Major Depressive Disorder, Recurrent
Conditions
Keywords
Current depressive episode, moderate to severe
Brief summary
The purpose of this study is to evaluate the safety and efficacy of filorexant (MK-6096) versus placebo as adjunctive treatment for major depressive disorder (MDD), in participants who are partial responders to antidepressant monotherapy with one of identified selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or bupropion. The primary hypothesis of the study is that filorexant is superior to placebo as augmentation therapy with respect to change from baseline to Week 6 in the Montgomery Asberg Depression Rating Scale (MADRS) total score.
Detailed description
Participants will continue to take their pretrial antidepressant medication as prescribed throughout the trial. Participants will be randomized in a 1:1 ratio to receive filorexant or placebo for a 6-week treatment period. Following completion of the treatment period, participants will enter a 2-week double-blind run-out period. During the run-out period, participants who received placebo in the 6-week treatment period will continue to receive placebo and participants who received filorexant in the 6-week treatment period will be randomized to receive either filorexant or placebo in a 1:1 ratio.
Interventions
DRUGFilorexant
Filorexant, one 10 mg tablet, orally, once daily at bedtime
DRUGPlacebo
Placebo, one tablet, orally, once daily at bedtime
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Participant is (a) male or (b) female and not of reproductive potential, or (c) female of reproductive potential has a serum beta-hCG level consistent with the nongravid state at screening and agrees to use acceptable contraception; * Current primary diagnosis of recurrent major depressive disorder, without psychotic features, with a current moderate or severe depressive episode; * Duration of the current major depressive episode must be at least 2 months but no more than 18 months at Screening; * Participant has undergone an adequate trial of an antidepressant (one of identified SSRIs or SNRIs, or bupropion) for the current depressive episode. Key
Exclusion criteria
* Current primary psychiatric diagnosis other than major depression; * Lifetime diagnosis of bipolar disorder, schizophrenia, schizoaffective disorder, or other psychotic disorder; * Alcohol or other substance abuse or dependence (excluding nicotine); * Clinically significant abnormality or disease of the central nervous system (including dementia and other cognitive disorders or traumatic brain injury); * Imminent risk of self-harm or of harm to others; * Participant is a psychiatric inpatient; * Participant has been on continuous antidepressant treatment for \>18 months prior to Screening visit; * Inadequate response to more than 3 adequate antidepressant trials (including the current antidepressant treatment trial) for treatment of the current depressive episode; * Participant ever received electroconvulsive therapy, transcranial magnetic stimulation, or vagal nerve stimulation for treatment of depression; * History of narcolepsy, cataplexy, circadian rhythm disorder, parasomnia, sleep-related breathing disorder, restless legs syndrome, periodic limb movement disorder, excessive daytime sleepiness or difficulty sleeping due to a medical condition; * Clinical, laboratory, or electrocardiogram (ECG) evidence of significant systemic disease; * Cardiovascular event (e.g., myocardial infarction) or procedure (e.g., coronary artery bypass surgery) within 3 months of study; * History of malignancy ≤5 years prior to study, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer; * Body Mass Index \>40 kg/m\^2; * Pregnancy, breast-feeding, or expecting to become pregnant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued Study Drug Due to an AE During Run-out Phase | From first run-out dose (following Week 6 visit) up to Week 8 (2 weeks) | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) or a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants who discontinued study drug treatment due to an AE during the 2-week run-out phase are counted once in this summary. |
| Number of Participants With an Adverse Event (AE) During Treatment Phase | Up to Week 6 | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants with one or more AEs during the treatment phase (up to study Week 6) are counted once in this summary. |
| Number of Participants Who Discontinued Study Drug Due to an AE During Treatment Phase | Up to Week 6 | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants who discontinued study drug treatment due to an AE during the treatment phase (up to study Week 6) are counted once in this summary. |
| Number of Participants With an AE During Run-out Phase | From first run-out dose (following Week 6 visit) up to 14 days after last dose of study drug (approximately 4 weeks) | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants with one or more AEs during the 2-week run-out phase and/or during the 2-week follow up after the last dose of study drug, are counted once in this summary. |
