Major Depressive Disorder
Conditions
Brief summary
This study will evaluate the efficacy of ALKS 5461 when administered daily for 4 weeks to adults with Major Depressive Disorder (MDD) and inadequate response to antidepressant therapy.
Detailed description
The study will measure efficacy using the HAM-D-17, the MADRS, and the CGI-S as well as using other scales and assessments.
Interventions
DRUGALKS 5461
Two active tablets, given daily
DRUGPlacebo
Two placebo tablets, given daily
Sponsors
Alkermes, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with a major depressive episode (MDE) * Body mass index less than or equal to 40 kg/m2 * Have been treated with an adequate dose of SSRI/SNRI during the current MDE for at least 8 weeks, with the same, adequate dose over the last 4 weeks that is expected to remain stable throughout the study * History of inadequate response during the entire current MDE to 1 or 2 adequate antidepressant treatments, including current treatment * Be otherwise physically healthy
Exclusion criteria
* Have an axis I diagnosis of delirium, dementia, amnestic or other cognitive disorder, schizophrenia or other psychotic disorder, bipolar I or II disorder, eating disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder, or posttraumatic stress disorder * Have a clinically significant current axis II diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder * Are experiencing hallucinations, delusions, or any psychotic symptomatology in the current MDE * Receive new onset psychotherapy within 6 weeks of screening * Use of opioid agonists (eg, codeine, oxycodone, morphine) within 14 days before screening * Have received electroconvulsive therapy during the current MDE * Have attempted suicide within the past 2 years * Have a thyroid pathology * Have a history of a seizure disorder or of neuroleptic malignant syndrome/serotonin syndrome * Have a positive test for human immunodeficiency virus (HIV) Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score | Baseline and 4 weeks for each stage | The HAM-D17 scale is a clinician-administered questionnaire comprised of 17 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | 4 weeks for each stage | The proportion of subjects demonstrating HAM-D17 treatment response, defined as a ≥ 50% reduction in HAM-D17 score from baseline to the end of the efficacy period (Week 4). The HAM-D17 is a clinician administered questionnaire comprised of 17 questions used to assess the severity of a patient's depression. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation. |
| Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | 4 weeks for each stage | The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms). Individual questionnaire items include: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. |
| Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score | 4 weeks for each stage | The CGI-S is a 7-point scale that requires the clinician to assess how mentally ill the patient is at a specific point in time. Based on the scale, patients are categorized as follows: 1: normal, not at all ill; 2: borderline mentally ill; 3: mildly ill; 4: moderately ill; 5: markedly ill; 6: severely ill; and 7: among the most extremely ill patients. |
Countries
United States
Participant flow
Recruitment details
Subjects were diagnosed with major depressive disorder (MDD) and had an inadequate response to 1 or 2 adequate courses of treatment with a commercially available antidepressant therapy (ADT) during the current major depressive episode (MDE). All subjects continued ADT for the duration of the study.
Pre-assignment details
This was a Sequential Parallel Comparison Design (SPCD) study comprised of 2 stages. In Stage 1 subjects were randomized to ALKS 5461 or placebo (2:2:9). In Stage 2 only placebo non-responders from Stage 1 were re-randomized to ALKS 5461 or placebo (1:1:1). One subject randomized to placebo did not receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo S1 Received placebo in Stage 1 | 98 |
| ALKS 5461 2mg/2mg S1 Received ALKS 5461 2mg/2mg in Stage 1 | 24 |
| ALKS 5461 8mg/8mg S1 Received ALKS 5461 8mg/8mg in Stage 1 | 19 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Stage 1 | Adverse Event | 1 | 4 | 5 | 0 | 0 | 0 |
| Stage 1 | Lost to Follow-up | 2 | 2 | 1 | 0 | 0 | 0 |
| Stage 1 | Noncompliance with Study Drug | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Withdrawal by Subject | 3 | 0 | 0 | 0 | 0 | 0 |
| Stage 2 | Adverse Event | 0 | 0 | 0 | 0 | 5 | 4 |
Baseline characteristics
| Characteristic | Placebo S1 | Total | ALKS 5461 8mg/8mg S1 | ALKS 5461 2mg/2mg S1 |
|---|---|---|---|---|
| Age, Continuous | 46.6 years STANDARD_DEVIATION 11 | 46.3 years STANDARD_DEVIATION 11.1 | 45.8 years STANDARD_DEVIATION 11.9 | 45.2 years STANDARD_DEVIATION 10.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 38 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 74 Participants | 102 Participants | 13 Participants | 15 Participants |
| Region of Enrollment United States | 98 Count of participants | 141 Count of participants | 19 Count of participants | 24 Count of participants |
| Sex: Female, Male Female | 68 Participants | 96 Participants | 11 Participants | 17 Participants |
| Sex: Female, Male Male | 30 Participants | 45 Participants | 8 Participants | 7 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 24 | 0 / 19 | 0 / 20 | 0 / 23 | 0 / 22 |
| other Total, other adverse events | 42 / 98 | 15 / 24 | 18 / 19 | 11 / 20 | 19 / 23 | 17 / 22 |
| serious Total, serious adverse events | 1 / 98 | 1 / 24 | 0 / 19 | 0 / 20 | 1 / 23 | 0 / 22 |
Outcome results
Primary
Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score
The HAM-D17 scale is a clinician-administered questionnaire comprised of 17 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.
