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Trial record 33 of 88 for:    "Neuromuscular Disease" | "Norepinephrine"

Discontinuation Study of the Durability of Effect of Milnacipran for the Treatment of Fibromyalgia

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ClinicalTrials.gov Identifier: NCT01014585
Recruitment Status : Completed
First Posted : November 17, 2009
Results First Posted : September 7, 2011
Last Update Posted : September 7, 2011
Sponsor:
Collaborator:
Cypress Bioscience, Inc.
Information provided by (Responsible Party):
Forest Laboratories

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Fibromyalgia
Interventions Drug: Placebo
Drug: Milnacipran
Enrollment 340
Recruitment Details Recruitment period was from November 2009 through February 2010 at 58 centers in the United States with the last patient visit occurring on June 7, 2010.
Pre-assignment Details Upon completion of a long term milnacipran open label study MLN-MD-06, patients were enrolled in the current study MLN-MD-27 (NCT01014585), and received open label treatment with milnacipran for four weeks prior to randomization.
Arm/Group Title Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Hide Arm/Group Description The Randomized Population for Responders The Randomized Population for Responders The Randomized Population for Non-Responders The Randomized Population for Non-Responders
Period Title: Overall Study
Started 51 100 60 129
Completed 31 75 37 99
Not Completed 20 25 23 30
Reason Not Completed
Adverse Event             0             2             0             3
Withdrawal by Subject             2             0             1             3
Lost to Follow-up             0             0             0             2
Withdrawn Due to Worsening Fibromyalgia             18             23             22             22
Arm/Group Title Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued) Total
Hide Arm/Group Description

Safety Population for Responders: placebo treatment assignment

One patient in the randomized population for responders assigned to placebo did not take at least one dose of double blind investigational product and therefore was not included in the Safety Population.

Safety Population for Responders: milnacipran treatment assignment Safety Population for Non-Responders: placebo treatment assignment

Safety Population for Non-Responders: milnacipran treatment assignment

One patient in the randomized population for non-responders assigned to milnacipran did not take at least one dose of double-blind investigational product and therefore was not included in the Safety population.

