it is used both as a screening tool and a measure of response to treatment for depression. 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.

Change from baseline in DARS total score over time will be reported. DARS is a 17-item self-report questionnaire that was designed to assess anhedonia in MDD, and particularly to increase scale generalizability while maintaining specificity. Respondents provide their own examples of rewarding experiences across the domains of hobbies, social activities, food/drink, and sensory experience. Participants answer a set of standardized questions about desire, motivation, effort and consummatory pleasure with a recall period of "right now" for the examples provided. The instrument is scored on 0 (not at all) to 4 (very much) and the total score is calculated as a sum of all items (range 0-68) with higher scores reflecting increased motivation, effort, and pleasure (that is, less anhedonia).

Change from baseline in the PHQ-9 Anhedonia-specific item (PHQ-9, item 1) over time will be reported. The 9-item PHQ-9 scale scores each of the 9 symptom domains of the diagnostic and statistical manual of mental disorders-5th edition (DSM-5) MDD criteria and it is used both as a screening tool and a measure of response to treatment for depression: 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.

Percentage of participants with a score < 2 in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) at Day 43 will be reported.

The PROMIS-APS 8a includes items selected from the PROMIS item bank to provide an assessment of the current degree of involvement in one's usual social roles, activities, and responsibilities, including work, family, friends, and leisure. The 8-item short form will be used in this study, and responses to every item are in a 5-point ordinal scale ranging from 1 = "Always" to 5 = "Never," with higher scores indicating better social functioning. The total scores of PROMIS-APS 8a are scaled on a T-score metric with a mean of 50 and a standard deviation (SD) of 10.

The WPAI:D questionnaire is a validated short instrument that assesses impairment in work and other regular activities over the past 7 days. The WPAI questionnaire assesses 4 separate measures: absenteeism (that is , the proportion of work time missed due to MDD), presenteeism (that is, the degree of impairment while working due to MDD), work productivity loss (ie, overall work impairment due to MDD/absenteeism plus presenteeism), and activity impairment (that is, the degree of impairment of regular, nonwork activity due to MDD). The WPAI outcomes are expressed as impairment percentages, with higher values indicating greater impairment and less productivity, that is, worse outcomes.

SW Biomedical Research LLC

Behavioral Research Specialists LLC

Viking Clinical Research Ltd

Amedica Research Institute Inc

ActivMed Practices and Research

Fieve Clinical Research Inc

Montefiore Medical Center PRIME

Patient Priority Clinical Sites LLC

Hospital Italiano

STAT Research S A

CIPREC

CENydET - Centro Neurobiologico y de Stress Traumatico

Fundacion Lennox

CENPIA

Instituto Medico de La Fundacion Estudios Clinicos

Resolution

Peninsula Therapeutic & Research Group

Albert Road Clinic

The Alfred Hospital

Pz Duffel

Universidade Federal do Ceara Hospital Universitario Walter Cantidio

Instituto Goiano de Neuropsiquiatria

NPCRS Nucleo de Pesquisa Clinica do Rio Grande do Sul

Ruschel Medicina e Pesquisa Clínica Ltda

CEMEC - Centro Multidisciplinar de Estudos Clínicos

Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto Hospital de Base

CPQuali Pesquisa Clinica LTDA ME

BR Trials

A Shine S R O

Clintrial s r o

Praglandia s r o

Obudai Egeszsegugyi Centrum Kft

Semmelweis Egyetem

Nyiro Gyula Korhaz

Bugat Pal Korhaz

Dr Mathe es Tarsa Bt

Tolna Megyei Balassa Janos Korhaz

PsychoTech Kft

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)

A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy

Trials at a glance

Trials at a glance

A Study of Aticaprant as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy

Outcome measures

Primary outcome measures

Secondary outcome measures