Safety and Efficacy of Levomilnacipran ER in Adolescent Participants With Major Depressive Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and Efficacy of Levomilnacipran ER in Adolescent Patients With Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: Levomilnacipran
* Drug: Fluoxetine


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria: Allergy, intolerance, or hypersensitivity to levomilnacipran, milnacipran, fluoxetine, or any other selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) Use of prohibited concomitant medication that cannot be discontinued Other Key Medical Exclusion Criteria: Any current medical condition that might interfere with the conduct of the study, confound the interpretation of study results, or affect participants safety Liver enzyme tests aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2X the upper limit of normal (ULN) Clinically significant cardiovascular disorders Seizure disorder or risk of seizure Drug or alcohol abuse or dependence (within the past year) Positive urine drug screen or blood alcohol

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Matched over-encapsulated placebo capsules administered orally on Day 1 to Week 8.<br>|
| Experimental: Levomilnacipran 40 mg<br>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. | Drug: Levomilnacipran<br>* Over-encapsulated levomilnacipran ER capsules administered orally on Day 1 to Week 8.<br>* Other names: Fetzima;|
| Experimental: Levomilnacipran 80 mg<br>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. | Drug: Levomilnacipran<br>* Over-encapsulated levomilnacipran ER capsules administered orally on Day 1 to Week 8.<br>* Other names: Fetzima;|
| Active Comparator: Fluoxetine 20 mg<br>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. | Drug: Fluoxetine<br>* Over-encapsulated fluoxetine tablets administered orally on Day 1 to Week 8.<br>* Other names: Prozac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Week 0) to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Week 0) to Week 8 |