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

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.

• Aticaprant (Drug), also known as JNJ-67953964: Aticaprant will be administered orally as tablets.
• Placebo (Other): Placebo will be administered orally as tablets.

Primary outcomes

• Change From Baseline to Day 43 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score [Baseline (Day 1) to Day 43]: 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.

Secondary outcomes

• Change From Baseline to Day 43 in Dimensional Anhedonia Rating Scale (DARS) Total Score [Baseline (Day 1) to Day 43]: 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 [Baseline (Day 1), Days 15, 29 and 43]: 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 [At Day 43]: 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 [At Day 43]: 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 Patient Health Questionnaire, 9-Item (PHQ-9) Total Score [Baseline (Day 1) to Day 43]: 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 [Baseline (Day 1), Days 15, 29, and 43]: 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) [Baseline (Day 1), Day 15, Day 29, and Day 43]: 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 Less Than (<) 2 in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) at Day 43 [At Day 43]: 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 Patient Reported Outcomes Measurement Information System Short Form - Ability to Participate in Social Roles and Activities - 8a (PROMIS-APS 8a) [Baseline (Day 1), Days 15, 29, and 43]: 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.
• Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) [Baseline (Day 1), Days 29 and 43]: 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.
• DB Treatment Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) [From start of treatment (Day 1) up to Day 43]: 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).
• Follow-up (FU) Phase: Percentage of Participants With AEs [From Day 44 up to Day 57]: 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.

Sex: All, ages: 18 Years to 74 Years

Inclusion Criteria:

* Be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening and baseline
* Have a Hamilton Depression Rating Scale 17 item (HDRS-17) total score of 20 or higher at the first and second screening interviews and must not demonstrate a clinically significant improvement between the first and the second independent HDRS-17 assessments
* Meet Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) diagnostic criteria for recurrent or single episode 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). Participants 65 years of age or older must have had the first onset of depression prior to 55 years of age
* Have had an inadequate response to at least 1 oral antidepressant treatment, administered at an adequate dose (at or above the minimum therapeutic dose per Massachusetts General Hospital Antidepressant Treatment Response Questionnaire \[MGH ATRQ\]) and duration (at least 6 weeks) in the current episode of depression. An inadequate response is defined as less than(<) 50% reduction in depressive symptom severity but with some improvement (>0%) (ie, there may be minimal to moderate symptomatic improvement since the initiation of treatment, but some of the initial symptoms are still present, troubling to the participant and affecting behavior and function), as assessed by the MGH ATRQ
* Is currently 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 approved formulation and available in the participating country/territory: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine at a stable dose for at least 6 weeks. The current antidepressant cannot be the first antidepressant treatment for the first lifetime episode of depression
* Participant's current major depressive episode, and antidepressant treatment response in the current depressive episode, must all be confirmed by the site independent qualification assessment

Exclusion Criteria:

* Have had in the current depressive episode, no response (treatment failure) to 5 or more antidepressant treatments including the current SSRI/SNRI (that is, the one presumed to be continued in the treatment phase) assessed using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ)
* Has a history or evidence of clinically meaningful noncompliance with current antidepressant therapy
* Has a history of moderate-to-severe substance use disorder including alcohol use disorder according to DSM-5 criteria within 6 months before screening
* Has had in the current episode an inadequate response to adequate course of intravenous or intranasal ketamine or esketamine, electroconvulsive therapy, vagal nerve stimulation, or deep brain stimulation device
* Has current, or a history (past 6 months), of seizures
* Has a current homicidal ideation/intent, per the investigator's clinical judgment, or has suicidal ideation with some intent to act within 3 months prior to the start of the Screening Phase, per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS), corresponding to a response of "Yes" on Item 4 or Item 5, or a history of suicidal behavior within the past 6 months prior to the start of the Screening Phase. Participants reporting suicidal ideation with intent to act or suicidal behavior at baseline should be excluded
* Has one or more of the following diagnoses: a) A DSM-5 diagnosis (which has been the primary focus of psychiatric treatment within the past 2 years) of any of the following: panic disorder, generalized anxiety disorder, social anxiety disorder, specific phobia; b) A current (in the past year) DSM-5 diagnosis of: obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), anorexia nervosa, bulimia nervosa; c) A current or prior (lifetime) DSM-5 diagnosis of: a psychotic disorder or MDD with psychotic features, bipolar or related disorders, intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, narcissistic personality disorders, somatoform disorders

Participant flow

Outcome results

• Change From Baseline to Day 43 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Primary), Least squares mean, Units on a scale: Placebo -11.4 +/- 0.98; Aticaprant 10 mg -12.3 +/- 0.95 (p =0.467)
• Change From Baseline to Day 43 in Dimensional Anhedonia Rating Scale (DARS) Total Score (Secondary), Least squares mean, Units on a scale: Placebo 10.5 +/- 1.50; Aticaprant 10 mg 12.0 +/- 1.43
• Change From Baseline Over Time in MADRS Total Score (Secondary), Least squares mean, Units on a scale: Placebo -5.4 +/- 0.76; Aticaprant 10 mg -6.6 +/- 0.72
• Percentage of Participants Who Achieved Response on Depressive Symptoms Scale Based on MADRS Total Score at Day 43 (Secondary), Number, Percentage of participants: Placebo 22.8; Aticaprant 10 mg 29.4
• Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score at Day 43 (Secondary), Number, Percentage of participants: Placebo 12.6; Aticaprant 10 mg 17.6
• Change From Baseline to Day 43 in Patient Health Questionnaire, 9-Item (PHQ-9) Total Score (Secondary), Least squares mean, Units on a scale: Placebo -5.9 +/- 0.58; Aticaprant 10 mg -6.7 +/- 0.55
• Change From Baseline Over Time in DARS Total Score (Secondary), Least squares mean, Units on a scale: Placebo 4.8 +/- 1.22; Aticaprant 10 mg 5.9 +/- 1.20
• Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) (Secondary), Mean, Units on a scale: Placebo -0.4 +/- 1.04; Aticaprant 10 mg -0.5 +/- 1.07
• Percentage of Participants With a Score Less Than (<) 2 in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) at Day 43 (Secondary), Number, Percentage of participants: Placebo 41.2; Aticaprant 10 mg 52.3
• Change From Baseline Over Time in Patient Reported Outcomes Measurement Information System Short Form - Ability to Participate in Social Roles and Activities - 8a (PROMIS-APS 8a) (Secondary), Least squares mean, T-score: Placebo 2.3 +/- 0.48; Aticaprant 10 mg 2.6 +/- 0.46
• Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) (Secondary), Least squares mean, Percent Change: Placebo -5.8 +/- 4.59; Aticaprant 10 mg -14.2 +/- 4.71
• DB Treatment Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) (Secondary), Number, Percentage of participants: DB: Placebo 39.5; DB: Aticaprant 10 mg 45.8
• Follow-up (FU) Phase: Percentage of Participants With AEs (Secondary), Number, Percentage of participants: FU: Placebo 8.3; FU: Aticaprant 10 mg 7.1

Adverse events

Time frame: DB treatment phase: start of treatment (Day 1) up to Day 43, FU Phase: From Day 44 up to Day 57

Serious adverse events by term

Other adverse events by term

20 more sites not listed.

• Study Protocol (PDF, 2024-01-26)
• Statistical Analysis Plan (PDF, 2024-08-08)

• Janssen Research & Development, LLC Clinical Trial, Study director, Janssen Research & Development, LLC