Efficacy, Safety, and Tolerability of Levomilnacipran ER in Pediatric Patients (7-17 Years) With Major Depressive Disorder

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03569475
• Collaborator: (none)
• Enrollment: 501
• Locations: 51
• Arms: 3
• Actual Duration (Months): 31.8
• Patients Per Site: 9.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 501 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 Pediatric Patients 7-17 Years With Major Depressive Disorder
• Actual Study Start Date: Jul 6, 2018
• Actual Primary Completion Date: Mar 1, 2021
• Actual Study Completion Date: Mar 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Levomilnacipran ER 40-80 mg/day Levomilnacipran extended release (ER) capsules, orally, 10 milligram per day (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.	Drug: Levomilnacipran ER; Levomilnacipran extended-release oral capsules
Active Comparator: 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.	Drug: Fluoxetine; Fluoxetine oral capsules
Placebo Comparator: 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.	Drug: Placebo; Matching placebo oral capsules

Outcome Measures

Primary Outcome Measures

1. 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 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 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Woodland International Research Group	Little Rock	Arkansas	United States	72211
2	Care Access Research, Beverly Hills	Beverly Hills	California	United States	90212
3	Kindred Medical Institute for Clinical Trials, LLC	Corona	California	United States	92879
4	Behavioral Research Specialists, LLC	Glendale	California	United States	91206
5	Sun Valley Research Center	Imperial	California	United States	92251
6	Alliance Research	Long Beach	California	United States	90807
7	Excell Research, Inc.	Oceanside	California	United States	92056
8	NRC Research Institute	Orange	California	United States	92868
9	Elite Clinical Trials, Inc.	Wildomar	California	United States	92595
10	Children's National Health System	Washington	District of Columbia	United States	20910
11	Advanced Research Institute of Miami	Homestead	Florida	United States	33030
12	Clinical Neuroscience Solutions, Inc	Jacksonville	Florida	United States	32256
13	Zynak Clinical	Lauderdale Lakes	Florida	United States	33313
14	Columbus Clinical Services, LLC	Miami	Florida	United States	33125
15	Clinical Neuroscience Solutions, Inc.	Orlando	Florida	United States	32801
16	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
17	Atlanta Behavioral Research, LLC	Atlanta	Georgia	United States	30338
18	iResearch Atlanta	Decatur	Georgia	United States	30030
19	Attalla Consultants, LLC	Smyrna	Georgia	United States	30082
20	Clinical Research Institute	Stockbridge	Georgia	United States	30281
21	Inova Clinical trials and Research Center	Tyrone	Georgia	United States	30290
22	Advanced Clinical Research	Meridian	Idaho	United States	83642
23	Capstone Clinical Research	Libertyville	Illinois	United States	60048
24	AMR Conventions Limited	Naperville	Illinois	United States	60563
25	AMR-Baber Research, Inc.	Naperville	Illinois	United States	60563
26	KU Wichita Clinical Trial Unit	Wichita	Kansas	United States	67214
27	Lake Charles Clinical Trials, LLC	Lake Charles	Louisiana	United States	70629
28	Rochester Center for Behavioral Medicine	Rochester Hills	Michigan	United States	48307
29	Millennium Center for Clinical Research	Creve Coeur	Missouri	United States	63141
30	Millennium Psychiatric Associates, LLC	Saint Louis	Missouri	United States	63132
31	Alivation Research	Lincoln	Nebraska	United States	68526
32	Manhattan Behavioral Medicine, PLLC	New York	New York	United States	10036
33	Finger Lake Clinical Research	Rochester	New York	United States	14618-1609
34	University of Cincinnati	Cincinnati	Ohio	United States	45219
35	The Ohio State University Department of Psychiatry	Columbus	Ohio	United States	43210
36	Professional Psychiatric Services	Mason	Ohio	United States	45040
37	CincyScience	West Chester	Ohio	United States	45069
38	IPS Research	Oklahoma City	Oklahoma	United States	73106
39	BioBehavioral Research of Austin	Austin	Texas	United States	78759
40	Houston Clinical Trials, LLC	Bellaire	Texas	United States	77401
41	Roque Medical Trails LLC	Dallas	Texas	United States	75243
42	El Campo Clinical Trials	El Campo	Texas	United States	77437
43	Mech Healthcare Associates	Frisco	Texas	United States	75034
44	Biopharma Informatic, LLC	Houston	Texas	United States	77084
45	Red Oak Psychiatry Associates, PA	Houston	Texas	United States	77090
46	Northpointe Psychiatry	Lewisville	Texas	United States	75057
47	Metroplex Pulmonary and Sleep Center	McKinney	Texas	United States	75069
48	AIM Trials	Plano	Texas	United States	75093
49	Clinical Trials of Texas, Inc. (CTT)	San Antonio	Texas	United States	78229
50	Family Psychiatry of The Woodlands	The Woodlands	Texas	United States	77381
51	Northwest Clinical Research Center	Bellevue	Washington	United States	98007

