Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder, Depression, Alkermes, ALKS 5461, Samidorphan
Brief summary
This study will evaluate the efficacy and safety of ALKS 5461.
Interventions
DRUGHigh Dose ALKS 5461
Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)
DRUGLow Dose ALKS 5461
Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)
DRUGPlacebo
Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)
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 Body Mass Index (BMI) of 18.0 to 40.0 kg/m2, inclusive * Agree to use an acceptable method of contraception for the duration of the study * Have a Major Depressive Disorder (MDD) primary diagnosis * Have no more than 2 inadequate responses to antidepressant therapy (ADT) in the current Major Depressive Episode (MDE) * Additional criteria may apply
Exclusion criteria
* Have a current primary Axis-I disorder other than MDD * Have used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid antagonists (eg, naloxone, naltrexone) within 14 days * Have received electroconvulsive therapy treatment within the last 2 years or received more than one course of electroconvulsive treatment during lifetime * Have attempted suicide within the past 2 years * Have a positive test for drugs of abuse * Are pregnant, planning to become pregnant, or breastfeeding * Have a history of intolerance, allergy, or hypersensitivity to buprenorphine or opioid antagonists (eg, naltrexone, naloxone) * Have had a significant blood loss or blood donation within 60 days * Additional criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score | Baseline and 5 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | Baseline and 5 weeks for each stage | The proportion of subjects demonstrating MADRS-10 treatment response, defined as a \>/= 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (Week 5). The MADRS-10 scale is a measure of the severity of 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). |
| Remission Rate | Baseline and 5 weeks for each stage | The proportion of subjects achieving remission, defined as a MADRS-10 score of \</= 10 at the end of the efficacy period. |
| Number of Subjects With Adverse Events (AEs) | 5 weeks for Stage 1 and 6 weeks for Stage 2 | — |
Countries
Australia, Canada, 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 the PBO group in Stage 1 did not receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo S1 Randomized to placebo in Stage 1 | 265 |
| ALKS 5461 0.5mg/0.5mg S1 Randomized to ALKS 0.5mg/0.5mg in Stage 1 | 59 |
| ALKS 5461 2mg/2mg S1 Randomized to ALKS 5461 2/2 in Stage 1 | 60 |
| Total | 384 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Stage 1 | Adverse Event | 6 | 4 | 7 | 0 | 0 | 0 |
| Stage 1 | Failure to Meet Eligibility Criteria | 0 | 1 | 0 | 0 | 0 | 0 |
| Stage 1 | Lack of Efficacy | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Lost to Follow-up | 3 | 1 | 0 | 0 | 0 | 0 |
| Stage 1 | Non-compliance with study visits | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Withdrawal by Subject | 3 | 2 | 1 | 0 | 0 | 0 |
| Stage 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Stage 2 | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 0 |
| Stage 2 | Lost to Follow-up | 0 | 0 | 0 | 1 | 1 | 2 |
| Stage 2 | Non-adherence with study visits | 0 | 0 | 0 | 0 | 0 | 1 |
| Stage 2 | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 |
| Stage 2 | Pregnancy | 0 | 0 | 0 | 1 | 0 | 0 |
| Stage 2 | Psychiatrist decision to try new tx | 0 | 0 | 0 | 1 | 0 | 0 |
| Stage 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo S1 | ALKS 5461 0.5mg/0.5mg S1 | ALKS 5461 2mg/2mg S1 | Total |
|---|---|---|---|---|
| Age, Continuous | 45.8 years STANDARD_DEVIATION 11.5 | 45.0 years STANDARD_DEVIATION 13.89 | 46.2 years STANDARD_DEVIATION 12.14 | 45.7 years STANDARD_DEVIATION 11.97 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants | 7 Participants | 4 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 232 Participants | 52 Participants | 56 Participants | 340 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 77 Participants | 16 Participants | 16 Participants | 109 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 | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 182 Participants | 42 Participants | 42 Participants | 266 Participants |
| Region of Enrollment Australia | 15 Participants | 2 Participants | 4 Participants | 21 Participants |
| Region of Enrollment Canada | 32 Participants | 4 Participants | 4 Participants | 40 Participants |
| Region of Enrollment United States | 218 Participants | 53 Participants | 52 Participants | 323 Participants |
| Sex: Female, Male Female | 182 Participants | 38 Participants | 40 Participants | 260 Participants |
| Sex: Female, Male Male | 83 Participants | 21 Participants | 20 Participants | 124 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 / 265 | 0 / 59 | 0 / 60 | 0 / 56 | 0 / 56 | 0 / 56 |
| other Total, other adverse events | 81 / 265 | 32 / 59 | 36 / 60 | 11 / 56 | 13 / 56 | 22 / 56 |
| serious Total, serious adverse events | 1 / 265 | 0 / 59 | 0 / 60 | 0 / 56 | 0 / 56 | 0 / 56 |
Outcome results
Primary
Change From Baseline to Week 5 in the 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: Baseline and 5 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 MADRS-10 assessment in the respective stage.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo S1 | Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -11.1 units on a scale | Standard Error 0.67 |
