A Study of Aticaprant 10 Milligrams (mg) as Adjunctive Therapy in Adult Participants With 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 MDD with ANH+. The total duration of the study will be up to 87 days. Safety evaluation 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 tablet will be administered orally.
• Placebo (Other): Placebo tablet will be administered orally.

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 (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 MADRS Total Score [Baseline (Day 1), Day 15, Day 29, and Day 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. Negative change in MADRS total score indicates improvement.
• 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. Negative change in MADRS total score indicates improvement.
• 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). PHQ-9, item 1 score ranged from 0-3. Higher score indicates more severe disease. Negative change in PHQ-9, item 1 score indicates 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 are scaled on a T-score metric with a mean of 50 and a standard deviation of 10. PROMIS-APS 8a total score ranges from 8 to 40 and T-score ranges from 25.9 to 65.4, a higher score indicates better social functioning. Positive change in score indicates improvement.
• 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. 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. TEAE is defined as any AE occurring at or after the initial administration of study intervention through the end of DB phase.
• Follow-up (FU) Phase: Percentage of Participants With AEs [From Day 44 up to Day 57]: Percentage of participants with AEs during FU phase are reported. 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 (that is, an improvement of more than 20 percent \[%\] on their HDRS-17 total score) 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 structural 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
* 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 (at or above the minimum therapeutic dose per Massachusetts General Hospital Antidepressant Treatment Response Questionnaire \[MGH-ATRQ\] 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 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 diagnostic and statistical manual of mental disorders-5th edition (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 (that is, at least 7 treatments), 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 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent), 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 diagnostic and statistical manual of mental disorders-5th edition (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 major depressive disorder (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 -9.4 +/- 0.96; Aticaprant 10 mg -10.0 +/- 0.96 (p =0.670)
• Change From Baseline to Day 43 in Dimensional Anhedonia Rating Scale (DARS) Total Score (Secondary), Least squares mean, Units on a scale: Placebo 8.2 +/- 1.39; Aticaprant 10 mg 8.8 +/- 1.39
• Change From Baseline Over Time in MADRS Total Score (Secondary), Least squares mean, Units on a scale: Placebo -4.4 +/- 0.75; Aticaprant 10 mg -5.4 +/- 0.74
• Percentage of Participants Who Achieved Response on Depressive Symptoms Scale Based on MADRS Total Score at Day 43 (Secondary), Number, Percentage of participants: Placebo 28.3; Aticaprant 10 mg 27.9
• Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score at Day 43 (Secondary), Number, Percentage of participants: Placebo 16.3; Aticaprant 10 mg 15.8
• 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 -5.5 +/- 0.58; Aticaprant 10 mg -5.2 +/- 0.58
• Change From Baseline Over Time in DARS Total Score (Secondary), Least squares mean, Units on a scale: Placebo 3.5 +/- 1.17; Aticaprant 10 mg 4.2 +/- 1.17
• 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 +/- 0.93; Aticaprant 10 mg -0.6 +/- 1.08
• 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 50.8; Aticaprant 10 mg 46.3
• 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 1.4 +/- 0.54; Aticaprant 10 mg 1.5 +/- 0.55
• DB Treatment Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) (Secondary), Number, Percentage of participants: DB: Placebo 38.1; DB: Aticaprant 10 mg 44.2
• Follow-up (FU) Phase: Percentage of Participants With AEs (Secondary), Number, Percentage of participants: FU: Placebo 0; FU: Aticaprant 10 mg 5.6

Adverse events

Time frame: All cause mortality: DB treatment phase: From screening (-30 days) up to Day 43, FU Phase: From Day 44 up to Day 57; Serious and Other AEs: DB phase: From 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

31 more sites not listed.

• Study Protocol (PDF, 2023-02-22)
• Statistical Analysis Plan (PDF, 2024-10-03)

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