Trial Outcomes & Findings for Safety and Efficacy of Levomilnacipran ER (Levomilnacipran SR) in Major Depressive Disorder (NCT NCT01377194)

NCT ID: NCT01377194

Last Updated: 2013-10-29

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 568 participants
• Primary outcome timeframe: From Baseline to Week 8
• Results posted on: 2013-10-29

Participant Flow

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.

All patients went through a 1-week single-blind placebo run-in period before randomization.

Participant milestones

Measure	Placebo Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran ER 40 mg 40mg of Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks	Levomilnacipran ER 80 mg 80mg of Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks
Overall Study STARTED	186	188	188
Overall Study COMPLETED	154	145	142
Overall Study NOT COMPLETED	32	43	46

Reasons for withdrawal

Measure	Placebo Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran ER 40 mg 40mg of Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks	Levomilnacipran ER 80 mg 80mg of Levomilnacipran ER, oral administration in capsule form, once daily, for 8 weeks
Overall Study Adverse Event	3	12	19
Overall Study Lack of Efficacy	3	3	3
Overall Study Protocol Violation	4	10	6
Overall Study Withdrawal by Subject	8	10	7
Overall Study Lost to Follow-up	14	8	11

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo n=186 Participants Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran ER 40 mg n=188 Participants 40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran 80 mg n=188 Participants 40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.	Total n=562 Participants Total of all reporting groups
Age Continuous	42.3 years STANDARD_DEVIATION 13.2 • n=5 Participants	42.9 years STANDARD_DEVIATION 13.4 • n=7 Participants	43.1 years STANDARD_DEVIATION 12.8 • n=5 Participants	42.8 years STANDARD_DEVIATION 13.1 • n=4 Participants
Age, Customized < 20	3 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants	9 participants n=4 Participants
Age, Customized ≥ 20-29	35 participants n=5 Participants	35 participants n=7 Participants	28 participants n=5 Participants	98 participants n=4 Participants
Age, Customized ≥ 30-39	43 participants n=5 Participants	40 participants n=7 Participants	44 participants n=5 Participants	127 participants n=4 Participants
Age, Customized ≥ 40-49	45 participants n=5 Participants	49 participants n=7 Participants	53 participants n=5 Participants	147 participants n=4 Participants
Age, Customized ≥ 50-59	43 participants n=5 Participants	42 participants n=7 Participants	36 participants n=5 Participants	121 participants n=4 Participants
Age, Customized ≥ 60	17 participants n=5 Participants	21 participants n=7 Participants	22 participants n=5 Participants	60 participants n=4 Participants
Sex: Female, Male Female	116 Participants n=5 Participants	117 Participants n=7 Participants	124 Participants n=5 Participants	357 Participants n=4 Participants
Sex: Female, Male Male	70 Participants n=5 Participants	71 Participants n=7 Participants	64 Participants n=5 Participants	205 Participants n=4 Participants
Race/Ethnicity, Customized White	135 participants n=5 Participants	142 participants n=7 Participants	139 participants n=5 Participants	416 participants n=4 Participants
Race/Ethnicity, Customized Black or African-American	35 participants n=5 Participants	37 participants n=7 Participants	36 participants n=5 Participants	108 participants n=4 Participants
Race/Ethnicity, Customized Asian	7 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	14 participants n=4 Participants
Race/Ethnicity, Customized American Indian of Alaska Native	3 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	3 participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized Other Race	5 participants n=5 Participants	5 participants n=7 Participants	10 participants n=5 Participants	20 participants n=4 Participants
Race/Ethnicity, Customized Hispanic	23 participants n=5 Participants	24 participants n=7 Participants	15 participants n=5 Participants	62 participants n=4 Participants
Race/Ethnicity, Customized Non-Hispanic	163 participants n=5 Participants	164 participants n=7 Participants	173 participants n=5 Participants	500 participants n=4 Participants
Region of Enrollment United States	177 participants n=5 Participants	183 participants n=7 Participants	180 participants n=5 Participants	540 participants n=4 Participants
Region of Enrollment Canada	9 participants n=5 Participants	5 participants n=7 Participants	8 participants n=5 Participants	22 participants n=4 Participants
Weight	81.60 kg STANDARD_DEVIATION 17.77 • n=5 Participants	81.35 kg STANDARD_DEVIATION 17.09 • n=7 Participants	81.73 kg STANDARD_DEVIATION 17.57 • n=5 Participants	81.56 kg STANDARD_DEVIATION 17.45 • n=4 Participants
Height	168.41 cm STANDARD_DEVIATION 9.69 • n=5 Participants	169.48 cm STANDARD_DEVIATION 9.79 • n=7 Participants	168.63 cm STANDARD_DEVIATION 8.91 • n=5 Participants	168.84 cm STANDARD_DEVIATION 9.47 • n=4 Participants
Body Mass Index (BMI)	28.67 Kilograms Per Meter Squared STANDARD_DEVIATION 5.19 • n=5 Participants	28.25 Kilograms Per Meter Squared STANDARD_DEVIATION 5.17 • n=7 Participants	28.71 Kilograms Per Meter Squared STANDARD_DEVIATION 5.68 • n=5 Participants	28.54 Kilograms Per Meter Squared STANDARD_DEVIATION 5.35 • n=4 Participants

PRIMARY outcome

Timeframe: From Baseline to Week 8

Population: 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.