Sponsors and Collaborators

• Allergan

Investigators

• Study Director: Daniel Radecki, PhD, Allergan

Study Documents (Full-Text)

• Study Protocol - Aug 5, 2020
• Statistical Analysis Plan - Apr 21, 2021

More Information

Publications

None provided.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT03569475
• Other Study ID Numbers: LVM-MD-14
• First Posted: Jun 26, 2018
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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 ER 40-80 mg/Day	Fluoxetine 20 mg/Day
Arm/Group Description	Matching placebo capsules once daily through 8 weeks in the Double-blind Treatment Period and Days 1 through 7 in the Down-taper Period.	Levomilnacipran extended release (ER) capsules, orally, 10 milligram per day (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.	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.
Period Title: Double-blind Treatment Period (8 Weeks)
STARTED	164	169	168
Safety Population	160	166	166
COMPLETED	146	146	144
NOT COMPLETED	18	23	24
Period Title: Double-blind Treatment Period (8 Weeks)
STARTED	140	141	140
COMPLETED	140	139	138
NOT COMPLETED	0	2	2

Baseline Characteristics

Arm/Group Title	Placebo	Levomilnacipran ER 40-80 mg/Day	Fluoxetine 20 mg/Day	Total
Arm/Group Description	Matching placebo capsules once daily through 8 weeks in the Double-blind Treatment Period and Days 1 through 7 in the Down-taper Period.	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.	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.	Total of all reporting groups
Overall Participants	160	166	166	492
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.6 (2.48)	13.7 (2.56)	13.3 (2.66)	13.5 (2.57)
Sex: Female, Male (Count of Participants)
Female	114 71.3%	99 59.6%	105 63.3%	318 64.6%
Male	46 28.8%	67 40.4%	61 36.7%	174 35.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	45 28.1%	40 24.1%	40 24.1%	125 25.4%
Not Hispanic or Latino	115 71.9%	126 75.9%	126 75.9%	367 74.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	0 0%	1 0.6%	2 0.4%
Asian	2 1.3%	4 2.4%	0 0%	6 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	54 33.8%	61 36.7%	58 34.9%	173 35.2%
White	102 63.8%	96 57.8%	104 62.7%	302 61.4%
More than one race	1 0.6%	5 3%	3 1.8%	9 1.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Children's Depression Rating Scale-Revised (CDRS-R) Total Score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	60.8 (8.99)	60.8 (9.17)	60.9 (9.88)	60.8 (9.34)
Clinical Global Impression-Severity (CGI-S) Scale (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	4.8 (0.64)	4.7 (0.64)	4.8 (0.60)	4.8 (0.63)

Outcome Measures

1. Primary Outcome

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

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 are the number of participants with data available for analyses.

Arm/Group Title	Placebo	Levomilnacipran ER 40-80 mg/Day	Fluoxetine 20 mg/Day
Arm/Group Description	Matching placebo capsules once daily through 8 weeks in the Double-blind Treatment Period and Days 1 through 7 in the Down-taper Period.	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.	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.
Measure Participants	146	148	144
Least Squares Mean (Standard Error) [score on a scale]	-21.3 (1.01)	-23.0 (1.01)	-23.1 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 40-80 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2215
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -4.49 to 1.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.41
	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, Fluoxetine 20 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1964
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -4.59 to 0.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.41
	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 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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Levomilnacipran ER 40-80 mg/Day	Fluoxetine 20 mg/Day
Arm/Group Description	Matching placebo capsules once daily through 8 weeks in the Double-blind Treatment Period and Days 1 through 7 in the Down-taper Period.	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.	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.
Measure Participants	146	148	144
Least Squares Mean (Standard Error) [score on a scale]	-1.5 (0.10)	-1.6 (0.10)	-1.7 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 40-80 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6789
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	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, Fluoxetine 20 mg/Day
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1126
	Comments
	Method	Mixed Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Adverse Events

