Depressive Disorder, Major
Conditions
Brief summary
This study will evaluate the efficacy, safety and tolerability of rapastinel 450 milligrams (mg) intravenous (IV) once weekly or once every 2 weeks versus placebo as an adjunctive treatment to ongoing anti-depressive therapy (ADT) in the prevention of relapse in participants with Major Depressive Disorder (MDD).
Interventions
DRUGRapastinel
Rapastinel pre-filled syringes for IV injections.
DRUGPlacebo-matching Rapastinel
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
TRIPLE (Subject, 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 Screening * 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 Screening * Lifetime history of meeting DSM-5 criteria for: * Schizophrenia spectrum or other psychotic disorder * Bipolar or related disorder * Major neurocognitive disorder * 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 * Dissociative disorder * Posttraumatic stress disorder * MDD with psychotic features * Significant suicide risk, as judged by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Relapse During the First 52 Weeks of the Double-Blind Treatment Period | 52 Weeks | The time in days to first relapse is defined as the number of days from the date of randomization to the first relapse. |
| Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales | 104 Weeks | On the C-SSRS, the 5 types of suicidal ideation are: Type 1: Wish to be dead Type 2: Non-specific active suicidal thoughts Type 3: Active suicidal ideation with any methods (not plan) without intent to act Type 4: Active suicidal ideation with some intent to act, without specific plan Type 5: Active suicidal ideation with specific plan and intent |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Relapse During the Entire Double-Blind Treatment Period | 104 Weeks | The time in days to first relapse is defined as the number of days from the date of randomization to the first relapse. |
Countries
United States
Participant flow
Recruitment details
Patients from RAP-MD-04, completed 1 of the rapastinel lead-in studies - RAP-MD-01, RAP-MD-02, or RAP-MD-03.
Pre-assignment details
A total of 1304 patients enrolled in the Open Label Treatment Period (OLTP). Of these, 1056 completed the OLTP and 604 entered the Double Blind Treatment Period (DBTP) and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Rapastinel 450 mg IV once a week during OLTP followed by placebo-matching rapastinel 450 mg IV once a week during DBTP. | 202 |
| Rapastinel 450 mg Every 2 Weeks Rapastinel 450 mg IV once a week during OLTP followed by rapastinel 450 mg IV once every 2 weeks during DBTP. | 202 |
| Rapastinel 450 mg Weekly Rapastinel 450 mg IV once a week during OLTP followed by rapastinel 450 mg IV once a week during DBTP. | 200 |
| Total | 604 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 0 | 8 | 3 | 6 |
| Double-Blind Treatment Period | Lost to Follow-up | 0 | 4 | 12 | 3 |
| Double-Blind Treatment Period | Miscellaneous Reasons | 0 | 2 | 1 | 0 |
| Double-Blind Treatment Period | Non-compliance with study drug | 0 | 1 | 3 | 0 |
| Double-Blind Treatment Period | Pregnancy | 0 | 1 | 1 | 0 |
| Double-Blind Treatment Period | Protocol Violation | 0 | 4 | 4 | 8 |
| Double-Blind Treatment Period | Site terminated by sponsor | 0 | 0 | 1 | 1 |
| Double-Blind Treatment Period | Study terminated by sponsor | 0 | 58 | 54 | 69 |
| Double-Blind Treatment Period | Withdrawal by Subject | 0 | 23 | 22 | 28 |
| Open-Label Treatment Period | Adverse Event | 45 | 0 | 0 | 0 |
| Open-Label Treatment Period | Lack of Efficacy | 49 | 0 | 0 | 0 |
| Open-Label Treatment Period | Lost to Follow-up | 28 | 0 | 0 | 0 |
| Open-Label Treatment Period | Miscellaneous Reasons | 8 | 0 | 0 | 0 |
| Open-Label Treatment Period | Non-compliance with background ADT | 2 | 0 | 0 | 0 |
| Open-Label Treatment Period | Non-compliance with study drug | 5 | 0 | 0 | 0 |
| Open-Label Treatment Period | Pregnancy | 2 | 0 | 0 | 0 |
| Open-Label Treatment Period | Protocol Violation | 22 | 0 | 0 | 0 |
| Open-Label Treatment Period | Study terminated by sponsor | 9 | 0 | 0 | 0 |
| Open-Label Treatment Period | Withdrawal by Subject | 78 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Rapastinel 450 mg Weekly | Rapastinel 450 mg Every 2 Weeks |
|---|---|---|---|---|
| Age, Continuous | 45.2 Years STANDARD_DEVIATION 12.45 | 45.1 Years STANDARD_DEVIATION 12.24 | 44.7 Years STANDARD_DEVIATION 12.15 | 45.4 Years STANDARD_DEVIATION 12.17 |
