Safety and Efficacy of Levomilnacipran ER (F2695 SR) in Adults With Fatigue Associated With Major Depressive Disorder

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01254305
• Collaborator: (none)
• Enrollment: 262
• Locations: 20
• Arms: 3
• Duration (Months): 15
• Patients Per Site: 13.1
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the efficacy, safety and tolerability of Levomilnacipran ER for the treatment of fatigue associated with major depressive disorder (MDD).

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Levomilnacipran ER; Drug: Paroxetine, Sertraline, Citalopram or Fluoxetine.; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 262 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Placebo- and Active-Controlled Study of F2695 SR in Adult Patients With Fatigue Associated With Major Depressive Disorder
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 40 -120 mg/day Levomilnacipran ER capsules, oral administration	Drug: Levomilnacipran ER; Drug: Levomilnacipran ER (40 -120 mg/day) Study drug is to be given orally, in capsule form, once daily for 8 weeks
Active Comparator: 2 Randomized to treatment with 1 of 4 Selective Serotonin Reuptake Inhibitors (SSRIs) - Paroxetine, Sertraline, Citalopram or Fluoxetine Oral administration, once daily dosing	Drug: Paroxetine, Sertraline, Citalopram or Fluoxetine.; Paroxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Sertraline (50, 100, or 150 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Citalopram (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks or Fluoxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks
Placebo Comparator: 3 Matching placebo capsules, oral administration	Drug: Placebo; Matching placebo capsules, oral administration, once daily dosing

Outcome Measures

Primary Outcome Measures

1. Change in Clinical Global Impression of Severity (CGI-S) for Fatigue Score [From Baseline to Week 8]

   The CGI-S is a clinician-rated scale that rates the severity of the patient's current state of fatigue based on the Investigator's clinical opinion with regard to the patient population with Major Depressive Disorder (MDD). Patient were rated on a scale from 1 to 7, with 1 indicating a normal state and 7 indicating that the patient was among the most extremely fatigued

2. Change in Patient Global Impressions of Severity (PGI-S) for Fatigue Score [From Baseline to Week 8]

   The PGI-S is a clinician-rated scale that rates was used to rate the severity of the patient's current state of overall fatigue. Patients were rated on a scale from 1 to 7, with 1 indicating no symptoms of fatigue and 7 indicating extreme fatigue.

Secondary Outcome Measures

1. Change in Cognitive and Physical Functioning Questionnaire (CPFQ), Last Observation Carried Forward [From Baseline to Week 8]

   The Cognitive and Physical Functioning Questionnaire is a patient-rated, 7-item scale used to measure cognitive and executive dysfunction in mood and anxiety disorders. The CPFQ is sensitive to change with treatment and displays convergent validity by significant correlations with other measures of sleepiness, fatigue, apathy, and neuropsychological functioning. Patients are rated on a scale from 1 to 6 for seven common complaints of depressed patients reporting fatigue or cognitive/executive problems-with 1 indicating greater than normal functioning, 2 indicating normal functioning, and 3 to 6 indicating degrees of impaired functioning. The CPFQ ranges from the best possible score of 7 (greater than normal functioning) to the worst possible score of 42 (totally absent).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women, 18-65 years old

• Currently meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria for Major Depressive Disorder

• The patient's current depressive episode must be at least 4 weeks in duration

Exclusion Criteria:

• Women who are pregnant, women who will be breastfeeding during the study, and women of child-bearing potential who are not practicing a reliable method of birth control

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

1. any manic or hypomanic episode;

2. schizophrenia or any other psychotic disorder;

3. obsessive-compulsive disorder.

