Safety and Efficacy of Levomilnacipran ER (Levomilnacipran SR) in Major Depressive Disorder

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ClinicalTrials.gov Identifier: NCT01377194

Recruitment Status : Completed

First Posted : June 21, 2011

Results First Posted : October 29, 2013

Last Update Posted : October 29, 2013

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Sponsor:

Information provided by (Responsible Party):

Forest Laboratories

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Major Depressive Disorder
Interventions	Drug: Levomilnacipran ER Drug: Placebo
Enrollment	568

Participant Flow

Recruitment Details	Patient recruitment occurred during a 6 month period from June to December 2011 at 47 study sites in the United States and 4 study sites in Canada.
Pre-assignment Details	All patients went through a 1-week single-blind placebo run-in period before randomization.


Arm/Group Title	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran ER 80 mg
Arm/Group Description	Dose matched placebo, oral administ...	40mg of Levomilnacipran ER, oral ad...	80mg of Levomilnacipran ER, oral ad...
Arm/Group Description	Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	40mg of Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks	80mg of Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks
Period Title: Overall Study
Started	186	188	188
Completed	154	145	142
Not Completed	32	43	46
Reason Not Completed
Adverse Event	3	12	19
Lack of Efficacy	3	3	3
Protocol Violation	4	10	6
Withdrawal by Subject	8	10	7
Lost to Follow-up	14	8	11

Baseline Characteristics

Arm/Group Title		Placebo	Levomilnacipran ER 40 mg	Levomilnacipran 80 mg	Total
Arm/Group Description		Dose matched placebo, oral administ...	40mg Levomilnacipran ER, oral admin...	40mg Levomilnacipran ER, oral admin...	Total of all reporting groups
Arm/Group Description		Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.	40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		186	188	188	562
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The Baseline Participant population is based on the 562 randomized patients who went on to receive double-blind treatment (Safety Population).
Age Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	186 participants	188 participants	188 participants	562 participants
		42.3 (13.2)	42.9 (13.4)	43.1 (12.8)	42.8 (13.1)
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	186 participants	188 participants	188 participants	562 participants
< 20		3	1	5	9
≥ 20-29		35	35	28	98
≥ 30-39		43	40	44	127
≥ 40-49		45	49	53	147
≥ 50-59		43	42	36	121
≥ 60		17	21	22	60
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	186 participants	188 participants	188 participants	562 participants
	Female	116 62.4%	117 62.2%	124 66.0%	357 63.5%
	Male	70 37.6%	71 37.8%	64 34.0%	205 36.5%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	186 participants	188 participants	188 participants	562 participants
White		135	142	139	416
Black or African-American		35	37	36	108
Asian		7	4	3	14
American Indian of Alaska Native		3	0	0	3
Native Hawaiian or other Pacific Islander		1	0	0	1
Other Race		5	5	10	20
Hispanic		23	24	15	62
Non-Hispanic		163	164	173	500
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	186 participants	188 participants	188 participants	562 participants
United States		177	183	180	540
Canada		9	5	8	22
Weight Mean (Standard Deviation) Unit of measure: Kg
	Number Analyzed	186 participants	188 participants	188 participants	562 participants
		81.60 (17.77)	81.35 (17.09)	81.73 (17.57)	81.56 (17.45)
Height Mean (Standard Deviation) Unit of measure: Cm
	Number Analyzed	186 participants	188 participants	188 participants	562 participants
		168.41 (9.69)	169.48 (9.79)	168.63 (8.91)	168.84 (9.47)
Body Mass Index (BMI) Mean (Standard Deviation) Unit of measure: Kilograms Per Meter Squared
	Number Analyzed	186 participants	188 participants	188 participants	562 participants
		28.67 (5.19)	28.25 (5.17)	28.71 (5.68)	28.54 (5.35)

Outcome Measures

1.Primary Outcome


Title	Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score - Mixed-effects Model for Repeated Measures (MMRM) Analysis.
Description	The Montgomery-Asberg Depression Rating Scale (MADRS) rates patients o...
Description	The Montgomery-Asberg Depression Rating Scale (MADRS) rates patients on 10 items to assess feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and lack of interest. Each item was scored on a 7-point scale. A score of 0 indicated the absence of symptoms, and a score of 6 indicated symptoms of maximum severity. The minimum overall score possible was 0 (absence of symptoms), with a maximum overall score of 60 (maximum severity).
Time Frame	From Baseline to Week 8

Outcome Measure Data

Analysis Population Description

Of the 568 patients randomized to receive double-blind treatment, 562 patients received at least 1 dose of treatment and were included in the Safety Population, and 557 patients received at least 1 dose of treatment and had at least 1 postbaseline MADRS assessment and were included in the ITT Population.


Arm/Group Title	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran ER 80 mg
Arm/Group Description:	Dose matched placebo oral administr...	40mg Levomilnacipran ER oral admini...	80mg of Levomilnacipran ER oral adm...
Arm/Group Description:	Dose matched placebo oral administration in capsule form, once daily, for 8 weeks.	40mg Levomilnacipran ER oral administration in capsule form, once daily, for 8 weeks.	80mg of Levomilnacipran ER oral administration in capsule form, once daily for 8 weeks
Overall Number of Participants Analyzed	185	185	187
Mean (Standard Deviation) Unit of Measure: Units on a scale
	-11.3 (0.77)	-14.6 (0.79)	-14.4 (0.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 40 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0027
	Comments	[Not Specified]
	Method	mixed-model for repeated measures
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-3.303
	Confidence Interval	(2-Sided) 95% -5.457 to -1.148
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 80 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0043
	Comments	[Not Specified]
	Method	mixed-model for repeated measures
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-3.141
	Confidence Interval	(2-Sided) 95% -5.293 to -0.988
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Change in Sheehan Disability Scale (SDS) Total Score
Description	The Sheehan Disability Scale (SDS) is a 3-item clinician-rated questio...
Description	The Sheehan Disability Scale (SDS) is a 3-item clinician-rated questionnaire used to evaluate impairments in the domains of work, social life/leisure, and family life/home responsibility. All items are rated on an 11-point continuum (0 = no impairment to 10 = most severe) with the total SDS score ranging from 0 (no impairment) to 30 (most severe)
Time Frame	From Baseline to Week 8

