Major Depressive Disorder
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety, and tolerability of levomilnacipran ER relative to placebo in adolescent outpatients (12-17 years) with Major Depressive Disorder (MDD). In addition, the study is designed to obtain pharmacokinetics (PK) data to guide dose selection for future pediatric studies of levomilnacipran.
Detailed description
Study LVM-MD-11 is a randomized, double-blind, placebo- and active-controlled, parallel group, fixed-dose study in adolescent patients, ages 12-17 years. The study will be approximately 10 weeks in duration: * 1-week screening/washout period * 8-week double-blind treatment period * 1-week double-blind down-taper period Participants who meet the eligibility criteria at Visit 2 (Baseline) will be randomized to 1 of 4 treatment groups: placebo, levomilnacipran 40 mg/day, levomilnacipran 80 mg/day, or fluoxetine 20 mg/day.
Interventions
DRUGPlacebo
Matched over-encapsulated placebo capsules administered orally on Day 1 to Week 8.
DRUGLevomilnacipran
Over-encapsulated levomilnacipran ER capsules administered orally on Day 1 to Week 8.
DRUGFluoxetine
Over-encapsulated fluoxetine tablets administered orally on Day 1 to Week 8.
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female outpatients;12-17 years of age * Meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for MDD, confirmed by Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children--Present and Lifetime (K-SADS-PL) * Score ≥ 40 on the Children's Depression Rating Scale-Revised (CDRS-R) at Visits 1 and 2 * Clinical Global Impressions-Severity (CGI-S) score ≥ 4 at Visits 1 and 2 * Reliable caregiver * Physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG) normal or not clinically significant Key Psychiatric
Exclusion criteria
* DSM-IV-TR-based diagnosis of an axis I disorder other than MDD that is the primary focus of treatment * Mental retardation or amnestic or other cognitive disorders * Significant suicide risk: * Suicide attempt within the past year OR * Investigator judgment (based on psychiatric interview and Columbia-Suicide Severity Rating Scale (C-SSRS)) Key Treatment-Related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score | Baseline (Week 0) to Week 8 | CDRS-R is a 17-item scale measuring presence and severity of symptoms commonly associated with childhood depression and is scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. The CDRS-R total score ranges from 17 to 113; higher score indicates more severe depression. A negative change from Baseline indicates improvement. Mixed Model for Repeated Measures (MMRM) was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | Baseline (Week 0) to Week 8 | The CGI-S is a clinician-rated scale used to rate the severity of the participants current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1= Very much improved; 2= Much improved; 3= Minimally improved; 4= No change; 5= Minimally worse; 6= Much worse; 7= Very much worse. Higher score indicates worsening of mental illness. A negative change from Baseline indicates improvement. MMRM was used for analysis. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received 2 dose matched over-encapsulated placebo capsules, once daily, orally during the Double-blind Treatment Period up to 8 weeks followed by a 1 week Taper-down Period if applicable as determined by the investigator. | 141 |
| Levomilnacipran 40 mg/Day Participants received over-encapsulated levomilnacipran extended release (ER) 40 mg/day capsules orally starting at a dose of 10 mg/day on Day 1-2, 20 mg/day on Days 3-7 and 40 mg/day on Week 2 through Week 8 during the Double-Blind Treatment Period, followed by a 1-week Double-Blind Taper-down Period if applicable as determined by the investigator. Participants received 1 dose matched placebo capsule each day to maintain the blind. | 134 |
| Levomilnacipran 80 mg/Day Participants received over-encapsulated levomilnacipran ER two 40 mg/day capsules (80 mg/day) orally starting at a dose of 10 mg/day on Day 1-2, 20 mg/day on Day 3-4, 40 mg/day on Day 5-7 and 80 mg/day on Week 2 through Week 8 during the Double-blind Treatment Period, followed by a 1-week Double-blind Taper-down Period if applicable as determined by the investigator. Participants received 1 dose matched placebo capsule the first week and during the taper-down period to maintain the blind. | 138 |
| Fluoxetine 20 mg/Day Participants received over-encapsulated fluoxetine 20 mg/day tablets orally starting at a dose of 10 mg/day in Week 1 and 20 mg/day in Week 2 through Week 8 during the Double-blind Treatment Period, followed by a 1-week Double-blind Taper-down Period if applicable as determined by the investigator. Participants received 1 dose matched placebo capsule each day to maintain the blind. | 134 |
| Total | 547 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 4 | 7 | 11 | 7 |
