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

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01377194
• Collaborator: (none)
• Enrollment: 568
• Locations: 51
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 11.1
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy, safety, and tolerability of Levomilnacipran ER compared to placebo in patients with Major Depressive Disorder (MDD).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 568 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Placebo-Controlled, Fixed-Dose Study of Levomilnacipran SR in Patients With Major Depressive Disorder
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 40mg Levomilnacipran ER	Drug: Levomilnacipran ER; Drug: Levomilnacipran ER 40mg/day Study drug is to be given orally, in capsule form, once daily, for 8 weeks
Experimental: 2 80mg of Levomilnacipran ER	Drug: Levomilnacipran ER; Drug: Levomilnacipran ER 80mg/day Study drug is to be given orally, in capsule form, once daily, for 8 weeks
Placebo Comparator: 3 Placebo	Drug: Placebo; Matching placebo to be given orally, in capsule form, once daily, for 8 weeks.

Outcome Measures

Primary Outcome Measures

1. Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score - Mixed-effects Model for Repeated Measures (MMRM) Analysis. [From Baseline to Week 8]

   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).

Secondary Outcome Measures

1. Change in Sheehan Disability Scale (SDS) Total Score [From Baseline to Week 8]

   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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women, 18-75 years old

• Currently meet the DSM-IV-TR criteria for Major Depressive Disorder

• The patient's current depressive episode must be at least 6 weeks in duration

Exclusion Criteria:

• Women who are pregnant, women who will be breastfeeding during the study, and women with childbearing potential who are not practicing a reliable method of birth control.

• Patients who are considered a suicide risk

• Patients with a history of meeting DSM-IV-TR criteria for

• 1. any manic or hypomanic episode
• 1. schizophrenia or any other psychotic disorder
• 1. obsessive-compulsive disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 039	Birmingham	Alabama	United States	35216
2	Forest Investigative Site 037	Beverly Hills	California	United States	90210
3	Forest Investigative Site 012	Encino	California	United States	91316
4	Forest Investigative Site 038	Newport Beach	California	United States	92660
5	Forest Investigative Site 024	Oceanside	California	United States	92056
6	Forest Investigative Site 001	Redlands	California	United States	92374
7	Forest Investigative Site 031	San Diego	California	United States	92108
8	Forest Investigative Site 050	Sherman Oaks	California	United States	91403
9	Forest Investigative Site 034	Cromwell	Connecticut	United States	06416
10	Forest Investigative Site 021	Coral Springs	Florida	United States	33067
11	Forest Investigative Site 043	Fort Myers	Florida	United States	33912
12	Forest Investigative Site 018	Gainesville	Florida	United States	32607
13	Forest Investigative Site 060	Hallandale Beach	Florida	United States	33009
14	Forest Investigative Site 020	Jacksonville	Florida	United States	32216
15	Forest Investigative Site 005	Ocala	Florida	United States	34471
16	Forest Investigative Site 014	Orlando	Florida	United States	32806
17	Forest Investigative Site 028	Orlando	Florida	United States	32806
18	Forest Investigative Site 046	Atlanta	Georgia	United States	30328
19	Forest Investigative Site 041	Chicago	Illinois	United States	60634
20	Forest Investigative Site 054	Chicago	Illinois	United States	60640
21	Forest Investigative Site 026	Hoffman Estates	Illinois	United States	60169
22	Forest Investigative Site 045	Indianapolis	Indiana	United States	46260
23	Forest Investigative Site 056	Prairie Village	Kansas	United States	66206
24	Forest Investigative Site 049	Haverhill	Massachusetts	United States	01830
25	Forest Investigative Site 044	Cherry Hill	New Jersey	United States	08002
26	Forest Investigative Site 023	Willingboro	New Jersey	United States	08046
27	Forest Investigative Site 004	Brooklyn	New York	United States	11214
28	Forest Investigative Site 002	Mount Kisco	New York	United States	10549
29	Forest Investigative Site 016	New York City	New York	United States	10003
30	Forest Investigative Site 051	New York	New York	United States	10021
31	Forest Investigative Site 042	Orangeburg	New York	United States	10962
32	Forest Investigative Site 061	Raleigh	North Carolina	United States	27607
33	Forest Investigative Site 010	Dayton	Ohio	United States	45417
34	Forest Investigative Site 048	Oklahoma City	Oklahoma	United States	73112
35	Forest Investigative Site 053	Portland	Oregon	United States	97210
36	Forest Investigative Site 017	Salem	Oregon	United States	97301
37	Forest Investigative Site 011	Allentown	Pennsylvania	United States	18104
38	Forest Investigative Site 052	Bridgeville	Pennsylvania	United States	15017
39	Forest Investigative Site 027	Philadelphia	Pennsylvania	United States	19107
40	Forest Investigative Site 059	Lincoln	Rhode Island	United States	02865
41	Forest Investigative Site 029	Memphis	Tennessee	United States	38119
42	Forest Investigative Site 009	Dallas	Texas	United States	75231
43	Forest Investigative Site 007	San Antonio	Texas	United States	78229
44	Forest Investigative Site 035	San Antonio	Texas	United States	78229
45	Forest Investigative Site 022	Bellevue	Washington	United States	98007
46	Forest Investigative Site 055	Seattle	Washington	United States	98104
47	Forest Investigative Site 057	Spokane	Washington	United States	99204
48	Forest Investigative Site 025	Kelowna	British Columbia	Canada	V1Y 1Z9
49	Forest Investigative Site 036	Sydney	Nova Scotia	Canada	B1S 2EB
50	Forest Investigative Site 006	Chatham	Ontario	Canada	N7M 1B7
51	Forest Investigative Site 003	Ottawa	Ontario	Canada	K1G 4G3