| BMI | 30.94 kg/m^2 STANDARD_DEVIATION 6.74 | 30.91 kg/m^2 STANDARD_DEVIATION 6.44 | 30.45 kg/m^2 STANDARD_DEVIATION 5.69 | 31.33 kg/m^2 STANDARD_DEVIATION 6.83 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 83 Participants | 29 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 177 Participants | 521 Participants | 171 Participants | 173 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 167.27 cm STANDARD_DEVIATION 8.85 | 167.58 cm STANDARD_DEVIATION 9.25 | 167.36 cm STANDARD_DEVIATION 9.13 | 168.12 cm STANDARD_DEVIATION 9.78 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 10 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 35 Participants | 91 Participants | 29 Participants | 27 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 4 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 162 Participants | 494 Participants | 162 Participants | 170 Participants |
| Sex: Female, Male Female | 148 Participants | 442 Participants | 152 Participants | 142 Participants |
| Sex: Female, Male Male | 54 Participants | 162 Participants | 48 Participants | 60 Participants |
| Weight | 86.49 kg STANDARD_DEVIATION 19.15 | 86.73 kg STANDARD_DEVIATION 18.49 | 85.39 kg STANDARD_DEVIATION 17.46 | 88.29 kg STANDARD_DEVIATION 18.78 |
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 / 1,304 | 1 / 202 | 0 / 202 | 0 / 200 |
| other Total, other adverse events | 290 / 1,304 | 62 / 202 | 72 / 202 | 66 / 200 |
| serious Total, serious adverse events | 26 / 1,304 | 6 / 202 | 3 / 202 | 5 / 200 |
Outcome results
Primary
Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales
On the C-SSRS, the 5 types of suicidal ideation are: Type 1: Wish to be dead Type 2: Non-specific active suicidal thoughts Type 3: Active suicidal ideation with any methods (not plan) without intent to act Type 4: Active suicidal ideation with some intent to act, without specific plan Type 5: Active suicidal ideation with specific plan and intent
Time frame: 104 Weeks
Population: The Double-blind modified Intent-to-Treat Population consists of all patients in the Open-label Safety Population who were randomized to a treatment group during the DBTP of the study and received at least 1 dose of IP during the DBTP. 1 subject in the Biweekly Rapastinel group did not have any responses regarding the C-SSRS during the DBTP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales | Suicidal Ideation | 17 Participants |
| Placebo | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales | Suicidal Behavior | 0 Participants |
| Rapastinel 450 mg Every 2 Weeks | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales | Suicidal Behavior | 0 Participants |
| Rapastinel 450 mg Every 2 Weeks | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales | Suicidal Ideation | 25 Participants |
| Rapastinel 450 mg Weekly | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales | Suicidal Ideation | 23 Participants |
| Rapastinel 450 mg Weekly | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Using 5-Point Scales | Suicidal Behavior | 1 Participants |
Primary
Time to First Relapse During the First 52 Weeks of the Double-Blind Treatment Period
The time in days to first relapse is defined as the number of days from the date of randomization to the first relapse.
Time frame: 52 Weeks
Population: The Double-blind modified Intent-to-Treat Population consists of all patients in the Open-label Safety Population who were randomized to a treatment group during the DBTP of the study and received at least 1 dose of IP during the DBTP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Relapse During the First 52 Weeks of the Double-Blind Treatment Period | 232 Days |
| Rapastinel 450 mg Every 2 Weeks | Time to First Relapse During the First 52 Weeks of the Double-Blind Treatment Period | 225 Days |
| Rapastinel 450 mg Weekly | Time to First Relapse During the First 52 Weeks of the Double-Blind Treatment Period | 336 Days |
p-value: 0.5305Log Rank
p-value: 0.4628Log Rank
Secondary
Time to First Relapse During the Entire Double-Blind Treatment Period
The time in days to first relapse is defined as the number of days from the date of randomization to the first relapse.
Time frame: 104 Weeks
Population: The Double-blind modified Intent-to-Treat Population consists of all patients in the Open-label Safety Population who were randomized to a treatment group during the DBTP of the study and received at least 1 dose of IP during the DBTP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Relapse During the Entire Double-Blind Treatment Period | 232 Days |
| Rapastinel 450 mg Every 2 Weeks | Time to First Relapse During the Entire Double-Blind Treatment Period | 225 Days |
| Rapastinel 450 mg Weekly | Time to First Relapse During the Entire Double-Blind Treatment Period | 336 Days |
p-value: 0.6153Log Rank
p-value: 0.4123Log Rank