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

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02431806
• Collaborator: (none)
• Enrollment: 552
• Locations: 49
• Arms: 4
• Actual Duration (Months): 49.9
• Patients Per Site: 11.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Placebo; Drug: Levomilnacipran; Drug: Fluoxetine	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 552 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Placebo- and Active-Controlled Evaluation of the Safety and Efficacy of Levomilnacipran ER in Adolescent Patients With Major Depressive Disorder
• Actual Study Start Date: Jun 23, 2015
• Actual Primary Completion Date: Aug 19, 2019
• Actual Study Completion Date: Aug 19, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harmonex, Inc	Dothan	Alabama	United States	36303
2	University of Arizona Department of Psychiatry	Tucson	Arizona	United States	85724
3	Advanced Research Center, Inc.	Anaheim	California	United States	92801
4	ProScience Research Group	Culver City	California	United States	90230
5	Sun Valley Research Center	Imperial	California	United States	92251
6	Alliance for Research	Long Beach	California	United States	90807
7	Asclepes Research Centers	Panorama City	California	United States	91402
8	Syrentis Clinical Research	Santa Ana	California	United States	97025
9	Pacific Clinical Research Medical Group	Upland	California	United States	91786
10	MCB Clinical Research Center	Colorado Springs	Colorado	United States	80910
11	Florida Clinical Research Center; LLC	Bradenton	Florida	United States	34201
12	Coastal Clinical Research Specialists	Fernandina Beach	Florida	United States	32034
13	Gulfcoast Clinical Research Center	Fort Myers	Florida	United States	33912
14	Research in Miami Inc	Hialeah	Florida	United States	33013
15	Advanced Research Institute of Miami	Homestead	Florida	United States	33030
16	Clinical Neuroscience Solutions, Inc.	Jacksonville	Florida	United States	32256
17	Innovative Clinical Research, Inc.	Lauderhill	Florida	United States	33319
18	Medical Research Group of Central Florida	Orange City	Florida	United States	32763
19	Clinical Neuroscience Solutions, Inc.	Orlando	Florida	United States	32801
20	University of South Florida Board of Trustee	Tampa	Florida	United States	33613
21	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
22	Institute for Behavioral Medicine	Smyrna	Georgia	United States	30080-2620
23	Clinical Research Institute	Stockbridge	Georgia	United States	30281
24	Sandeep Gaonkar, MD	Naperville	Illinois	United States	60563
25	NeuroMedical Institute	Panama City	Illinois	United States	32405
26	Kentucky Pediatric Research	Bardstown	Kentucky	United States	40004
27	Adams Clinical Trials, LLC	Watertown	Massachusetts	United States	02472
28	Alivation Research	Lincoln	Nebraska	United States	68526
29	Kolade Research Institute	Las Vegas	Nevada	United States	89102
30	Healthy Perspectives - Innovative Mental Health Services. PLLC	Nashua	New Hampshire	United States	03060
31	Princeton Medical Institute	Princeton	New Jersey	United States	08540
32	Manhattan Behavioral Medicine	New York	New York	United States	10036
33	Midwest Clinical Research Center	Dayton	Ohio	United States	45417
34	Professional Psychiatric Services	Mason	Ohio	United States	45040
35	IPS Research Company	Oklahoma City	Oklahoma	United States	73106
36	Sooner Clinical Research	Oklahoma City	Oklahoma	United States	73112
37	Cutting Edge Research Group	Oklahoma City	Oklahoma	United States	73116
38	Paradigm Research Professionals	Oklahoma City	Oklahoma	United States	73118
39	Tulsa Clinical Research, LLC	Tulsa	Oklahoma	United States	74104
40	Oregon Center for Clinical Investigations, Inc.	Salem	Oregon	United States	97301
41	UTHSC-Houston	Houston	Texas	United States	77054
42	Bay Area Clinical Services dba Earle Research	Houston	Texas	United States	77058
43	Red Oak Psychiatry Associates	Houston	Texas	United States	77090
44	Family Psychiatry of The Woodlands	The Woodlands	Texas	United States	77381
45	UVA Child and Family Psychiatry Clinic	Charlottesville	Virginia	United States	22903
46	Carilion Medical Center	Roanoke	Virginia	United States	24014
47	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
48	Eastside Therapeutic Resource dba Core Clinical	Everett	Washington	United States	98201
49	INSPIRA Clinical Research	San Juan		Puerto Rico	00918

