Depressive Disorder, Major
Conditions
Brief summary
This study will evaluate the efficacy, safety, and tolerability of two doses of rapastinel, 225 milligrams (mg) and 450 mg, compared to placebo adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who have a partial response to ADT.
Interventions
DRUGRapastinel
Rapastinel pre-filled syringes for weekly IV injections.
DRUGPlacebo
Placebo-matching rapastinel pre-filled syringes for weekly IV injections.
Sponsors
Naurex, Inc, an affiliate of Allergan plc
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
* Meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD * Current major depressive episode of at least 8 weeks and not exceeding 18 months in duration at Visit 1 * Have no more than partial response (\< 50% improvement) to ongoing treatment with a protocol-allowed antidepressant * If female of childbearing potential, have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test.
Exclusion criteria
* DSM-5-based diagnosis of any disorder other than MDD that was the primary focus of treatment within 6 months before Visit 1 * Lifetime history of meeting DSM-5 criteria for: 1. Schizophrenia spectrum or other psychotic disorder 2. Bipolar or related disorder 3. Major neurocognitive disorder 4. Neurodevelopmental disorder of greater than mild severity or of a severity that impacts the participant's ability to consent, follow study directions, or otherwise safely participate in the study 5. Dissociative disorder 6. Posttraumatic stress disorder 7. MDD with psychotic features * Significant suicide risk, as judged by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at the End of Study | Baseline and 3 Weeks | The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in MADRS Total Score | Baseline and Day 8 | The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement. |
Countries
United States
Participant flow
Recruitment details
658 total enrolled. 20 discontinued prior to randomization.
Pre-assignment details
Prior to randomization, patients entered a 1-wk, double-blind, placebo lead-in period to identify placebo responders. Upon completion of the placebo lead-in period, patients were randomized in 1:1 ratio to receive either rapastinel or placebo. Randomization was stratified by patient's responder status (placebo non-responder vs. placebo responder).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo-matching rapastinel weekly IV injections. Each participant will continue to take the same dose of antidepressant therapy the participant was receiving prior to entering this study throughout treatment. | 217 |
| Rapastinel 225 mg Rapastinel 225 milligram (mg) weekly intravenous (IV) injections. Each participant will continue to take the same dose of antidepressant therapy the participant was receiving prior to entering this study throughout treatment. | 211 |
| Rapastinel 450 mg Rapastinel 450 mg weekly IV injections. Each participant will continue to take the same dose of antidepressant therapy the participant was receiving prior to entering this study throughout treatment. | 210 |
| Total | 638 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Miscellaneous Reasons | 0 | 0 | 3 |
| Overall Study | Non-compliance with study drug | 0 | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 2 | 2 | 2 |
| Overall Study | Site terminated by sponsor | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 5 | 2 |
Baseline characteristics
| Characteristic | Total | Rapastinel 450 mg | Rapastinel 225 mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 44.3 Years STANDARD_DEVIATION 12.38 | 44.7 Years STANDARD_DEVIATION 12.27 | 44.3 Years STANDARD_DEVIATION 13.16 | 44.1 Years STANDARD_DEVIATION 11.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 73 Participants | 26 Participants | 22 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 565 Participants | 184 Participants | 189 Participants | 192 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| MADRS total score at baseline | 33.6 Scores on a Scale STANDARD_DEVIATION 4.7 | 33.5 Scores on a Scale STANDARD_DEVIATION 4.85 | 33.5 Scores on a Scale STANDARD_DEVIATION 4.67 | 33.6 Scores on a Scale STANDARD_DEVIATION 4.47 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 5 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 129 Participants | 42 Participants | 46 Participants | 41 Participants |
| Race/Ethnicity, Customized Multiple | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 491 Participants | 159 Participants | 162 Participants | 170 Participants |
| Sex: Female, Male Female | 441 Participants | 153 Participants | 147 Participants | 141 Participants |
| Sex: Female, Male Male | 197 Participants | 57 Participants | 64 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 217 | 0 / 211 | 0 / 210 |
| other Total, other adverse events | 14 / 217 | 11 / 211 | 14 / 210 |
| serious Total, serious adverse events | 1 / 217 | 1 / 211 | 1 / 210 |
Outcome results
Primary
Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at the End of Study
The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement.
Time frame: Baseline and 3 Weeks
Population: The modified Intent-to-Treat (mITT) Population will consist of all patients who were randomized, received at least 1 dose of IP during the randomized treatment period, and had at least 1 post-randomization assessment of the MADRS total score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at the End of Study | -4.9 Score on a Scale | Standard Error 0.59 |
| Rapastinel 225 mg | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at the End of Study | -4.8 Score on a Scale | Standard Error 0.6 |
| Rapastinel 450 mg | Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at the End of Study | -5.4 Score on a Scale | Standard Error 0.6 |
p-value: 0.886295% CI: [-1.5, 1.73]Mixed Model Repeated Measures (MMRM)
p-value: 0.577295% CI: [-2.07, 1.16]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in MADRS Total Score
The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Participants are rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A negative change score indicates improvement.
Time frame: Baseline and Day 8
Population: The modified Intent-to-Treat (mITT) Population will consist of all patients who were randomized, received at least 1 dose of IP during the randomized treatment period, and had at least 1 post-randomization assessment of the MADRS total score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MADRS Total Score | -4.5 Score on a Scale | Standard Error 0.51 |
| Rapastinel 225 mg | Change From Baseline in MADRS Total Score | -4.6 Score on a Scale | Standard Error 0.52 |
| Rapastinel 450 mg | Change From Baseline in MADRS Total Score | -4.5 Score on a Scale | Standard Error 0.52 |
p-value: 0.896795% CI: [-1.48, 1.29]Mixed Model Repeated Measures (MMRM)
p-value: 0.996395% CI: [-1.38, 1.39]Mixed Model Repeated Measures (MMRM)