| Double-blind Treatment Period | Did not Receive Treatment | 1 | 2 | 1 | 1 |
| Double-blind Treatment Period | Investigational Product Non-compliance | 1 | 0 | 3 | 1 |
| Double-blind Treatment Period | Lack of Efficacy | 2 | 0 | 2 | 2 |
| Double-blind Treatment Period | Lost to Follow-up | 7 | 4 | 5 | 8 |
| Double-blind Treatment Period | Reason Not Specified | 0 | 1 | 5 | 2 |
| Double-blind Treatment Period | Withdrawal of Consent | 10 | 7 | 5 | 5 |
Baseline characteristics
| Characteristic | Placebo | Levomilnacipran 40 mg/Day | Levomilnacipran 80 mg/Day | Fluoxetine 20 mg/Day | Total |
|---|---|---|---|---|---|
| Age, Continuous | 14.3 years STANDARD_DEVIATION 1.59 | 14.8 years STANDARD_DEVIATION 1.62 | 14.8 years STANDARD_DEVIATION 1.75 | 14.7 years STANDARD_DEVIATION 1.67 | 14.7 years STANDARD_DEVIATION 1.67 |
| Children's Depression Rating Scale-Revised (CDRS-R) Total Score | 61.1 score on a scale | 61.8 score on a scale | 59.4 score on a scale | 61.5 score on a scale | 60.95 score on a scale |
| Clinical Global Impression-Severity (CGI-S) Scale | 4.7 score on a scale | 4.8 score on a scale | 4.7 score on a scale | 4.7 score on a scale | 4.7 score on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants | 36 Participants | 32 Participants | 36 Participants | 137 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 98 Participants | 106 Participants | 98 Participants | 410 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 52 Participants | 46 Participants | 49 Participants | 40 Participants | 187 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 4 Participants | 3 Participants | 4 Participants | 17 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 81 Participants | 81 Participants | 83 Participants | 88 Participants | 333 Participants |
| Sex: Female, Male Female | 98 Participants | 94 Participants | 87 Participants | 84 Participants | 363 Participants |
| Sex: Female, Male Male | 43 Participants | 40 Participants | 51 Participants | 50 Participants | 184 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 / 141 | 0 / 134 | 0 / 138 | 0 / 134 |
| other Total, other adverse events | 33 / 141 | 54 / 134 | 63 / 138 | 41 / 134 |
| serious Total, serious adverse events | 0 / 141 | 2 / 134 | 0 / 138 | 4 / 134 |
Outcome results
Primary
Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score
CDRS-R is a 17-item scale measuring presence and severity of symptoms commonly associated with childhood depression and is scored on a 1-to-5- or 1-to-7-point scale. Rating of 1 indicates normal function. The CDRS-R total score ranges from 17 to 113; higher score indicates more severe depression. A negative change from Baseline indicates improvement. Mixed Model for Repeated Measures (MMRM) was used for analysis.
Time frame: Baseline (Week 0) to Week 8
Population: ITT Population included all participants in the Safety Population who had the baseline and at least 1 postbaseline assessment of the CDRS-R total score. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score | -22.90 score on a scale | Standard Error 1.09 |
| Levomilnacipran 40 mg/Day | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score | -23.28 score on a scale | Standard Error 1.11 |
| Levomilnacipran 80 mg/Day | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score | -22.64 score on a scale | Standard Error 1.12 |
| Fluoxetine 20 mg/Day | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score | -24.37 score on a scale | Standard Error 1.12 |
p-value: 0.803595% CI: [-3.41, 2.64]Mixed Model Repeated Measures (MMRM)
p-value: 0.868195% CI: [-2.8, 3.31]MMRM
p-value: 0.343995% CI: [-4.52, 1.58]MMRM
Secondary
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale
The CGI-S is a clinician-rated scale used to rate the severity of the participants current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1= Very much improved; 2= Much improved; 3= Minimally improved; 4= No change; 5= Minimally worse; 6= Much worse; 7= Very much worse. Higher score indicates worsening of mental illness. A negative change from Baseline indicates improvement. MMRM was used for analysis.
Time frame: Baseline (Week 0) to Week 8
Population: ITT Population included all participants in the Safety Population who had the baseline and at least 1 postbaseline assessment of the Children's Depression Rating Scale-Revised (CDRS-R) total score. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | -1.54 score on a scale | Standard Error 0.1 |
| Levomilnacipran 40 mg/Day | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | -1.52 score on a scale | Standard Error 0.1 |
| Levomilnacipran 80 mg/Day | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | -1.52 score on a scale | Standard Error 0.1 |
| Fluoxetine 20 mg/Day | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | -1.68 score on a scale | Standard Error 0.1 |
p-value: 0.878895% CI: [-0.25, 0.29]MMRM
p-value: 0.92395% CI: [-0.26, 0.29]MMRM
p-value: 0.289595% CI: [-0.42, 0.13]MMRM