Sponsors and Collaborators

• Forest Laboratories

Investigators

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

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 3, 2019
• Study Protocol - Mar 25, 2019

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT02431806
• Other Study ID Numbers: LVM-MD-11; NCT03087916
• First Posted: May 1, 2015
• Last Update Posted: Sep 7, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Milnacipran; Fluoxetine; Levomilnacipran

Study Results

Participant Flow

Arm/Group Title	Placebo	Levomilnacipran 40 mg/Day	Levomilnacipran 80 mg/Day	Fluoxetine 20 mg/Day
Arm/Group Description	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.	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.	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.	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.
Period Title: Double-blind Treatment Period
STARTED	142	136	139	135
Safety Population	141	134	138	134
COMPLETED	117	115	107	109
NOT COMPLETED	25	21	32	26
Period Title: Double-blind Treatment Period
STARTED	111	109	104	107
COMPLETED	111	109	104	107
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Levomilnacipran 40 mg/Day	Levomilnacipran 80 mg/Day	Fluoxetine 20 mg/Day	Total
Arm/Group Description	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	141	134	138	134	547
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.3 (1.59)	14.8 (1.62)	14.8 (1.75)	14.7 (1.67)	14.7 (1.67)
Sex: Female, Male (Count of Participants)
Female	98 69.5%	94 70.1%	87 63%	84 62.7%	363 66.4%
Male	43 30.5%	40 29.9%	51 37%	50 37.3%	184 33.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	33 23.4%	36 26.9%	32 23.2%	36 26.9%	137 25%
Not Hispanic or Latino	108 76.6%	98 73.1%	106 76.8%	98 73.1%	410 75%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.7%	0 0%	1 0.7%	1 0.7%	3 0.5%
Asian	1 0.7%	1 0.7%	1 0.7%	1 0.7%	4 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.7%	0 0%	0 0%	1 0.2%
Black or African American	52 36.9%	46 34.3%	49 35.5%	40 29.9%	187 34.2%
White	81 57.4%	81 60.4%	83 60.1%	88 65.7%	333 60.9%
More than one race	6 4.3%	4 3%	3 2.2%	4 3%	17 3.1%
Unknown or Not Reported	0 0%	1 0.7%	1 0.7%	0 0%	2 0.4%
Children's Depression Rating Scale-Revised (CDRS-R) Total Score (score on a scale) [Mean (Full Range) ]
Mean (Full Range) [score on a scale]	61.1	61.8	59.4	61.5	60.95
Clinical Global Impression-Severity (CGI-S) Scale (score on a scale) [Mean (Full Range) ]
Mean (Full Range) [score on a scale]	4.7	4.8	4.7	4.7	4.7

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Levomilnacipran 40 mg/Day	Levomilnacipran 80 mg/Day	Fluoxetine 20 mg/Day
Arm/Group Description	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.	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.	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.	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.
Measure Participants	118	115	110	112
Least Squares Mean (Standard Error) [score on a scale]	-22.90 (1.09)	-23.28 (1.11)	-22.64 (1.12)	-24.37 (1.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran 40 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8035
	Comments
	Method	Mixed Model Repeated Measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -3.41 to 2.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates and p-values are based on MMRM with treatment group, pooled study center, visit, and treatment group-by-visit interaction as fixed effects, and baseline and baseline-by-visit as covariates using an unstructured covariance matrix.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran 80 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8681
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; -2.80 to 3.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates and p-values are based on MMRM with treatment group, pooled study center, visit, and treatment group-by-visit interaction as fixed effects, and baseline and baseline-by-visit as covariates using an unstructured covariance matrix.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fluoxetine 20 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3439
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.47
	Confidence Interval	(2-Sided) 95%; -4.52 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates and p-values are based on MMRM with treatment group, pooled study center, visit, and treatment group-by-visit interaction as fixed effects, and baseline and baseline-by-visit as covariates using an unstructured covariance matrix.

2. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scale
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Levomilnacipran 40 mg/Day	Levomilnacipran 80 mg/Day	Fluoxetine 20 mg/Day
Arm/Group Description	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.	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.	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.	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.
Measure Participants	118	115	110	112
Least Squares Mean (Standard Error) [score on a scale]	-1.54 (0.10)	-1.52 (0.10)	-1.52 (0.10)	-1.68 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran 40 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8788
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates and p-values are based on MMRM with treatment group, pooled study center, visit, and treatment group-by-visit interaction as fixed effects, and baseline and baseline-by-visit as covariates using an unstructured covariance matrix.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran 80 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9230
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates and p-values are based on MMRM with treatment group, pooled study center, visit, and treatment group-by-visit interaction as fixed effects, and baseline and baseline-by-visit as covariates using an unstructured covariance matrix.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fluoxetine 20 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2895
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates and p-values are based on MMRM with treatment group, pooled study center, visit, and treatment group-by-visit interaction as fixed effects, and baseline and baseline-by-visit as covariates using an unstructured covariance matrix.

Adverse Events

Time Frame	First dose of study treatment to end of study follow-up (Up to 10 Weeks)
Adverse Event Reporting Description	Safety Population included all participants in the Randomized Population who took at least 1 dose of double-blind investigational product.
Arm/Group Title	Placebo		Levomilnacipran 40 mg/Day		Levomilnacipran 80 mg/Day		Fluoxetine 20 mg/Day
Arm/Group Description	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.		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.		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.		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.
All Cause Mortality
	Placebo		Levomilnacipran 40 mg/Day		Levomilnacipran 80 mg/Day		Fluoxetine 20 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/141 (0%)		0/134 (0%)		0/138 (0%)		0/134 (0%)
Serious Adverse Events
	Placebo		Levomilnacipran 40 mg/Day		Levomilnacipran 80 mg/Day		Fluoxetine 20 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/141 (0%)		2/134 (1.5%)		0/138 (0%)		4/134 (3%)
Gastrointestinal disorders
Faecaloma	0/141 (0%)		0/134 (0%)		0/138 (0%)		1/134 (0.7%)
Injury, poisoning and procedural complications
Overdose	0/141 (0%)		1/134 (0.7%)		0/138 (0%)		0/134 (0%)
Intentional overdose	0/141 (0%)		0/134 (0%)		0/138 (0%)		1/134 (0.7%)
Psychiatric disorders
Suicide attempt	0/141 (0%)		1/134 (0.7%)		0/138 (0%)		1/134 (0.7%)
Suicidal ideation	0/141 (0%)		0/134 (0%)		0/138 (0%)		1/134 (0.7%)
Other (Not Including Serious) Adverse Events
	Placebo		Levomilnacipran 40 mg/Day		Levomilnacipran 80 mg/Day		Fluoxetine 20 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/141 (23.4%)		54/134 (40.3%)		63/138 (45.7%)		41/134 (30.6%)
Cardiac disorders
Tachycardia	1/141 (0.7%)		13/134 (9.7%)		12/138 (8.7%)		5/134 (3.7%)
Gastrointestinal disorders
Nausea	8/141 (5.7%)		19/134 (14.2%)		22/138 (15.9%)		5/134 (3.7%)
Abdominal pain upper	4/141 (2.8%)		6/134 (4.5%)		7/138 (5.1%)		4/134 (3%)
Vomiting	3/141 (2.1%)		11/134 (8.2%)		11/138 (8%)		4/134 (3%)
Infections and infestations
Nasopharyngitis	3/141 (2.1%)		4/134 (3%)		7/138 (5.1%)		7/134 (5.2%)
Metabolism and nutrition disorders
Decreased appetite	2/141 (1.4%)		7/134 (5.2%)		9/138 (6.5%)		10/134 (7.5%)
Nervous system disorders
Headache	15/141 (10.6%)		20/134 (14.9%)		19/138 (13.8%)		13/134 (9.7%)
Dizziness	5/141 (3.5%)		5/134 (3.7%)		9/138 (6.5%)		3/134 (2.2%)
Somnolence	3/141 (2.1%)		6/134 (4.5%)		8/138 (5.8%)		2/134 (1.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.