| Change From Baseline to Week 6 in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | Baseline and Week 6 | The MADRS is a 10-item clinician-rated instrument for evaluating severity of symptoms of depression. Each item is rated on a scale from 0 to 6, with total scores ranging from 0 to 60; higher scores correspond to greater symptom severity. The reported measure is the mean change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score | Baseline and Week 6 | The HAM-D, an instrument for evaluating severity of symptoms of depression, was completed by the participant. The instrument used in this study was the 17-item version (HAM-D17). The Bech subscale of the HAM-D17 is composed of 6 identified items out of the 17 items rated. Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4). Total score ranged from 0 to 22, with a higher score indicating greater symptom severity. The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), work and interests, psychomotor retardation, and anxiety (psychic). The following symptom was rated on a 3-point scale (0-2): somatic symptoms (general). The reported measure is the change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values. |
| Percentage of Participants With HAM-D17 Remission (HAM-D17 Total Score ≤7) at Week 6 | Week 6 | The HAM-D, an instrument for evaluating severity of symptoms of depression, was completed by the participant. The instrument used in this study was the 17-item version (HAM-D17). Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4), with higher scores indicating greater symptom severity. Total score ranged from 0 to 54. The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), suicidal thoughts, work and interests, psychomotor retardation, psychomotor agitation, anxiety (psychic), anxiety (somatic), and hypochondriasis (somatization). The following symptoms were rated on a 3-point scale (0-2): insomnia (initial), insomnia (middle), insomnia (late), gastrointestinal symptoms (appetite), somatic symptoms (general), sexual disturbances, insight, and weight loss. A participant with HAM-D17 total score ≤7 at Week 6 of the Treatment Phase was defined to have achieved HAM-D17 remission. |
| Change From Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item | Baseline and Week 6 | The MADRS is a 10-item clinician-rated instrument for evaluating severity of symptoms of depression. Each item is rated on a scale from 0 to 6, with higher scores indicating greater symptom severity. The total score ranged from 0 to 54, with higher scores corresponding to greater symptom severity. This measure considered 9 of the 10 MADRS items: apparent sadness, reported sadness, inner tension, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. It excluded reduced sleep. The reported measure is the mean change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values. |
Participant flow
Recruitment details
One participant in the Filorexant 10 mg (Treatment Phase) arm did not receive study drug and was discontinued from the study; the reason given for discontinuation is given as non-compliance with study drug.
Pre-assignment details
During the 1-2 week screening period participants will be evaluated to determine if they meet study entry criteria. The screening period will serve as a wash-out period for participants taking prohibited medications.
Participants by arm
| Arm | Count |
|---|---|
| Filorexant 10 mg (Treatment Phase) Treatment Phase: Participants in this group were administered filorexant 10 mg once daily at bedtime for 6 weeks. | 65 |
| Placebo (Treatment Phase) Treatment Phase: Participants in this group were administered placebo once daily at bedtime for 6 weeks. | 64 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Run-out Phase | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
| Treatment Phase | Adverse event, non-fatal | 1 | 1 | 0 | 0 | 0 |
| Treatment Phase | Lack of Efficacy | 0 | 1 | 0 | 0 | 0 |
| Treatment Phase | Lost to Follow-up | 3 | 0 | 0 | 0 | 0 |
| Treatment Phase | Non-compliance with study drug | 1 | 0 | 0 | 0 | 0 |
| Treatment Phase | Physician Decision | 1 | 1 | 0 | 0 | 0 |
| Treatment Phase | Protocol Violation | 1 | 2 | 0 | 0 | 0 |
| Treatment Phase | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Filorexant 10 mg (Treatment Phase) | Placebo (Treatment Phase) | Total |
|---|---|---|---|
| Age, Continuous | 47.8 Years STANDARD_DEVIATION 12.4 | 50.0 Years STANDARD_DEVIATION 10.3 | 48.9 Years STANDARD_DEVIATION 11.4 |
| Sex: Female, Male Female | 40 Participants | 42 Participants | 82 Participants |
| Sex: Female, Male Male | 25 Participants | 22 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 64 | 7 / 64 | 3 / 29 | 1 / 28 | 1 / 59 |
| serious Total, serious adverse events | 1 / 64 | 0 / 64 | 0 / 29 | 0 / 28 | 1 / 59 |
Outcome results
Primary
Change From Baseline to Week 6 in Montgomery Asberg Depression Rating Scale (MADRS) Total Score
The MADRS is a 10-item clinician-rated instrument for evaluating severity of symptoms of depression. Each item is rated on a scale from 0 to 6, with total scores ranging from 0 to 60; higher scores correspond to greater symptom severity. The reported measure is the mean change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values.
