Major Depressive Disorder
Conditions
Brief summary
The objective of this study is to evaluate the efficacy, safety, and tolerability of levomilnacipran compared with placebo in pediatric outpatients (7-17 years) with major depressive disorder (MDD).
Interventions
Levomilnacipran extended-release oral capsules
DRUGFluoxetine
Fluoxetine oral capsules
DRUGPlacebo
Matching placebo oral capsules
Sponsors
Allergan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Patients must meet Diagnostic and statistical manual of mental disorders fifth edition (DSM-5) criteria for MDD, confirmed by Kiddie Schedule for Affective Disorders - Present and Lifetime (K-SADS-PL) * Patients must have a score ≥ 40 on the Children's Depression Rating Scale-Revised (CDRS-R) at Visits 1 and 2 * Patients must have a Clinical Global Impressions-Severity (CGI-S) score ≥ 4 at Visits 1 and 2 * Patients must have a caregiver who can and is willing to consent to be responsible for safety monitoring of the Patient, provide information about the patient's condition, oversee the administration of investigational product, and accompany the patients to all study visits * Female patients of childbearing potential who are sexually active must agree to use a reliable method of contraception that will continue for the duration of the study and within 30 days following the end of study participation. * A sexually active male patients must agree to use contraception as detailed below during the treatment period and for at least 30 days after the last dose of investigational product.
Exclusion criteria
* DSM-5-based diagnosis of an axis I disorder other than MDD that is the primary focus of treatment. * Prior diagnosis of mental retardation or amnestic or other cognitive disorders based on DSM-5 criteria * Imminent risk of injuring self or others or causing damage to property as judged by the Investigator * Suicide risk as determined by meeting either of the following criteria: * Any suicide attempt within the past year * Significant risk at Visit 1 (Screening) or Visit 2 (Baseline), as judged by the Investigator based on the psychiatric interview or information collected in the Columbia-Suicide Severity Rating Scale (C-SSRS) treatment-Related Criteria * History of allergy, intolerance, or hypersensitivity to levomilnacipran, milnacipran, fluoxetine, or any other Selective serotonin reuptake inhibitors (SSRI) or Serotonin and norepinephrine reuptake inhibitors (SNRI) or known hypersensitivity to the investigational products' non-medicinal ingredients including gelatin and cellulose * Patients requiring prohibited concomitant medication or herbal supplements that could not be discontinued or switched to an allowable alternative medication and stabilized for at least 2 weeks preceding Visit 2 (Baseline) * Patients taking any psychoactive drug or psychoactive herbal remedy within 5 half-lives before Baseline (Visit 2), Patients who have ever been treated with a depot antipsychotic must also be excluded * Patients who have initiated or terminated psychotherapy or behavior therapy within1 month before Visit 1 (Screening), or who plan to initiate or change such therapies during the course of the study Other Medical criteria * A clinically significant disease state that, in the investigator's opinion, might indicate that the patients is unsuitable for the study * Any cardiovascular disease or condition that is clinically significant, unstable, or decompensated. * Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change in dosage for at least 3 months before Visit 1 (Screening) * Any condition that would be expected to affect drug absorption (eg, gastric bypass surgery) * History of seizure disorder (except simple childhood febrile seizures before age 5), unexplained syncope or black-out episodes, stroke, significant head injury, tumor of the central nervous system, or any other condition that predisposes the patient toward a risk for seizure * History of drug or alcohol abuse or dependence within the past year * Pregnant, breastfeeding, and/or planning to become pregnant and/or breastfeed during the study or within 30 days following the end of study participation * Patients who are unable to swallow capsules * Treatment with any investigational product within 3 months (or at least 5 half-lives, whichever is longer) of Visit 1. Treatment with any investigational product other than those provided by AGN during study participation will be a protocol violation, and the patient will be terminated from this study * Employee or immediate relative of an employee of Allergan (AGN), any of its affiliates or partners, or of the study center * Patients or patients whose parent/guardian/ legally authorized representative (LAR) and/or caregivers are unable to speak and understand English (or their native language if this can be accommodated by the site and is approved by the Sponsor) sufficiently to understand the nature of the study, to provide informed assent/consent, or to allow the completion of all study assessments * Unable or unlikely to comply with the study protocol or are unsuitable for any other reason, Other Criteriaas judged by the Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Children's Depression Rating Scale- Revised (CDRS-R) | Baseline (Week 0) to Week 8 | The CDRS-R is a semi-structured, clinician-rated instrument designed for use with children and adolescents between the ages of 6-17 years. It contains 17 ordinally-scaled items that evaluate the 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 participant's current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1=normal, not at all ill and 7=among the most extremely ill participants. Higher score indicates worsening of mental illness. A negative change from Baseline indicates improvement. MMRM was used for analysis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo capsules once daily through 8 weeks in the Double-blind Treatment Period and Days 1 through 7 in the Down-taper Period. | 160 |