Time frame: Baseline and 4 weeks for each stage
Population: Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline HAM-D17 assessment in the respective stage. Two subjects randomized to 8/8 in Stage 1 received 2/2. These subjects are included in the 8/8 group for efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo S1 | Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score | -7.1 score on a scale | Standard Error 0.6 |
| ALKS 5461 2mg/2mg S1 | Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score | -9.3 score on a scale | Standard Error 1.5 |
| ALKS 5461 8mg/8mg S1 | Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score | -6.6 score on a scale | Standard Error 1.6 |
| Placebo S2 | Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score | -1.5 score on a scale | Standard Error 1.1 |
| ALKS 5461 2mg/2mg S2 | Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score | -5.2 score on a scale | Standard Error 1.2 |
| ALKS 5461 8mg/8mg S2 | Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score | -3.3 score on a scale | Standard Error 1.1 |
Comparison: Analysis was conducted for each stage separately and overall efficacy was based on combined stage analysis where stage-specific estimates were combined using pre-specified weights (0.6/0.4 for Stage 1/Stage 2). Within each stage ALKS 5461 2mg/2mg was compared to placebo (i.e., ALKS 5461 2mg/2mg S1 vs Placebo S1; and ALKS 5461 2mg/2mg S2 vs Placebo S2.p-value: 0.014Mixed Models Analysis
Comparison: Analysis was conducted for each stage separately and overall efficacy was based on combined stage analysis where stage-specific estimates were combined using pre-specified weights (0.6/0.4 for Stage 1/Stage 2). Within each stage ALKS 5461 8mg/8mg was compared to placebo (i.e., ALKS 5461 8mg/8mg S1 vs Placebo S1; and ALKS 5461 8mg/8mg S2 vs Placebo S2.p-value: 0.699Mixed Models Analysis
Secondary
Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score
The CGI-S is a 7-point scale that requires the clinician to assess how mentally ill the patient is at a specific point in time. Based on the scale, patients are categorized as follows: 1: normal, not at all ill; 2: borderline mentally ill; 3: mildly ill; 4: moderately ill; 5: markedly ill; 6: severely ill; and 7: among the most extremely ill patients.
Time frame: 4 weeks for each stage
Population: Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline HAM-D17 assessment in the respective stage. Two subjects randomized to 8/8 in Stage 1 received 2/2. These subjects are included in the 8/8 group for efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo S1 | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score | -1.0 score on a scale | Standard Error 0.1 |
| ALKS 5461 2mg/2mg S1 | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score | -1.3 score on a scale | Standard Error 0.2 |
| ALKS 5461 8mg/8mg S1 | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score | -1.2 score on a scale | Standard Error 0.3 |
| Placebo S2 | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score | -0.5 score on a scale | Standard Error 0.2 |
| ALKS 5461 2mg/2mg S2 | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score | -1.1 score on a scale | Standard Error 0.2 |
| ALKS 5461 8mg/8mg S2 | Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score | -0.6 score on a scale | Standard Error 0.2 |
Secondary
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score
The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms). Individual questionnaire items include: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts.
Time frame: 4 weeks for each stage
Population: Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline HAM-D17 assessment in the respective stage. Two subjects randomized to 8/8 in Stage 1 received 2/2. These subjects are included in the 8/8 group for efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo S1 | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -9.6 score on a scale | Standard Error 0.9 |
| ALKS 5461 2mg/2mg S1 | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -13.3 score on a scale | Standard Error 2.2 |
| ALKS 5461 8mg/8mg S1 | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -11.3 score on a scale | Standard Error 2.3 |
| Placebo S2 | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -2.1 score on a scale | Standard Error 1.6 |
| ALKS 5461 2mg/2mg S2 | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -8.8 score on a scale | Standard Error 1.7 |
| ALKS 5461 8mg/8mg S2 | Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -4.7 score on a scale | Standard Error 1.7 |
Secondary
Proportion of Patients Who Exhibited Treatment Response (HAM-D17)
The proportion of subjects demonstrating HAM-D17 treatment response, defined as a ≥ 50% reduction in HAM-D17 score from baseline to the end of the efficacy period (Week 4). The HAM-D17 is a clinician administered questionnaire comprised of 17 questions used to assess the severity of a patient's depression. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.
Time frame: 4 weeks for each stage
Population: Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline HAM-D17 assessment in the respective stage.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo S1 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | No | 67 Participants |
| Placebo S1 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | Yes | 23 Participants |
| ALKS 5461 2mg/2mg S1 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | Yes | 8 Participants |
| ALKS 5461 2mg/2mg S1 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | No | 9 Participants |
| ALKS 5461 8mg/8mg S1 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | Yes | 5 Participants |
| ALKS 5461 8mg/8mg S1 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | No | 9 Participants |
| Placebo S2 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | Yes | 3 Participants |
| Placebo S2 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | No | 17 Participants |
| ALKS 5461 2mg/2mg S2 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | Yes | 6 Participants |
| ALKS 5461 2mg/2mg S2 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | No | 12 Participants |
| ALKS 5461 8mg/8mg S2 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | No | 13 Participants |
| ALKS 5461 8mg/8mg S2 | Proportion of Patients Who Exhibited Treatment Response (HAM-D17) | Yes | 5 Participants |