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

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

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.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Levomilnacipran; Drug: Fluoxetine

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.

• Study Type: Interventional
• Enrollment (Actual): 552
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00918
    • INSPIRA Clinical Research
• United States
  • Alabama
    • Dothan, Alabama, United States, 36303
      • Harmonex, Inc
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Department of Psychiatry
  • California
    • Anaheim, California, United States, 92801
      • Advanced Research Center, Inc.
    • Culver City, California, United States, 90230
      • ProScience Research Group
    • Imperial, California, United States, 92251
      • Sun Valley Research Center
    • Long Beach, California, United States, 90807
      • Alliance for Research
    • Panorama City, California, United States, 91402
      • ASCLEPES Research Centers
    • Santa Ana, California, United States, 97025
      • Syrentis Clinical Research
    • Upland, California, United States, 91786
      • Pacific Clinical Research Medical Group
  • Colorado
    • Colorado Springs, Colorado, United States, 80910
      • MCB Clinical Research Center
  • Florida
    • Bradenton, Florida, United States, 34201
      • Florida Clinical Research Center; LLC
    • Fernandina Beach, Florida, United States, 32034
      • Coastal Clinical Research Specialists
    • Fort Myers, Florida, United States, 33912
      • Gulfcoast Clinical Research Center
    • Hialeah, Florida, United States, 33013
      • Research in Miami Inc
    • Homestead, Florida, United States, 33030
      • Advanced Research Institute of Miami
    • Jacksonville, Florida, United States, 32256
      • Clinical Neuroscience Solutions, Inc.
    • Lauderhill, Florida, United States, 33319
      • Innovative Clinical Research, Inc.
    • Orange City, Florida, United States, 32763
      • Medical Research Group of Central Florida
    • Orlando, Florida, United States, 32801
      • Clinical Neuroscience Solutions, Inc.
    • Tampa, Florida, United States, 33613
      • University of South Florida Board of Trustee
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center for Medical Research
    • Smyrna, Georgia, United States, 30080-2620
      • Institute For Behavioral Medicine
    • Stockbridge, Georgia, United States, 30281
      • Clinical Research Institute
  • Illinois
    • Naperville, Illinois, United States, 60563
      • Sandeep Gaonkar, MD
    • Panama City, Illinois, United States, 32405
      • NeuroMedical Institute
  • Kentucky
    • Bardstown, Kentucky, United States, 40004
      • Kentucky Pediatric Research
  • Massachusetts
    • Watertown, Massachusetts, United States, 02472
      • Adams Clinical Trials, LLC
  • Nebraska
    • Lincoln, Nebraska, United States, 68526
      • Alivation Research
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • Kolade Research Institute
  • New Hampshire
    • Nashua, New Hampshire, United States, 03060
      • Healthy Perspectives - Innovative Mental Health Services. PLLC
  • New Jersey
    • Princeton, New Jersey, United States, 08540
      • Princeton Medical Institute
  • New York
    • New York, New York, United States, 10036
      • Manhattan Behavioral Medicine
  • Ohio
    • Dayton, Ohio, United States, 45417
      • Midwest Clinical Research Center
    • Mason, Ohio, United States, 45040
      • Professional Psychiatric Services
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73116
      • Cutting Edge Research Group
    • Oklahoma City, Oklahoma, United States, 73112
      • Sooner Clinical Research
    • Oklahoma City, Oklahoma, United States, 73118
      • Paradigm Research Professionals
    • Oklahoma City, Oklahoma, United States, 73106
      • IPS Research Company
    • Tulsa, Oklahoma, United States, 74104
      • Tulsa Clinical Research, LLC
  • Oregon
    • Salem, Oregon, United States, 97301
      • Oregon Center for Clinical Investigations, Inc.
  • Texas
    • Houston, Texas, United States, 77054
      • UTHSC-Houston
    • Houston, Texas, United States, 77058
      • Bay Area Clinical Services dba Earle Research
    • Houston, Texas, United States, 77090
      • Red Oak Psychiatry Associates
    • The Woodlands, Texas, United States, 77381
      • Family Psychiatry of The Woodlands
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • UVA Child and Family Psychiatry Clinic
    • Roanoke, Virginia, United States, 24014
      • Carilion Medical Center
  • Washington
    • Bellevue, Washington, United States, 98007
      • Northwest Clinical Research Center
    • Everett, Washington, United States, 98201
      • Eastside Therapeutic Resource dba Core Clinical

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Investigators: Study Director: Daniel Radecki, Forest Research Institute, Inc., an affiliate of Allergan, plc

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2015
• Primary Completion (Actual): August 19, 2019
• Study Completion (Actual): August 19, 2019

Study Registration Dates

• First Submitted: April 28, 2015
• First Submitted That Met QC Criteria: April 30, 2015
• First Posted (Estimate): May 1, 2015

Study Record Updates

• Last Update Posted (Actual): September 7, 2020
• Last Update Submitted That Met QC Criteria: August 19, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Cytochrome P-450 CYP2D6 Inhibitors; Fluoxetine; Milnacipran; Levomilnacipran
• Other Study ID Numbers: LVM-MD-11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No