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran ER 80 mg
Arm/Group Description:	Dose matched placebo, oral administ...	40mg Levomilnacipran ER, oral admin...	80mg of Levomilnacipran ER, oral ad...
Arm/Group Description:	Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	40mg Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks	80mg of Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks
Overall Number of Participants Analyzed	185	185	187
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	-5.4 (0.66)	-7.3 (0.68)	-8.2 (0.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 40 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0459
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Mixed-effects model for repeated measures.

Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-1.827
	Confidence Interval	(2-Sided) 95% -3.620 to -0.033
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 80 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0028
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	Mixed-effects model for repeated measures.

Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-2.720
	Confidence Interval	(2-Sided) 95% -4.494 to -0.946
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse event data was collected over a 10 month period from June 2011 to March 2012.
Adverse Event Reporting Description	The Serious Adverse Event data presented here is for the safety population. The Other Adverse Event data presented here is for the safety population during the 8 week double-blind treatment period.

Arm/Group Title	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran 80 mg
Arm/Group Description	Dose matched placebo, oral administ...	40mg Levomilnacipran ER, oral admin...	40mg Levomilnacipran ER, oral admin...
Arm/Group Description	Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.	40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.
All-Cause Mortality
	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/186 (0.54%)	3/188 (1.60%)	0/188 (0.00%)
Gastrointestinal disorders
Intussusception ^† 1	0/186 (0.00%)	1/188 (0.53%)	0/188 (0.00%)
General disorders
Non-cardiac chest pain ^† 1	0/186 (0.00%)	1/188 (0.53%)	0/188 (0.00%)
Injury, poisoning and procedural complications
Facial Bones Fracture ^† 1	1/186 (0.54%)	0/188 (0.00%)	0/188 (0.00%)
Road traffic accident ^† 1	1/186 (0.54%)	0/188 (0.00%)	0/188 (0.00%)
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1	0/186 (0.00%)	1/188 (0.53%)	0/188 (0.00%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 14.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	58/186 (31.18%)	90/188 (47.87%)	110/188 (58.51%)
Cardiac disorders
Tachycardia ^† 1	6/186 (3.23%)	4/188 (2.13%)	15/188 (7.98%)
Gastrointestinal disorders
Nausea ^† 1	11/186 (5.91%)	27/188 (14.36%)	29/188 (15.43%)
Dry mouth ^† 1	7/186 (3.76%)	19/188 (10.11%)	18/188 (9.57%)
Constipation ^† 1	4/186 (2.15%)	13/188 (6.91%)	12/188 (6.38%)
Diarrhoea ^† 1	10/186 (5.38%)	7/188 (3.72%)	7/188 (3.72%)
Infections and infestations
Upper respiratory tract infection ^† 1	11/186 (5.91%)	10/188 (5.32%)	8/188 (4.26%)
Investigations
Heart rate increased ^† 1	0/186 (0.00%)	13/188 (6.91%)	11/188 (5.85%)
Nervous system disorders
Headache ^† 1	16/186 (8.60%)	22/188 (11.70%)	25/188 (13.30%)
Dizziness ^† 1	1/186 (0.54%)	7/188 (3.72%)	12/188 (6.38%)
Renal and urinary disorders
Urinary hesitation ^† 1	0/186 (0.00%)	6/188 (3.19%)	12/188 (6.38%)
Reproductive system and breast disorders
Erectile dysfunction ^† 1	1/70 (1.43%)	4/71 (5.63%)	9/64 (14.06%)
Testicular pain ^† 1	0/70 (0.00%)	3/71 (4.23%)	5/64 (7.81%)
Skin and subcutaneous tissue disorders
Hyperhidrosis ^† 1	6/186 (3.23%)	4/188 (2.13%)	15/188 (7.98%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 14.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

All data generated in this study will be the property of Forest Research Institute, Inc. An integrated clinical and statistical report will be prepared at the completion of the study.

Publication of the results by the PI will be patient to mutual agreement between the PI and Forest Research Institute, Inc.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Carl Gommoll, MS, Sr. Dir. Clinical Development Psychiatry
Organization:	Forest Research Institute
Phone:	201-427-8000 ext 8124
EMail:	carl.gommoll@frx.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cutler AJ, Gommoll CP, Chen C, Greenberg WM, Ruth A. Levomilnacipran Extended-Release Treatment in Patients With Major Depressive Disorder: Improvements in Functional Impairment Categories. Prim Care Companion CNS Disord. 2015 Jun 11;17(3):10.4088/PCC.14m01753. doi: 10.4088/PCC.14m01753. eCollection 2015.

Bakish D, Bose A, Gommoll C, Chen C, Nunez R, Greenberg WM, Liebowitz M, Khan A. Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study. J Psychiatry Neurosci. 2014 Jan;39(1):40-9. doi: 10.1503/jpn.130040.

Layout table for additonal information

Responsible Party:	Forest Laboratories
ClinicalTrials.gov Identifier:	NCT01377194
Other Study ID Numbers:	LVM-MD-10
First Submitted:	June 10, 2011
First Posted:	June 21, 2011
Results First Submitted:	August 22, 2013
Results First Posted:	October 29, 2013
Last Update Posted:	October 29, 2013

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