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).

Outcome measures

Measure	Placebo n=185 Participants Dose matched placebo oral administration in capsule form, once daily, for 8 weeks.	Levomilnacipran ER 40 mg n=185 Participants 40mg Levomilnacipran ER oral administration in capsule form, once daily, for 8 weeks.	Levomilnacipran ER 80 mg n=187 Participants 80mg of Levomilnacipran ER oral administration in capsule form, once daily for 8 weeks
Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score - Mixed-effects Model for Repeated Measures (MMRM) Analysis.	-11.3 Units on a scale Standard Deviation 0.77	-14.6 Units on a scale Standard Deviation 0.79	-14.4 Units on a scale Standard Deviation 0.79

SECONDARY outcome

Timeframe: From Baseline to Week 8

Population: 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.

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)

Outcome measures

Measure	Placebo n=185 Participants Dose matched placebo oral administration in capsule form, once daily, for 8 weeks.	Levomilnacipran ER 40 mg n=185 Participants 40mg Levomilnacipran ER oral administration in capsule form, once daily, for 8 weeks.	Levomilnacipran ER 80 mg n=187 Participants 80mg of Levomilnacipran ER oral administration in capsule form, once daily for 8 weeks
Change in Sheehan Disability Scale (SDS) Total Score	-5.4 units on a scale Standard Error 0.66	-7.3 units on a scale Standard Error 0.68	-8.2 units on a scale Standard Error 0.66

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 58 other events

Deaths: 0 deaths

Levomilnacipran ER 40 mg

Serious events: 3 serious events

Other events: 90 other events

Deaths: 0 deaths

Levomilnacipran 80 mg

Serious events: 0 serious events

Other events: 110 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=186 participants at risk Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran ER 40 mg n=188 participants at risk 40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran 80 mg n=188 participants at risk 40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.
Injury, poisoning and procedural complications Facial Bones Fracture	0.54% 1/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.00% 0/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.00% 0/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
General disorders Non-cardiac chest pain	0.00% 0/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.53% 1/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.00% 0/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Gastrointestinal disorders Intussusception	0.00% 0/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.53% 1/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.00% 0/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.53% 1/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.00% 0/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Injury, poisoning and procedural complications Road traffic accident	0.54% 1/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.00% 0/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	0.00% 0/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.

Other adverse events

Measure	Placebo n=186 participants at risk Dose matched placebo, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran ER 40 mg n=188 participants at risk 40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.	Levomilnacipran 80 mg n=188 participants at risk 40mg Levomilnacipran ER, oral administration in capsule form, once daily for 8 weeks.
Gastrointestinal disorders Nausea	5.9% 11/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	14.4% 27/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	15.4% 29/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Nervous system disorders Headache	8.6% 16/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	11.7% 22/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	13.3% 25/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Gastrointestinal disorders Dry mouth	3.8% 7/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	10.1% 19/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	9.6% 18/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Skin and subcutaneous tissue disorders Hyperhidrosis	3.2% 6/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	2.1% 4/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	8.0% 15/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Cardiac disorders Tachycardia	3.2% 6/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	2.1% 4/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	8.0% 15/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Gastrointestinal disorders Constipation	2.2% 4/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	6.9% 13/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	6.4% 12/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Nervous system disorders Dizziness	0.54% 1/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	3.7% 7/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	6.4% 12/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Renal and urinary disorders Urinary hesitation	0.00% 0/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	3.2% 6/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	6.4% 12/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Investigations Heart rate increased	0.00% 0/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	6.9% 13/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	5.9% 11/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Reproductive system and breast disorders Erectile dysfunction	1.4% 1/70 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	5.6% 4/71 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	14.1% 9/64 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Infections and infestations Upper respiratory tract infection	5.9% 11/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	5.3% 10/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	4.3% 8/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Gastrointestinal disorders Diarrhoea	5.4% 10/186 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	3.7% 7/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	3.7% 7/188 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.
Reproductive system and breast disorders Testicular pain	0.00% 0/70 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	4.2% 3/71 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.	7.8% 5/64 • Adverse event data was collected over a 10 month period from June 2011 to March 2012. 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.

Additional Information

Carl Gommoll, MS, Sr. Dir. Clinical Development Psychiatry

Forest Research Institute

Phone: 201-427-8000

Email: carl.gommoll@frx.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER