Major Depressive Disorder
Conditions
Keywords
Alkermes, Major Depressive Disorder, Treatment Refractory MDD, ALKS 5461
Brief summary
This study will evaluate the efficacy, safety, and tolerability of adjunctive ALKS 5461 in adults who have treatment refractory MDD.
Interventions
DRUGALKS 5461
Samidorphan + buprenorphine, administered sublingually
DRUGALKS 5461 Placebo
Placebo tablet, administered sublingually
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 70 Years
Healthy volunteers
No
Inclusion criteria
* Have a Major Depressive Disorder (MDD) primary diagnosis * Have a body mass index (BMI) of 18.0 to \</= 40.0 kg/m\^2 * Be willing and able to follow the study procedures and visits as outlined in the protocol (including agreeing not to enroll in any other clinical trials) * Have inadequate responses to antidepressant therapy (ADT) in the current Major Depressive Episode (MDE) * Additional criteria may apply
Exclusion criteria
* Has any finding that would compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements * Has any other significant medical condition (eg, neurological, psychiatric, or metabolic) or clinical symptom that could unduly risk the subject or affect the interpretation of study data * Has any current primary diagnosis other than MDD, where primary diagnosis is defined as the primary source of current distress and functional impairment * Has experienced hallucinations, delusions, or any psychotic symptoms in the current MDE * Has been hospitalized for MDD within 3 months before screening * Has used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid antagonists (eg, naloxone, naltrexone) within 14 days prior to screening * Has received electroconvulsive therapy treatment within the last 2 years or within the current MDE or failed a course of electroconvulsive treatment at any time * Has a significant risk for suicide * Has a positive breath alcohol test at screening * Has a positive test for drugs of abuse at screening or visit 2 * Is pregnant, planning to become pregnant, or is breastfeeding during the study * Additional criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores | Baseline and 5 weeks for Stage 1, Baseline and 6 weeks for Stage 2 | The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of Major Depressive Disorder (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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | Baseline and 5 weeks for Stage 1, Baseline and 6 weeks for Stage 2 | The percentage of subjects demonstrating a MADRS-10 treatment response, defined as a \>/= 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (Week 5 for Stage 1, Week 6 for Stage 2). The MADRS-10 scale is a measure of the severity of Major Depressive Disorder (MDD) symptoms and includes the following 10 items: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms). |
| Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | 5 weeks for Stage 1, 6 weeks for Stage 2 | The percentage of subjects achieving remission, defined as a subject with a score \</= 10 at the end of the efficacy period (Week 5 for Stage 1, Week 6 for Stage 2). The MADRS-10 scale is a measure of the severity of Major Depressive Disorder (MDD) symptoms and includes the following 10 items: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms).the end of the efficacy period. |
Countries
Australia, Puerto Rico, United States
Participant flow
Recruitment details
Subjects were diagnosed with treatment refractory major depressive disorder (MDD), defined as having at least 2 inadequate responses to commercially available antidepressant therapies (ADTs) during the current major depressive episode (MDE). All subjects continued to take an approved 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. In Stage 2 only placebo non-responders from Stage 1 were re-randomized to ALKS 5461 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| S1: Placebo Randomized to placebo in Stage 1. | 198 |
| S1: ALKS 5461 2mg/2mg Randomized to ALKS 5461 2mg/2mg in Stage 1. | 80 |
| Total | 278 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Stage 1 | Adverse Event | 4 | 12 | 0 | 0 |
| Stage 1 | Identified as a professional patient | 0 | 1 | 0 | 0 |
| Stage 1 | Lack of Efficacy | 0 | 2 | 0 | 0 |
| Stage 1 | Lost to Follow-up | 6 | 1 | 0 | 0 |
| Stage 1 | Withdrawal by Subject | 9 | 0 | 0 | 0 |
| Stage 2 | Adverse Event | 0 | 0 | 2 | 4 |
| Stage 2 | Lack of Efficacy | 0 | 0 | 3 | 0 |
| Stage 2 | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Stage 2 | Physician Decision | 0 | 0 | 0 | 1 |
| Stage 2 | Withdrawal by Subject | 0 | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | S1: Placebo | Total | S1: ALKS 5461 2mg/2mg |
|---|---|---|---|
| Age, Continuous | 44 years | 43 years | 40.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 41 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 167 Participants | 237 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 33 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) White | 160 Participants | 223 Participants | 63 Participants |
| Region of Enrollment Australia | 22 Participants | 30 Participants | 8 Participants |
| Region of Enrollment United States | 176 Participants | 248 Participants | 72 Participants |
| Sex: Female, Male Female | 139 Participants | 196 Participants | 57 Participants |
| Sex: Female, Male Male | 59 Participants | 82 Participants | 23 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 / 198 | 0 / 80 | 0 / 64 | 0 / 63 |
| other Total, other adverse events | 43 / 198 | 56 / 80 | 3 / 64 | 29 / 63 |
| serious Total, serious adverse events | 0 / 198 | 1 / 80 | 1 / 64 | 0 / 63 |
Outcome results
Primary
Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores
The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of Major Depressive Disorder (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: Baseline and 5 weeks for Stage 1, Baseline and 6 weeks for Stage 2
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 MADRS assessment in the respective stage.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| S1: Placebo | Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores | -11.4 score on a scale | Standard Error 0.7 |
| S1: ALKS 5461 2mg/2mg | Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores | -13.9 score on a scale | Standard Error 1.12 |
| S2: Placebo | Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores | -4.2 score on a scale | Standard Error 1.06 |
| S2: ALKS 5461 2mg/2mg | Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores | -4.7 score on a scale | Standard Error 1.11 |
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 equal weights. 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: 0.12895% CI: [-3.5, 0.4]Mixed Models Analysis
Secondary
Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate
The percentage of subjects achieving remission, defined as a subject with a score \</= 10 at the end of the efficacy period (Week 5 for Stage 1, Week 6 for Stage 2). The MADRS-10 scale is a measure of the severity of Major Depressive Disorder (MDD) symptoms and includes the following 10 items: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms).the end of the efficacy period.
Time frame: 5 weeks for Stage 1, 6 weeks for Stage 2
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 MADRS assessment in the respective stage.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| S1: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | Yes | 31 Participants |
| S1: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | No | 164 Participants |
| S1: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | No | 62 Participants |
| S1: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | Yes | 14 Participants |
| S2: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | Yes | 10 Participants |
| S2: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | No | 54 Participants |
| S2: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | Yes | 8 Participants |
| S2: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate | No | 55 Participants |
Secondary
Montgomery Asberg Depression Rating Scale (MADRS) Response Rate
The percentage of subjects demonstrating a MADRS-10 treatment response, defined as a \>/= 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (Week 5 for Stage 1, Week 6 for Stage 2). The MADRS-10 scale is a measure of the severity of Major Depressive Disorder (MDD) symptoms and includes the following 10 items: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms).
Time frame: Baseline and 5 weeks for Stage 1, Baseline and 6 weeks for Stage 2
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 MADRS assessment in the respective stage.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| S1: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | Yes | 53 Participants |
| S1: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | No | 142 Participants |
| S1: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | No | 49 Participants |
| S1: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | Yes | 27 Participants |
| S2: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | Yes | 10 Participants |
| S2: Placebo | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | No | 54 Participants |
| S2: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | Yes | 11 Participants |
| S2: ALKS 5461 2mg/2mg | Montgomery Asberg Depression Rating Scale (MADRS) Response Rate | No | 52 Participants |