Sponsors and Collaborators

• Forest Laboratories

Investigators

• Study Director: Carl Gommoll, MS, Forest Research Institute, a subsidiary of Forest Laboratories

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT01377194
• Other Study ID Numbers: LVM-MD-10
• First Posted: Jun 21, 2011
• Last Update Posted: Oct 29, 2013
• Last Verified: Aug 1, 2013

• Keywords provided by Forest Laboratories: Depression; Major Depressive Disorder
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Milnacipran; Levomilnacipran

Study Results

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 Detail	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 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

Baseline Characteristics

Arm/Group Title	Placebo	Levomilnacipran ER 40 mg	Levomilnacipran 80 mg	Total
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 Participants	186	188	188	562
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.3 (13.2)	42.9 (13.4)	43.1 (12.8)	42.8 (13.1)
Age, Customized (participants) [Number]
< 20	3 1.6%	1 0.5%	5 2.7%	9 1.6%
≥ 20-29	35 18.8%	35 18.6%	28 14.9%	98 17.4%
≥ 30-39	43 23.1%	40 21.3%	44 23.4%	127 22.6%
≥ 40-49	45 24.2%	49 26.1%	53 28.2%	147 26.2%
≥ 50-59	43 23.1%	42 22.3%	36 19.1%	121 21.5%
≥ 60	17 9.1%	21 11.2%	22 11.7%	60 10.7%
Sex: Female, Male (Count of Participants)
Female	116 62.4%	117 62.2%	124 66%	357 63.5%
Male	70 37.6%	71 37.8%	64 34%	205 36.5%
Race/Ethnicity, Customized (participants) [Number]
White	135 72.6%	142 75.5%	139 73.9%	416 74%
Black or African-American	35 18.8%	37 19.7%	36 19.1%	108 19.2%
Asian	7 3.8%	4 2.1%	3 1.6%	14 2.5%
American Indian of Alaska Native	3 1.6%	0 0%	0 0%	3 0.5%
Native Hawaiian or other Pacific Islander	1 0.5%	0 0%	0 0%	1 0.2%
Other Race	5 2.7%	5 2.7%	10 5.3%	20 3.6%
Hispanic	23 12.4%	24 12.8%	15 8%	62 11%
Non-Hispanic	163 87.6%	164 87.2%	173 92%	500 89%
Region of Enrollment (participants) [Number]
United States	177 95.2%	183 97.3%	180 95.7%	540 96.1%
Canada	9 4.8%	5 2.7%	8 4.3%	22 3.9%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	81.60 (17.77)	81.35 (17.09)	81.73 (17.57)	81.56 (17.45)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	168.41 (9.69)	169.48 (9.79)	168.63 (8.91)	168.84 (9.47)
Body Mass Index (BMI) (Kilograms Per Meter Squared) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms Per Meter Squared]	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 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 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
Measure Participants	185	185	187
Mean (Standard Deviation) [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0027
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-3.303
	Confidence Interval	(2-Sided) 95%; -5.457 to -1.148
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-3.141
	Confidence Interval	(2-Sided) 95%; -5.293 to -0.988
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Sheehan Disability Scale (SDS) Total Score
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

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 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
Measure Participants	185	185	187
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0459
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levomilnacipran ER 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0028
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Levomilnacipran ER 40 mg		Levomilnacipran 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/186 (0.5%)		3/188 (1.6%)		0/188 (0%)
Gastrointestinal disorders
Intussusception	0/186 (0%)		1/188 (0.5%)		0/188 (0%)
General disorders
Non-cardiac chest pain	0/186 (0%)		1/188 (0.5%)		0/188 (0%)
Injury, poisoning and procedural complications
Facial Bones Fracture	1/186 (0.5%)		0/188 (0%)		0/188 (0%)
Road traffic accident	1/186 (0.5%)		0/188 (0%)		0/188 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/186 (0%)		1/188 (0.5%)		0/188 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Levomilnacipran ER 40 mg		Levomilnacipran 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/186 (31.2%)		90/188 (47.9%)		110/188 (58.5%)
Cardiac disorders
Tachycardia	6/186 (3.2%)		4/188 (2.1%)		15/188 (8%)
Gastrointestinal disorders
Nausea	11/186 (5.9%)		27/188 (14.4%)		29/188 (15.4%)
Dry mouth	7/186 (3.8%)		19/188 (10.1%)		18/188 (9.6%)
Constipation	4/186 (2.2%)		13/188 (6.9%)		12/188 (6.4%)
Diarrhoea	10/186 (5.4%)		7/188 (3.7%)		7/188 (3.7%)
Infections and infestations
Upper respiratory tract infection	11/186 (5.9%)		10/188 (5.3%)		8/188 (4.3%)
Investigations
Heart rate increased	0/186 (0%)		13/188 (6.9%)		11/188 (5.9%)
Nervous system disorders
Headache	16/186 (8.6%)		22/188 (11.7%)		25/188 (13.3%)
Dizziness	1/186 (0.5%)		7/188 (3.7%)		12/188 (6.4%)
Renal and urinary disorders
Urinary hesitation	0/186 (0%)		6/188 (3.2%)		12/188 (6.4%)
Reproductive system and breast disorders
Erectile dysfunction	1/70 (1.4%)		4/71 (5.6%)		9/64 (14.1%)
Testicular pain	0/70 (0%)		3/71 (4.2%)		5/64 (7.8%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	6/186 (3.2%)		4/188 (2.1%)		15/188 (8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.