| ALKS 5461 0.5mg/0.5mg S1 | Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -8.4 units on a scale | Standard Error 1.49 |
| ALKS 5461 2mg/2mg S1 | Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -13.0 units on a scale | Standard Error 1.5 |
| Placebo S2 | Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -2.2 units on a scale | Standard Error 1.08 |
| ALKS 5461 0.5mg/0.5mg S2 | Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -4.8 units on a scale | Standard Error 1.27 |
| ALKS 5461 2mg/2mg S2 | Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score | -3.9 units on a scale | Standard Error 1.13 |
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. The pre-specified order of hypothesis tests was ALKS 5461 2/2 compared to placebo followed by ALKS 5461 0.5mg/0.5mg compared to placebo.p-value: 0.10995% CI: [-4.1, 0.4]Mixed 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 equal weights. Within each stage ALKS 5461 0.5mg/0.5mg was compared to placebo (i.e., ALKS 5461 0.5mg/0.5mg S1 vs Placebo S1; and ALKS 5461 0.5mg/0.5mg S2 vs Placebo S2). The pre-specified order of hypothesis tests was ALKS 5461 2/2 compared to placebo followed by ALKS 5461 0.5/0.5 compared to placebo.p-value: 0.97595% CI: [-2.3, 2.3]Mixed Models Analysis
Secondary
Number of Subjects With Adverse Events (AEs)
Time frame: 5 weeks for Stage 1 and 6 weeks for Stage 2
Population: Safety population consists of all randomized subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo S1 | Number of Subjects With Adverse Events (AEs) | 142 Participants |
| ALKS 5461 0.5mg/0.5mg S1 | Number of Subjects With Adverse Events (AEs) | 34 Participants |
| ALKS 5461 2mg/2mg S1 | Number of Subjects With Adverse Events (AEs) | 41 Participants |
| Placebo S2 | Number of Subjects With Adverse Events (AEs) | 29 Participants |
| ALKS 5461 0.5mg/0.5mg S2 | Number of Subjects With Adverse Events (AEs) | 27 Participants |
| ALKS 5461 2mg/2mg S2 | Number of Subjects With Adverse Events (AEs) | 29 Participants |
Secondary
Proportion of Patients Who Exhibited Treatment Response (MADRS-10)
The proportion of subjects demonstrating MADRS-10 treatment response, defined as a \>/= 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (Week 5). The MADRS-10 scale is a measure of the severity of 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 each stage
Population: Stage 1 Full Analysis Set (FAS) consisted of subjects who took at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 1. Stage 2 FAS consisted of Stage 1 placebo non-responders who entered Stage 2 and who received at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 2.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo S1 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | Yes | 79 Participants |
| Placebo S1 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | No | 177 Participants |
| ALKS 5461 0.5mg/0.5mg S1 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | Yes | 9 Participants |
| ALKS 5461 0.5mg/0.5mg S1 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | No | 49 Participants |
| ALKS 5461 2mg/2mg S1 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | Yes | 20 Participants |
| ALKS 5461 2mg/2mg S1 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | No | 39 Participants |
| Placebo S2 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | Yes | 6 Participants |
| Placebo S2 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | No | 48 Participants |
| ALKS 5461 0.5mg/0.5mg S2 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | Yes | 9 Participants |
| ALKS 5461 0.5mg/0.5mg S2 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | No | 46 Participants |
| ALKS 5461 2mg/2mg S2 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | Yes | 9 Participants |
| ALKS 5461 2mg/2mg S2 | Proportion of Patients Who Exhibited Treatment Response (MADRS-10) | No | 45 Participants |
Secondary
Remission Rate
The proportion of subjects achieving remission, defined as a MADRS-10 score of \</= 10 at the end of the efficacy period.
Time frame: Baseline and 5 weeks for each stage
Population: Stage 1 Full Analysis Set (FAS) consisted of subjects who took at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 1. Stage 2 FAS consisted of Stage 1 placebo non-responders who entered Stage 2 and who received at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 2.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo S1 | Remission Rate | Yes | 47 Participants |
| Placebo S1 | Remission Rate | No | 209 Participants |
| ALKS 5461 0.5mg/0.5mg S1 | Remission Rate | Yes | 6 Participants |
| ALKS 5461 0.5mg/0.5mg S1 | Remission Rate | No | 52 Participants |
| ALKS 5461 2mg/2mg S1 | Remission Rate | Yes | 13 Participants |
| ALKS 5461 2mg/2mg S1 | Remission Rate | No | 46 Participants |
| Placebo S2 | Remission Rate | Yes | 4 Participants |
| Placebo S2 | Remission Rate | No | 50 Participants |
| ALKS 5461 0.5mg/0.5mg S2 | Remission Rate | Yes | 7 Participants |
| ALKS 5461 0.5mg/0.5mg S2 | Remission Rate | No | 48 Participants |
| ALKS 5461 2mg/2mg S2 | Remission Rate | Yes | 7 Participants |
| ALKS 5461 2mg/2mg S2 | Remission Rate | No | 47 Participants |