| Levomilnacipran ER 40-80 mg/Day Levomilnacipran ER capsules, orally, 10 mg/day on Days 1 to 3, 20 mg/day on Days 4 to 7, and 40 mg/day from Week 2 through Week 8 of the Double-blind Treatment Period followed by levomilnacipran ER 40 mg/day on Days 1 and 2, and then 20 mg/day from Day 3 through Day 7 in the Down-taper Period. Based on therapeutic response and tolerability, an additional dose increase to 80 mg/day was permitted at Week 3 of the Double-blind Treatment Period. | 166 |
| Fluoxetine 20 mg/Day Fluoxetine capsule, orally, 10 mg/day at Week 1, and 20 mg/day from Week 2 through Week 8 of the Double-blind Treatment Period followed by fluoxetine 10 mg/day from Day 1 through Day 7 of the Down-taper Period. | 166 |
| Total | 492 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Down-taper Period (1 Week) | Lost to Follow-up | 0 | 1 | 1 |
| Double-blind Down-taper Period (1 Week) | Withdrawal by Subject | 0 | 1 | 1 |
| Double-blind Treatment Period (8 Weeks) | Adverse Event | 1 | 2 | 5 |
| Double-blind Treatment Period (8 Weeks) | Lack of Efficacy | 0 | 1 | 0 |
| Double-blind Treatment Period (8 Weeks) | Lost to Follow-up | 7 | 7 | 6 |
| Double-blind Treatment Period (8 Weeks) | Non-compliance with Study Drug | 1 | 1 | 1 |
| Double-blind Treatment Period (8 Weeks) | Protocol Deviation | 1 | 1 | 1 |
| Double-blind Treatment Period (8 Weeks) | Reason not Specified | 1 | 1 | 2 |
| Double-blind Treatment Period (8 Weeks) | Withdrawal by Subject | 7 | 10 | 9 |
Baseline characteristics
| Characteristic | Levomilnacipran ER 40-80 mg/Day | Fluoxetine 20 mg/Day | Total | Placebo |
|---|---|---|---|---|
| Age, Continuous | 13.7 years STANDARD_DEVIATION 2.56 | 13.3 years STANDARD_DEVIATION 2.66 | 13.5 years STANDARD_DEVIATION 2.57 | 13.6 years STANDARD_DEVIATION 2.48 |
| Children's Depression Rating Scale-Revised (CDRS-R) Total Score | 60.8 score on a scale STANDARD_DEVIATION 9.17 | 60.9 score on a scale STANDARD_DEVIATION 9.88 | 60.8 score on a scale STANDARD_DEVIATION 9.34 | 60.8 score on a scale STANDARD_DEVIATION 8.99 |
| Clinical Global Impression-Severity (CGI-S) Scale | 4.7 score on a scale STANDARD_DEVIATION 0.64 | 4.8 score on a scale STANDARD_DEVIATION 0.6 | 4.8 score on a scale STANDARD_DEVIATION 0.63 | 4.8 score on a scale STANDARD_DEVIATION 0.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 40 Participants | 125 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 126 Participants | 126 Participants | 367 Participants | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 0 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 58 Participants | 173 Participants | 54 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 3 Participants | 9 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 96 Participants | 104 Participants | 302 Participants | 102 Participants |
| Sex: Female, Male Female | 99 Participants | 105 Participants | 318 Participants | 114 Participants |
| Sex: Female, Male Male | 67 Participants | 61 Participants | 174 Participants | 46 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 / 164 | 0 / 169 | 0 / 168 | 0 / 160 | 0 / 166 | 0 / 166 |
| other Total, other adverse events | 32 / 160 | 44 / 166 | 37 / 166 | 3 / 160 | 3 / 166 | 1 / 166 |
| serious Total, serious adverse events | 1 / 160 | 1 / 166 | 4 / 166 | 1 / 160 | 0 / 166 | 0 / 166 |
Outcome results
Primary
Change From Baseline in Children's Depression Rating Scale- Revised (CDRS-R)
The CDRS-R is a semi-structured, clinician-rated instrument designed for use with children and adolescents between the ages of 6-17 years. It contains 17 ordinally-scaled items that evaluate the 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 are 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) | -21.3 score on a scale | Standard Error 1.01 |
| Levomilnacipran ER 40-80 mg/Day | Change From Baseline in Children's Depression Rating Scale- Revised (CDRS-R) | -23.0 score on a scale | Standard Error 1.01 |
| Fluoxetine 20 mg/Day | Change From Baseline in Children's Depression Rating Scale- Revised (CDRS-R) | -23.1 score on a scale | Standard Error 1.01 |
p-value: 0.221595% CI: [-4.49, 1.04]Mixed Model for Repeated Measures
p-value: 0.196495% CI: [-4.59, 0.95]Mixed Model for Repeated Measures
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 participant's current state of mental illness compared with MDD population. The participant was rated on a scale from 1 to 7, where 1=normal, not at all ill and 7=among the most extremely ill participants. 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 post-baseline assessment of the Children's Depression Rating Scale-Revised (CDRS-R) total score. If a participant received an intervention different from the planned intervention, the participant is counted in the planned group. Overall number of participants analyzed are 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 | -1.5 score on a scale | Standard Error 0.1 |
| Levomilnacipran ER 40-80 mg/Day | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | -1.6 score on a scale | Standard Error 0.1 |
| Fluoxetine 20 mg/Day | Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale | -1.7 score on a scale | Standard Error 0.1 |
p-value: 0.678995% CI: [-0.32, 0.21]Mixed Model for Repeated Measures
p-value: 0.112695% CI: [-0.48, 0.05]Mixed Model for Repeated Measures