Total of all reporting groups
Overall Number of Baseline Participants 50 100 60 128 338
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 50 participants 100 participants 60 participants 128 participants 338 participants
54.0  (8.3) 54.5  (9.3) 54.7  (9.6) 54.8  (9.4) 54.6  (9.2)
Age, Customized  
Measure Type: Number
Unit of measure:  Years
Number Analyzed 50 participants 100 participants 60 participants 128 participants 338 participants
Between 20 and 60 years 39 73 38 86 236
>=60 years 11 27 22 42 102
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants 100 participants 60 participants 128 participants 338 participants
Female
48
  96.0%
96
  96.0%
59
  98.3%
122
  95.3%
325
  96.2%
Male
2
   4.0%
4
   4.0%
1
   1.7%
6
   4.7%
13
   3.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 50 participants 100 participants 60 participants 128 participants 338 participants
50 100 60 128 338
1.Primary Outcome
Title Time to Loss of Therapeutic Response (LTR)
Hide Description Time to loss of therapeutic response is defined as the time from the first dose of double-blind investigational product to the first visit when a patient has a < 30% reduction in Visual Analog Scale (VAS) pain score from pre-milnacipran exposure OR a worsening of fibromyalgia requiring, in the judgment of the investigator, an alternative treatment
Time Frame From baseline Visit 3 (week 5) to Visit 7 (week 17)
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent to Treat (ITT) Population for Responders is defined as all patients in the Safety Population for Responders with at least 1 post-baseline assessment of primary efficacy parameter. All patients in the Safety Population were included in the ITT population. No efficacy statistical analyses were performed for the Non-Responder population.
Arm/Group Title Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Hide Arm/Group Description:
Intent to Treat (ITT) Population for Responders: placebo treatment assignment, matching placebo administered orally twice per day.
Intent to Treat (ITT) Population for Responders: milnacipran treatment assignment, milnacipran 50-200 mg per day, administered orally twice per day.
Intent to Treat (ITT) Population for Non-Responders: placebo treatment assignment, matching placebo, administered orally twice per day.
Intent to Treat (ITT) Population for Non-Responders: milnacipran treatment assignment, 50-200 mg per day, administered orally twice per day.
Overall Number of Participants Analyzed 50 100 0 0
Median (95% Confidence Interval)
Unit of Measure: Days
56
(28 to 85)
NA [1] 
(NA to NA)
[1]
NA represents not estimable. Not enough participants experienced a loss of therapeutic response to calculate the median value and 95 percent confidence interval.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders: Placebo (Milnacipran Withdrawn), Responders: Milnacipran (Milnacipran Continued)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.27 to 0.71
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Responders: Placebo (Milnacipran Withdrawn)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Days until LTR at the 25th percentile
Estimated Value 18
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Responders: Milnacipran (Milnacipran Continued)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Days until LTR at the 25th percentile
Estimated Value 45
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time to Worsening in Patient Global Impression of Change (PGIC)
Hide Description Time to worsening in Patient Global Impression of Change is defined as the time from the first dose of double-blind investigational product to the first visit when a patient has a PGIC score of 6 or 7. The PGIC is an efficacy assessment on a scale of 1-7 taken at visits 4, 5, 6 and 7. The wording of the assessment is as follows: "Since the start of the study, overall my fibromyalgia is:" 1=Very Much Improved, 2=Much Improved, 3=Minimally Improved, 4=No Change, 5=Minimally Worse, 6=Much Worse, and 7=Very Much Worse.
Time Frame From baseline Visit 3 (week 5) to Visit 7 (week 17)
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent to Treat (ITT) Population for Responders is defined as all patients in the Safety Population for Responders with at least 1 post-baseline assessment of primary efficacy parameter. All patients in the Safety Population were included in the ITT population. No efficacy statistical analyses were performed for the Non-Responder population.
Arm/Group Title Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Hide Arm/Group Description:
Intent to Treat (ITT) Population for Responders: placebo treatment assignment, matching placebo administered orally twice per day.
Intent to Treat (ITT) Population for Responders: milnacipran treatment assignment, milnacipran 50-200 mg per day, administered orally twice per day.
Intent to Treat (ITT) Population for Non-Responders: placebo treatment assignment, matching placebo, administered orally twice per day.
Intent to Treat (ITT) Population for Non-Responders: milnacipran treatment assignment, 50-200 mg per day, administered orally twice per day.
Overall Number of Participants Analyzed 50 100 0 0
Median (95% Confidence Interval)
Unit of Measure: Days
86 [1] 
(30 to NA)
NA [2] 
(NA to NA)
[1]
NA represents not estimable. Not enough participants experienced a worsening in PGIC to calculate the upper bound of 95 percent confidence interval.
[2]
NA represents not estimable. Not enough participants experienced a worsening in PGIC to calculate the median value and the 95 percent confidence interval.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders: Placebo (Milnacipran Withdrawn), Responders: Milnacipran (Milnacipran Continued)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.36
Confidence Interval (2-Sided) 95%
0.20 to 0.63
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Responders: Placebo (Milnacipran Withdrawn)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Days until LTR at the 25th percentile
Estimated Value 22
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time to Worsening in Multidimensional Assessment of Fatigue (MAF)
Hide Description Time to worsening in MAF is defined as the time from the first dose of double-blind investigational product to the first visit when a patient has a 10-point increase from baseline in the global index of fatigue in MAF. Scores range from 1 (no fatigue) to 50 (severe fatigue). The MAF contains 16 items measuring 4 dimensions of fatigue: severity, distress, degree of interference in activities of daily living, and timing. Fourteen of the items contain numerical rating scales (increasing in severity); the remaining 2 items have multiple-choice responses (decreasing in severity).
Time Frame From baseline Visit 3 (week 5) to Visit 7 (week 17)
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent to Treat (ITT) Population for Responders is defined as all patients in the Safety Population for Responders with at least 1 post-baseline assessment of primary efficacy parameter. All patients in the Safety Population were included in the ITT population. No efficacy statistical analyses were performed for the Non-Responder population.
Arm/Group Title Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Hide Arm/Group Description:
Intent to Treat (ITT) Population for Responders: placebo treatment assignment, matching placebo administered orally twice per day.
Intent to Treat (ITT) Population for Responders: milnacipran treatment assignment, milnacipran 50-200 mg per day, administered orally twice per day.
Intent to Treat (ITT) Population for Non-Responders: placebo treatment assignment, matching placebo, administered orally twice per day.
Intent to Treat (ITT) Population for Non-Responders: milnacipran treatment assignment, 50-200 mg per day, administered orally twice per day.
Overall Number of Participants Analyzed 50 100 0 0
Median (95% Confidence Interval)
Unit of Measure: Days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA represents not estimable. Not enough participants experienced a worsening in the MAF to calculate the median value and the 95 percent confidence interval.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Responders: Placebo (Milnacipran Withdrawn), Responders: Milnacipran (Milnacipran Continued)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4104
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.46 to 1.38
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Responders: Placebo (Milnacipran Withdrawn)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Days until LTR at the 25th percentile
Estimated Value 18
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Responders: Milnacipran (Milnacipran Continued)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Days until LTR at the 25th percentile
Estimated Value 30
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Hide Arm/Group Description

Safety Population for Responders: placebo treatment assignment

One patient in the randomized population for responders assigned to placebo did not take at least one dose of double blind investigational product and therefore was not included in the Safety Population.

