Anhedonia, Depressive Disorder, Major
Conditions
Brief summary
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).
Detailed description
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.
Interventions
DRUGAticaprant
Aticaprant will be administered orally as tablets.
OTHERPlacebo
Placebo will be administered orally as tablets.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Czechia, Hungary, Italy, Poland, Portugal, Spain, Sweden, United States
Participant flow
Pre-assignment details
Adult participants aged 18 to 64 years who had major depressive disorder (MDD) with or without moderate-to-severe anhedonia (ANH+ or ANH-) and elderly participants aged 65 to 74 years with MDD (ANH+ and ANH-) who had an inadequate response to an ongoing antidepressant therapy were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo During DB treatment phase, participants received placebo matching to aticaprant tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149). | 258 |
| Aticaprant 10 mg During DB treatment phase, participants received aticaprant 10 mg tablet orally once daily from Day 1 to Day 42 in addition to the ongoing antidepressant therapy (SSRI/SNRI). Participants were then followed up for safety up to 7 to 14 days after end of DB phase at Day 43 (up to Day 57). Participants who completed the DB phase (at Day 43) and were compliant to the study intervention were eligible to participate in a separate 52-week open-label long-term safety study 67953964MDD3003 (NCT05518149). | 253 |
| Total | 511 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | Non-Compliant with study drug | 0 | 1 |
| Overall Study | Other | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Randomized but not treated | 1 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Aticaprant 10 mg |
|---|---|---|---|
| Age, Continuous | 51.4 Years STANDARD_DEVIATION 13.3 | 50.8 Years STANDARD_DEVIATION 13.73 | 50.2 Years STANDARD_DEVIATION 14.6 |
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Between 18 and 64 years | 213 Participants | 425 Participants | 212 Participants |
| Age, Customized Between 65 to 74 years | 45 Participants | 86 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 73 Participants | 144 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 179 Participants | 355 Participants | 176 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 12 Participants | 6 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 25 Participants | 49 Participants | 24 Participants |
| Race/Ethnicity, Customized Missing or Not reported | 3 Participants | 11 Participants | 8 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 5 Participants | 8 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 222 Participants | 435 Participants | 213 Participants |
| Region of Enrollment Argentina | 18 Participants | 34 Participants | 16 Participants |
| Region of Enrollment Australia | 6 Participants | 13 Participants | 7 Participants |
| Region of Enrollment Belgium | 12 Participants | 24 Participants | 12 Participants |
| Region of Enrollment Brazil | 23 Participants | 41 Participants | 18 Participants |
| Region of Enrollment Bulgaria | 17 Participants | 33 Participants | 16 Participants |
| Region of Enrollment Czech Republic | 20 Participants | 38 Participants | 18 Participants |
| Region of Enrollment Hungary | 2 Participants | 6 Participants | 4 Participants |
| Region of Enrollment Italy | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Poland | 14 Participants | 31 Participants | 17 Participants |
| Region of Enrollment Portugal | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Spain | 7 Participants | 16 Participants | 9 Participants |
| Region of Enrollment Sweden | 19 Participants | 37 Participants | 18 Participants |
| Region of Enrollment United States | 116 Participants | 230 Participants | 114 Participants |
| Sex/Gender, Customized Female | 185 Participants | 369 Participants | 184 Participants |
| Sex/Gender, Customized Male | 72 Participants | 141 Participants | 69 Participants |
| Sex/Gender, Customized Undifferentiated | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 258 | 0 / 253 | 0 / 24 | 0 / 14 |
| other Total, other adverse events | 34 / 258 | 54 / 253 | 0 / 24 | 1 / 14 |
| serious Total, serious adverse events | 1 / 258 | 3 / 253 | 0 / 24 | 0 / 14 |
Outcome results
Primary
Change From Baseline to Day 43 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score
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.
Time frame: Baseline (Day 1) to Day 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Day 43 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -11.4 Units on a scale | Standard Error 0.98 |
| Aticaprant 10 mg | Change From Baseline to Day 43 in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score | -12.3 Units on a scale | Standard Error 0.95 |
p-value: =0.46795% CI: [-3.24, 1.49]Mixed Model for Repeated Measures
Secondary
Change From Baseline Over Time in DARS Total Score
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.