• Patients who are considered a suicide risk

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 010	Birmingham	Alabama	United States	35216
2	Forest Investigative Site 002	Little Rock	Arkansas	United States	72223
3	Forest Investigative Site 001	Cerritos	California	United States	90703
4	Forest Investigative Site 014	Fort Myers	Florida	United States	33912
5	Forest Investigative Site 006	Jacksonville	Florida	United States	32216
6	Forest Investigative Site 017	Orange City	Florida	United States	32763
7	Forest Investigative Site 005	Orlando	Florida	United States	32806
8	Forest Investigative Site 012	Tampa	Florida	United States	33613
9	Forest Investigative Site 009	Atlanta	Georgia	United States	30308
10	Forest Investigative Site 016	Joliet	Illinois	United States	60435
11	Forest Investigative Site 004	New Orleans	Louisiana	United States	70122
12	Forest Investigative Site 022	Boston	Massachusetts	United States	02135
13	Forest Investigative Site 011	Bronx	New York	United States	10467
14	Forest Investigative Site 015	Cedarhurst	New York	United States	11516
15	Forest Investigative Site 003	Cincinnati	Ohio	United States	45227
16	Forest Investigative Site 013	Dayton	Ohio	United States	45417
17	Forest Investigative Site 020	Lincoln	Rhode Island	United States	02865
18	Forest Investigative Site 018	Memphis	Tennessee	United States	38119
19	Forest Investigative Site 008	Dallas	Texas	United States	75235
20	Forest Investigative Site 007	Middleton	Wisconsin	United States	53562

Sponsors and Collaborators

• Forest Laboratories

Investigators

• Study Director: Carl Gommoll, MS, Forest Laboratories

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT01254305
• Other Study ID Numbers: LVM-MD-06
• First Posted: Dec 6, 2010
• Last Update Posted: Aug 6, 2014
• Last Verified: Aug 1, 2014

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

Study Results

Participant Flow

Recruitment Details	Patients were recruited over a 12-month period from April of 2011 to April of 2012 at 20 studies sites in the United States.
Pre-assignment Detail	Patients went through a 1-week single-blind placebo run-in period, followed by an 8-week double-blind treatment period.

Arm/Group Title	Placebo	Levomilnacipran ER	SSRI
Arm/Group Description	Matching placebo capsules, oral administration, once daily dosing.	40 -120 mg Levomilnacipran ER capsules, oral administration once daily for 8 weeks.	Randomized to treatment with 1 of 4 Selective Serotonin Reuptake Inhibitors (SSRIs) - Paroxetine, Sertraline, Citalopram or Fluoxetine. Paroxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Sertraline (50, 100, or 150 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Citalopram (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks or Fluoxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks.
Period Title: Overall Study
STARTED	93	90	79
Safety Population	89	85	77
COMPLETED	71	72	62
NOT COMPLETED	22	18	17

Baseline Characteristics

Arm/Group Title	Placebo	Levomilnacipran ER	SSRI	Total
Arm/Group Description	Matching placebo capsules, oral administration Placebo : Matching placebo capsules, oral administration, once daily dosing	40 - 120 mg Levomilnacipran ER capsules, oral administration, once daily for 8 weeks	Randomized to treatment with 1 of 4 Selective Serotonin Reuptake Inhibitors (SSRIs) - Paroxetine, Sertraline, Citalopram or Fluoxetine. Paroxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Sertraline (50, 100, or 150 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Citalopram (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks or Fluoxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks.	Total of all reporting groups
Overall Participants	89	85	77	251
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.4 (12.0)	42.9 (12.6)	42.8 (11.3)	42.3 (12.0)
Sex: Female, Male (Count of Participants)
Female	58 65.2%	49 57.6%	49 63.6%	156 62.2%
Male	31 34.8%	36 42.4%	28 36.4%	95 37.8%
Race/Ethnicity, Customized (participants) [Number]
White	62 69.7%	57 67.1%	47 61%	166 66.1%
Black or African American	26 29.2%	25 29.4%	25 32.5%	76 30.3%
Asian	1 1.1%	3 3.5%	2 2.6%	6 2.4%
American Indian or Alaska Native	0 0%	0 0%	1 1.3%	1 0.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Other	0 0%	0 0%	2 2.6%	2 0.8%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	8 9%	4 4.7%	10 13%	22 8.8%
Not Hispanic or Latino	81 91%	81 95.3%	67 87%	229 91.2%
Region of Enrollment (participants) [Number]
United States	89 100%	85 100%	77 100%	251 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	79.95 (15.27)	82.23 (18.14)	83.31 (17.61)	81.75 (17.00)
Body Mass Index (BMI) (Kilograms Per Meter Squared) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms Per Meter Squared]	28.16 (4.85)	28.61 (5.22)	28.80 (5.10)	28.51 (5.04)

Outcome Measures

1. Primary Outcome

Title	Change in Clinical Global Impression of Severity (CGI-S) for Fatigue Score
Description	The CGI-S is a clinician-rated scale that rates the severity of the patient's current state of fatigue based on the Investigator's clinical opinion with regard to the patient population with Major Depressive Disorder (MDD). Patient were rated on a scale from 1 to 7, with 1 indicating a normal state and 7 indicating that the patient was among the most extremely fatigued
Time Frame	From Baseline to Week 8

Outcome Measure Data

Analysis Population Description

The Randomized Population consisted of 262 patients, with 251 patients who took at least 1 dose of double-blind treatment to comprise the Safety population. The Intent-to-Treat (ITT) Population consisted of 248 patients in the Safety Population who had a baseline and at least 1 postbaseline assessment of either the CGI-S or PGI-I fatigue score.

Arm/Group Title	Placebo	Levomilnacipran ER	SSRI
Arm/Group Description	Dose matched placebo, oral administration in capsule form, once daily for 8 weeks	40 - 120 mg Levomilnacipran ER capsules, oral administration in capsule form, once daily for 8 weeks	Randomized to treatment with 1 of 4 Selective Serotonin Reuptake Inhibitors (SSRIs) - Paroxetine, Sertraline, Citalopram or Fluoxetine. Paroxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Sertraline (50, 100, or 150 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Citalopram (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks or Fluoxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks.
Measure Participants	88	85	75
Mean (Standard Deviation) [units on a scale]	-1.5 (1.3)	-1.8 (1.4)	-1.9 (1.4)

2. Secondary Outcome

Title	Change in Cognitive and Physical Functioning Questionnaire (CPFQ), Last Observation Carried Forward
Description	The Cognitive and Physical Functioning Questionnaire is a patient-rated, 7-item scale used to measure cognitive and executive dysfunction in mood and anxiety disorders. The CPFQ is sensitive to change with treatment and displays convergent validity by significant correlations with other measures of sleepiness, fatigue, apathy, and neuropsychological functioning. Patients are rated on a scale from 1 to 6 for seven common complaints of depressed patients reporting fatigue or cognitive/executive problems-with 1 indicating greater than normal functioning, 2 indicating normal functioning, and 3 to 6 indicating degrees of impaired functioning. The CPFQ ranges from the best possible score of 7 (greater than normal functioning) to the worst possible score of 42 (totally absent).
Time Frame	From Baseline to Week 8

Outcome Measure Data

Analysis Population Description

The Randomized Population consisted of 262 patients, with 251 patients who took at least 1 dose of double-blind treatment to comprise the Safety population.

Arm/Group Title	Placebo	Levomilnacipran ER	SSRI
Arm/Group Description	Dose matched placebo capsules, oral administration for 8 weeks.	40 - 120 mg Levomilnacipran ER capsules, oral administration once per day for 8 weeks	Randomized to treatment with 1 of 4 Selective Serotonin Reuptake Inhibitors (SSRIs) - Paroxetine, Sertraline, Citalopram or Fluoxetine. Paroxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Sertraline (50, 100, or 150 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Citalopram (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks or Fluoxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks.
Measure Participants	88	85	75
Mean (Standard Deviation) [units on a scale]	-5.9 (7.9)	-7.0 (7.3)	-6.4 (7.0)