Time frame: Baseline and Week 6
Population: Full Analysis Set (FAS) - population included participants who took ≥1 dose of study drug and had a baseline and Week 6 value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Change From Baseline to Week 6 in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | Baseline | 30.3 score on a scale | Standard Deviation 4.6 |
| Filorexant 10 mg (Treatment Phase) | Change From Baseline to Week 6 in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | Change at Week 6 | -11 score on a scale | Standard Deviation 9.5 |
| Placebo (Treatment Phase) | Change From Baseline to Week 6 in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | Baseline | 31 score on a scale | Standard Deviation 4.3 |
| Placebo (Treatment Phase) | Change From Baseline to Week 6 in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | Change at Week 6 | -10.3 score on a scale | Standard Deviation 8.2 |
Comparison: Number of participants included for calculation of mean ± SD baseline and mean ± SD change from baseline MADRS Total Score is 119. Constrained longitudinal data analysis (cLDA) model uses efficacy Full Analysis Set (FAS) population (number of participants: filorexant 10 mg - 64, placebo - 64; total number of participants in cLDA analysis - 128).p-value: 0.67995% CI: [-3.8, 2.5]cLDA
Primary
Number of Participants Who Discontinued Study Drug Due to an AE During Run-out Phase
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) or a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants who discontinued study drug treatment due to an AE during the 2-week run-out phase are counted once in this summary.
Time frame: From first run-out dose (following Week 6 visit) up to Week 8 (2 weeks)
Population: All Participants as Treated (APaT): Population includes participants who took ≥1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Number of Participants Who Discontinued Study Drug Due to an AE During Run-out Phase | 0 Participants |
| Placebo (Treatment Phase) | Number of Participants Who Discontinued Study Drug Due to an AE During Run-out Phase | 0 Participants |
| Placebo/Placebo (Run-out Phase) | Number of Participants Who Discontinued Study Drug Due to an AE During Run-out Phase | 0 Participants |
Primary
Number of Participants Who Discontinued Study Drug Due to an AE During Treatment Phase
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants who discontinued study drug treatment due to an AE during the treatment phase (up to study Week 6) are counted once in this summary.
Time frame: Up to Week 6
Population: All Participants as Treated (APaT): Population includes participants who took ≥1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Number of Participants Who Discontinued Study Drug Due to an AE During Treatment Phase | 1 Participants |
| Placebo (Treatment Phase) | Number of Participants Who Discontinued Study Drug Due to an AE During Treatment Phase | 1 Participants |
Comparison: Estimated parameter is between-group difference in percentage of participants discontinued from study drug due to an AE = percentage (filorexant 10 mg) - percentage (placebo).95% CI: [-7, 7]
Primary
Number of Participants With an Adverse Event (AE) During Treatment Phase
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants with one or more AEs during the treatment phase (up to study Week 6) are counted once in this summary.
Time frame: Up to Week 6
Population: All Participants as Treated (APaT): Population includes participants who took ≥1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Number of Participants With an Adverse Event (AE) During Treatment Phase | 27 Participants |
| Placebo (Treatment Phase) | Number of Participants With an Adverse Event (AE) During Treatment Phase | 17 Participants |
Comparison: Estimated parameter is between-group difference in percentage of participants with an AE = percentage (filorexant 10 mg) - percentage (placebo) for participants with one or more AE.95% CI: [-0.9, 31.4]
Primary
Number of Participants With an AE During Run-out Phase
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants with one or more AEs during the 2-week run-out phase and/or during the 2-week follow up after the last dose of study drug, are counted once in this summary.