Time Frame	Up to approximately 9 weeks
Adverse Event Reporting Description	All-cause Mortality: All enrolled participants. Adverse Events: Safety Population included all participants in the Randomized Population who received at least 1 dose of double-blind investigational product. Data was collected and reported separately for the Double-blind Treatment Period and the Double-blind Down-taper Period.
Arm/Group Title	Placebo (Double-blind Treatment Period)		Levomilnacipran ER 40-80 mg/Day (Double-blind Treatment Period)		Fluoxetine 20 mg/Day (Double-blind Treatment Period)		Placebo (Down-taper Period)		Levomilnacipran ER 40-80 mg/Day (Down-taper Period)		Fluoxetine 20 mg/Day (Down-taper Period)
Arm/Group Description	Matching placebo capsules once daily through 8 weeks in the Double-blind Treatment Period.		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. 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.		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.		Matching placebo capsules once daily on Days 1 through 7 in the Down-taper Period.		Levomilnacipran ER capsules, orally, 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.		Fluoxetine capsule, orally, 10 mg/day from Day 1 through Day 7 of the Down-taper Period.
All Cause Mortality
	Placebo (Double-blind Treatment Period)		Levomilnacipran ER 40-80 mg/Day (Double-blind Treatment Period)		Fluoxetine 20 mg/Day (Double-blind Treatment Period)		Placebo (Down-taper Period)		Levomilnacipran ER 40-80 mg/Day (Down-taper Period)		Fluoxetine 20 mg/Day (Down-taper Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/164 (0%)		0/169 (0%)		0/168 (0%)		0/160 (0%)		0/166 (0%)		0/166 (0%)
Serious Adverse Events
	Placebo (Double-blind Treatment Period)		Levomilnacipran ER 40-80 mg/Day (Double-blind Treatment Period)		Fluoxetine 20 mg/Day (Double-blind Treatment Period)		Placebo (Down-taper Period)		Levomilnacipran ER 40-80 mg/Day (Down-taper Period)		Fluoxetine 20 mg/Day (Down-taper Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/160 (0.6%)		1/166 (0.6%)		4/166 (2.4%)		1/160 (0.6%)		0/166 (0%)		0/166 (0%)
Psychiatric disorders
Major depression	0/160 (0%)		1/166 (0.6%)		0/166 (0%)		1/160 (0.6%)		0/166 (0%)		0/166 (0%)
Suicidal ideation	0/160 (0%)		0/166 (0%)		2/166 (1.2%)		0/160 (0%)		0/166 (0%)		0/166 (0%)
Bipolar I disorder	0/160 (0%)		0/166 (0%)		1/166 (0.6%)		0/160 (0%)		0/166 (0%)		0/166 (0%)
Intentional self-injury	0/160 (0%)		0/166 (0%)		1/166 (0.6%)		0/160 (0%)		0/166 (0%)		0/166 (0%)
Suicide attempt	1/160 (0.6%)		0/166 (0%)		0/166 (0%)		0/160 (0%)		0/166 (0%)		0/166 (0%)
Other (Not Including Serious) Adverse Events
	Placebo (Double-blind Treatment Period)		Levomilnacipran ER 40-80 mg/Day (Double-blind Treatment Period)		Fluoxetine 20 mg/Day (Double-blind Treatment Period)		Placebo (Down-taper Period)		Levomilnacipran ER 40-80 mg/Day (Down-taper Period)		Fluoxetine 20 mg/Day (Down-taper Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/160 (20%)		44/166 (26.5%)		37/166 (22.3%)		3/160 (1.9%)		3/166 (1.8%)		1/166 (0.6%)
Cardiac disorders
Tachycardia	0/160 (0%)		10/166 (6%)		2/166 (1.2%)		0/160 (0%)		0/166 (0%)		0/166 (0%)
Gastrointestinal disorders
Nausea	6/160 (3.8%)		16/166 (9.6%)		5/166 (3%)		1/160 (0.6%)		1/166 (0.6%)		1/166 (0.6%)
Metabolism and nutrition disorders
Decreased appetite	5/160 (3.1%)		11/166 (6.6%)		12/166 (7.2%)		0/160 (0%)		0/166 (0%)		0/166 (0%)
Nervous system disorders
Headache	19/160 (11.9%)		21/166 (12.7%)		19/166 (11.4%)		2/160 (1.3%)		2/166 (1.2%)		0/166 (0%)
Psychiatric disorders
Insomnia	9/160 (5.6%)		2/166 (1.2%)		5/166 (3%)		0/160 (0%)		1/166 (0.6%)		0/166 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.