3. Primary Outcome

Title	Change in Patient Global Impressions of Severity (PGI-S) for Fatigue Score
Description	The PGI-S is a clinician-rated scale that rates was used to rate the severity of the patient's current state of overall fatigue. Patients were rated on a scale from 1 to 7, with 1 indicating no symptoms of fatigue and 7 indicating extreme fatigue.
Time Frame	From Baseline to Week 8

Outcome Measure Data

Analysis Population Description

The Randomized Population consisted of 262 patients, with 251 patients who took at least 1 dose of double-blind treatment to comprise the Safety population. The Intent-to-Treat (ITT) Population consisted of 248 patients in the Safety Population who had a baseline and at least 1 postbaseline assessment of either the CGI-S or PGI-I fatigue score.

Arm/Group Title	Placebo	Levomilnacipran ER	SSRI
Arm/Group Description	Dose matched placebo, oral administration in capsule form, once daily for 8 weeks	40 - 120 mg Levomilnacipran ER capsules, oral administration once per day for 8 weeks.	Randomized to treatment with 1 of 4 Selective Serotonin Reuptake Inhibitors (SSRIs) - Paroxetine, Sertraline, Citalopram or Fluoxetine. Paroxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Sertraline (50, 100, or 150 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Citalopram (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks or Fluoxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks.
Measure Participants	88	85	75
Mean (Standard Deviation) [units on a scale]	-1.4 (1.5)	-1.7 (1.5)	-1.7 (1.5)

Adverse Events

Time Frame	Adverse event data occurred over a 16-month period from April of 2011 to September of 2012 at 20 studies sites in the United States.
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		SSRI
Arm/Group Description	Matching placebo capsules, oral administration Placebo : Matching placebo capsules, oral administration, once daily dosing		40 -120 mg Levomilnacipran ER capsules, oral administration, once daily for 8 weeks		Randomized to treatment with 1 of 4 Selective Serotonin Reuptake Inhibitors (SSRIs) - Paroxetine, Sertraline, Citalopram or Fluoxetine. Paroxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Sertraline (50, 100, or 150 mg/day) to be given orally, in capsule form, once daily for 8 weeks, or Citalopram (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks or Fluoxetine (20, 40, or 60 mg/day) to be given orally, in capsule form, once daily for 8 weeks.
All Cause Mortality
	Placebo		Levomilnacipran ER		SSRI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Levomilnacipran ER		SSRI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		1/85 (1.2%)		0/77 (0%)
Infections and infestations
Pneumonia	0/89 (0%)		1/85 (1.2%)		0/77 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Levomilnacipran ER		SSRI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/89 (43.8%)		41/85 (48.2%)		37/77 (48.1%)
Gastrointestinal disorders
Dry mouth	6/89 (6.7%)		8/85 (9.4%)		9/77 (11.7%)
Diarrhoea	8/89 (9%)		4/85 (4.7%)		9/77 (11.7%)
General disorders
Nausea	4/89 (4.5%)		14/85 (16.5%)		6/77 (7.8%)
Infections and infestations
Upper respiratory tract infection	7/89 (7.9%)		0/85 (0%)		3/77 (3.9%)
Investigations
Heart rate increased	3/89 (3.4%)		6/85 (7.1%)		0/77 (0%)
Nervous system disorders
Headache	14/89 (15.7%)		12/85 (14.1%)		6/77 (7.8%)
Dizziness	2/89 (2.2%)		6/85 (7.1%)		1/77 (1.3%)
Somnolence	4/89 (4.5%)		3/85 (3.5%)		6/77 (7.8%)
Psychiatric disorders
Insomnia	1/89 (1.1%)		2/85 (2.4%)		5/77 (6.5%)
Anxiety	1/89 (1.1%)		1/85 (1.2%)		5/77 (6.5%)
Initial insomnia	1/89 (1.1%)		1/85 (1.2%)		5/77 (6.5%)

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 Investigator will be subject to mutual agreement between the Investigator and Forest Research Institute, Inc.