Time frame: From first run-out dose (following Week 6 visit) up to 14 days after last dose of study drug (approximately 4 weeks)
Population: All Participants as Treated (APaT): Population includes participants who took ≥1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Number of Participants With an AE During Run-out Phase | 6 Participants |
| Placebo (Treatment Phase) | Number of Participants With an AE During Run-out Phase | 3 Participants |
| Placebo/Placebo (Run-out Phase) | Number of Participants With an AE During Run-out Phase | 9 Participants |
Secondary
Change From Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item
The MADRS is a 10-item clinician-rated instrument for evaluating severity of symptoms of depression. Each item is rated on a scale from 0 to 6, with higher scores indicating greater symptom severity. The total score ranged from 0 to 54, with higher scores corresponding to greater symptom severity. This measure considered 9 of the 10 MADRS items: apparent sadness, reported sadness, inner tension, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. It excluded reduced sleep. The reported measure is the mean change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values.
Time frame: Baseline and Week 6
Population: Full Analysis Set (FAS) - population included participants who took ≥1 dose of study drug and had a baseline and Week 6 MADRS score.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Change From Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item | Baseline | 26.5 score on a scale | Standard Deviation 4.1 |
| Filorexant 10 mg (Treatment Phase) | Change From Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item | Change at Week 6 | -9.5 score on a scale | Standard Deviation 8.5 |
| Placebo (Treatment Phase) | Change From Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item | Baseline | 27.2 score on a scale | Standard Deviation 4.1 |
| Placebo (Treatment Phase) | Change From Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item | Change at Week 6 | -9.1 score on a scale | Standard Deviation 7.4 |
Comparison: Pairwise Comparison: Filorexant 10 mg vs. Placebop-value: 0.8295% CI: [-3.2, 2.5]cLDA
Secondary
Change From Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score
The HAM-D, an instrument for evaluating severity of symptoms of depression, was completed by the participant. The instrument used in this study was the 17-item version (HAM-D17). The Bech subscale of the HAM-D17 is composed of 6 identified items out of the 17 items rated. Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4). Total score ranged from 0 to 22, with a higher score indicating greater symptom severity. The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), work and interests, psychomotor retardation, and anxiety (psychic). The following symptom was rated on a 3-point scale (0-2): somatic symptoms (general). The reported measure is the change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values.
Time frame: Baseline and Week 6
Population: Full Analysis Set (FAS) - population included participants who took ≥1 dose of study drug and had a baseline and Week 6 HAM-D17 Beck Subscale score.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Change From Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score | Baseline | 13.1 score on a scale | Standard Deviation 2.4 |
| Filorexant 10 mg (Treatment Phase) | Change From Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score | Change at Week 6 | -4.7 score on a scale | Standard Deviation 4.8 |
| Placebo (Treatment Phase) | Change From Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score | Baseline | 13.0 score on a scale | Standard Deviation 2.1 |
| Placebo (Treatment Phase) | Change From Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score | Change at Week 6 | -4.2 score on a scale | Standard Deviation 4 |
Comparison: Pairwise Comparison: Filorexant 10 mg vs. Placebop-value: 0.70195% CI: [-1.9, 1.3]cLDA
Secondary
Percentage of Participants With HAM-D17 Remission (HAM-D17 Total Score ≤7) at Week 6
The HAM-D, an instrument for evaluating severity of symptoms of depression, was completed by the participant. The instrument used in this study was the 17-item version (HAM-D17). Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4), with higher scores indicating greater symptom severity. Total score ranged from 0 to 54. The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), suicidal thoughts, work and interests, psychomotor retardation, psychomotor agitation, anxiety (psychic), anxiety (somatic), and hypochondriasis (somatization). The following symptoms were rated on a 3-point scale (0-2): insomnia (initial), insomnia (middle), insomnia (late), gastrointestinal symptoms (appetite), somatic symptoms (general), sexual disturbances, insight, and weight loss. A participant with HAM-D17 total score ≤7 at Week 6 of the Treatment Phase was defined to have achieved HAM-D17 remission.
Time frame: Week 6
Population: Full Analysis Set (FAS) - population included participants who took ≥1 dose of study drug and had a baseline and Week 6 HAM-D17 score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Filorexant 10 mg (Treatment Phase) | Percentage of Participants With HAM-D17 Remission (HAM-D17 Total Score ≤7) at Week 6 | 21.4 percentage of participants |
| Placebo (Treatment Phase) | Percentage of Participants With HAM-D17 Remission (HAM-D17 Total Score ≤7) at Week 6 | 9.8 percentage of participants |
Comparison: Pairwise Comparison: Filorexant 10 mg vs. Placebop-value: 0.096595% CI: [0.8, 7.3]Generalized Linear Mixed Effects Model