Safety Population for Responders: milnacipran treatment assignment Safety Population for Non-Responders: placebo treatment assignment

Safety Population for Non-Responders: milnacipran treatment assignment

One patient in the randomized population for non-responders assigned to milnacipran did not take at least one dose of double blind investigational product and therefore was not included in the Safety population.

All-Cause Mortality
Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/50 (0.00%)   1/100 (1.00%)   1/60 (1.67%)   3/128 (2.34%) 
Cardiac disorders         
Bradycardia  1  0/50 (0.00%)  0/100 (0.00%)  0/60 (0.00%)  1/128 (0.78%) 
Cardiac failure congestive  1  0/50 (0.00%)  0/100 (0.00%)  0/60 (0.00%)  1/128 (0.78%) 
General disorders         
Non-cardiac chest pain  1  0/50 (0.00%)  1/100 (1.00%)  0/60 (0.00%)  0/128 (0.00%) 
Infections and infestations         
Gastroenteritis  1  0/50 (0.00%)  0/100 (0.00%)  0/60 (0.00%)  1/128 (0.78%) 
Musculoskeletal and connective tissue disorders         
Osteoarthritis  1  0/50 (0.00%)  0/100 (0.00%)  1/60 (1.67%)  0/128 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Dyspnoea  1  0/50 (0.00%)  0/100 (0.00%)  0/60 (0.00%)  1/128 (0.78%) 
Skin and subcutaneous tissue disorders         
Hidradenitis  1  0/50 (0.00%)  0/100 (0.00%)  0/60 (0.00%)  1/128 (0.78%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Responders: Placebo (Milnacipran Withdrawn) Responders: Milnacipran (Milnacipran Continued) Non-Responders: Placebo (Milnacipran Withdrawn) Non-Responders: Milnacipran (Milnacipran Continued)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/50 (16.00%)   6/100 (6.00%)   10/60 (16.67%)   30/128 (23.44%) 
Gastrointestinal disorders         
Nausea  1  1/50 (2.00%)  4/100 (4.00%)  3/60 (5.00%)  4/128 (3.13%) 
Constipation  1  0/50 (0.00%)  2/100 (2.00%)  3/60 (5.00%)  2/128 (1.56%) 
General disorders         
Oedema peripheral  1  3/50 (6.00%)  2/100 (2.00%)  1/60 (1.67%)  0/128 (0.00%) 
Irritability  1  3/50 (6.00%)  0/100 (0.00%)  0/60 (0.00%)  0/128 (0.00%) 
Infections and infestations         
Sinusitis  1  3/50 (6.00%)  4/100 (4.00%)  1/60 (1.67%)  11/128 (8.59%) 
Upper respiratory tract infection  1  2/50 (4.00%)  4/100 (4.00%)  1/60 (1.67%)  7/128 (5.47%) 
Bronchitis  1  1/50 (2.00%)  2/100 (2.00%)  3/60 (5.00%)  2/128 (1.56%) 
Musculoskeletal and connective tissue disorders         
Fibromyalgia  1  1/50 (2.00%)  3/100 (3.00%)  3/60 (5.00%)  3/128 (2.34%) 
Nervous system disorders         
Headache  1  0/50 (0.00%)  4/100 (4.00%)  1/60 (1.67%)  9/128 (7.03%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.0
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 is the property of Forest Research Institute, Inc. An integrated clinical and statistical report was 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Joel Trugman, MD
Organization: Forest Research Institute, Inc., a subsidiary of Forest Laboratories, Inc.
Phone: 201-427-8681
EMail: joel.trugman@frx.com
Layout table for additonal information
Responsible Party: Forest Laboratories
ClinicalTrials.gov Identifier: NCT01014585     History of Changes
Other Study ID Numbers: MLN-MD-27
First Submitted: November 13, 2009
First Posted: November 17, 2009
Results First Submitted: June 7, 2011
Results First Posted: September 7, 2011
Last Update Posted: September 7, 2011