Time frame: Baseline (Day 1), Days 15, 29, and 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Over Time in DARS Total Score | At Day 15 | 4.8 Units on a scale | Standard Error 1.22 |
| Placebo | Change From Baseline Over Time in DARS Total Score | At Day 29 | 8.3 Units on a scale | Standard Error 1.38 |
| Placebo | Change From Baseline Over Time in DARS Total Score | At Day 43 | 10.5 Units on a scale | Standard Error 1.5 |
| Aticaprant 10 mg | Change From Baseline Over Time in DARS Total Score | At Day 15 | 5.9 Units on a scale | Standard Error 1.2 |
| Aticaprant 10 mg | Change From Baseline Over Time in DARS Total Score | At Day 29 | 10.0 Units on a scale | Standard Error 1.32 |
| Aticaprant 10 mg | Change From Baseline Over Time in DARS Total Score | At Day 43 | 12.0 Units on a scale | Standard Error 1.43 |
Secondary
Change From Baseline Over Time in MADRS Total Score
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.
Time frame: Baseline (Day 1), Days 15, 29 and 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants analyzed at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Over Time in MADRS Total Score | At Day 15 | -5.4 Units on a scale | Standard Error 0.76 |
| Placebo | Change From Baseline Over Time in MADRS Total Score | At Day 29 | -9.4 Units on a scale | Standard Error 0.9 |
| Placebo | Change From Baseline Over Time in MADRS Total Score | At Day 43 | -11.4 Units on a scale | Standard Error 0.98 |
| Aticaprant 10 mg | Change From Baseline Over Time in MADRS Total Score | At Day 15 | -6.6 Units on a scale | Standard Error 0.72 |
| Aticaprant 10 mg | Change From Baseline Over Time in MADRS Total Score | At Day 29 | -11.1 Units on a scale | Standard Error 0.87 |
| Aticaprant 10 mg | Change From Baseline Over Time in MADRS Total Score | At Day 43 | -12.3 Units on a scale | Standard Error 0.95 |
Secondary
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)
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.
Time frame: Baseline (Day 1), Days 15, 29, and 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants analyzed at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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) | At Day 15 | 2.3 T-score | Standard Error 0.48 |
| Placebo | 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) | At Day 29 | 2.8 T-score | Standard Error 0.54 |
| Placebo | 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) | At Day 43 | 4.3 T-score | Standard Error 0.63 |
| Aticaprant 10 mg | 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) | At Day 15 | 2.6 T-score | Standard Error 0.46 |
| Aticaprant 10 mg | 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) | At Day 29 | 3.9 T-score | Standard Error 0.52 |
| Aticaprant 10 mg | 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) | At Day 43 | 5.5 T-score | Standard Error 0.61 |
Secondary
Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1)
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.
Time frame: Baseline (Day 1), Day 15, Day 29, and Day 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) | At Day 15 | -0.4 Units on a scale | Standard Deviation 1.04 |
| Placebo | Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) | At Day 29 | -0.5 Units on a scale | Standard Deviation 1.04 |
| Placebo | Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) | At Day 43 | -0.7 Units on a scale | Standard Deviation 1.09 |
| Aticaprant 10 mg | Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) | At Day 15 | -0.5 Units on a scale | Standard Deviation 1.07 |
| Aticaprant 10 mg | Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) | At Day 29 | -0.8 Units on a scale | Standard Deviation 1.05 |
| Aticaprant 10 mg | Change From Baseline Over Time in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) | At Day 43 | -1.0 Units on a scale | Standard Deviation 1.09 |
Secondary
Change From Baseline to Day 43 in Dimensional Anhedonia Rating Scale (DARS) Total Score
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.
Time frame: Baseline (Day 1) to Day 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Day 43 in Dimensional Anhedonia Rating Scale (DARS) Total Score | 10.5 Units on a scale | Standard Error 1.5 |
| Aticaprant 10 mg | Change From Baseline to Day 43 in Dimensional Anhedonia Rating Scale (DARS) Total Score | 12.0 Units on a scale | Standard Error 1.43 |
Secondary
Change From Baseline to Day 43 in Patient Health Questionnaire, 9-Item (PHQ-9) Total Score
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.
Time frame: Baseline (Day 1) to Day 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Day 43 in Patient Health Questionnaire, 9-Item (PHQ-9) Total Score | -5.9 Units on a scale | Standard Error 0.58 |
| Aticaprant 10 mg | Change From Baseline to Day 43 in Patient Health Questionnaire, 9-Item (PHQ-9) Total Score | -6.7 Units on a scale | Standard Error 0.55 |
95% CI: [-2.21, 0.52]
Secondary
DB Treatment Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
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).
Time frame: From start of treatment (Day 1) up to Day 43
Population: Safety analysis set included all randomized participants (adults and elderly) who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | DB Treatment Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) | 39.5 Percentage of participants |
| Aticaprant 10 mg | DB Treatment Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) | 45.8 Percentage of participants |
Secondary
Follow-up (FU) Phase: Percentage of Participants With AEs
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.
Time frame: From Day 44 up to Day 57
Population: Follow-up analysis set included all randomized participants who entered the follow-up phase after the double-blind treatment phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Follow-up (FU) Phase: Percentage of Participants With AEs | 8.3 Percentage of participants |
| Aticaprant 10 mg | Follow-up (FU) Phase: Percentage of Participants With AEs | 7.1 Percentage of participants |
Secondary
Percentage of Participants Who Achieved Response on Depressive Symptoms Scale Based on MADRS Total Score 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.
Time frame: At Day 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieved Response on Depressive Symptoms Scale Based on MADRS Total Score at Day 43 | 22.8 Percentage of participants |
| Aticaprant 10 mg | Percentage of Participants Who Achieved Response on Depressive Symptoms Scale Based on MADRS Total Score at Day 43 | 29.4 Percentage of participants |
Secondary
Percentage of Participants With a Score Less Than (<) 2 in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) 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).
Time frame: At Day 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. Here, 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Score Less Than (<) 2 in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) at Day 43 | 41.2 Percentage of participants |
| Aticaprant 10 mg | Percentage of Participants With a Score Less Than (<) 2 in the PHQ-9 Anhedonia-specific Item (PHQ-9, Item 1) at Day 43 | 52.3 Percentage of participants |
Secondary
Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score 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.
Time frame: At Day 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score at Day 43 | 12.6 Percentage of participants |
| Aticaprant 10 mg | Percentage of Participants With Remission of Depressive Symptoms Based on MADRS Total Score at Day 43 | 17.6 Percentage of participants |
Secondary
Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D)
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.
Time frame: Baseline (Day 1), Days 29 and 43
Population: Full analysis set (ANH+) included all adult randomized participants with MDD ANH+ who received at least 1 dose of study intervention. As planned overall work impairment (absenteeism plus presenteeism) and activity impairment is reported. Here, 'N' (overall number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants who were analyzed at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Overall work impairment: Day 29 | -5.8 Percent Change | Standard Error 4.59 |
| Placebo | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Overall work impairment: Day 43 | -13.9 Percent Change | Standard Error 5.07 |
| Placebo | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Activity impairment: Day29 | -9.2 Percent Change | Standard Error 2.12 |
| Placebo | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Activity impairment: Day43 | -13.9 Percent Change | Standard Error 2.28 |
| Aticaprant 10 mg | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Activity impairment: Day43 | -18.1 Percent Change | Standard Error 2.2 |
| Aticaprant 10 mg | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Overall work impairment: Day 29 | -14.2 Percent Change | Standard Error 4.71 |
| Aticaprant 10 mg | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Activity impairment: Day29 | -13.9 Percent Change | Standard Error 2.03 |
| Aticaprant 10 mg | Percent Change From Baseline Over Time in Work Productivity and Activity Impairment: Depression (WPAI:D) | Overall work impairment: Day 43 | -12.9 Percent Change | Standard Error 5.09 |