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Trial record 41 of 88 for:    "Neuromuscular Disease" | "Norepinephrine"

Study of Milnacipran for the Treatment of Fibromyalgia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00314249
Recruitment Status : Completed
First Posted : April 13, 2006
Results First Posted : November 2, 2009
Last Update Posted : January 20, 2010
Sponsor:
Collaborator:
Cypress Bioscience, Inc.
Information provided by:
Forest Laboratories

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Fibromyalgia
Interventions Drug: Placebo
Drug: Milnacipran 100mg
Enrollment 1025
Recruitment Details Recruitment period was from 4/28/06 through 12/27/07 with last patient last visit on 6/30/08 at 65 centers in the US and 3 centers in Canada
Pre-assignment Details Upon completion of the washout period, a two-week baseline period was completed prior to randomization. Patients were then randomized in a 1:1 ratio to either placebo or milnacipran 100 mg/day (50 mg BID [twice a day])
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
Period Title: Overall Study
Started 509 516
Completed 357 353
Not Completed 152 163
Reason Not Completed
Adverse Event             73             94
Lack of Efficacy             33             24
Withdrawal by Subject             21             28
Lost to Follow-up             15             9
Physician Decision             1             1
Withdrawn for other reasons             4             1
Non-Compliant             5             6
Arm/Group Title Placebo Milnacipran Total
Hide Arm/Group Description Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase Total of all reporting groups
Overall Number of Baseline Participants 509 516 1025
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 509 participants 516 participants 1025 participants
48.73  (10.56) 49.07  (10.79) 48.90  (10.67)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 509 participants 516 participants 1025 participants
<=20 years 2 2 4
Between 20 and 60 years 437 429 866
>=60 years 70 85 155
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 509 participants 516 participants 1025 participants
Female
477
  93.7%
500
  96.9%
977
  95.3%
Male
32
   6.3%
16
   3.1%
48
   4.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 509 participants 516 participants 1025 participants
United States 463 469 932
Canada 46 47 93
1.Primary Outcome
Title Composite Syndrome Responder Status
Hide Description Composite Syndrome Responder Status is the number of responders based on 3 domains: (1) 30% reduction in pain (as recorded in the Patient Experience Diary [PED], electronic diary, during the morning report; 24 hour recall); (2) patient global impression of change (PGIC) score of "very much improved" and "much improved;" and (3) physical function improvement of 6 or more points on Short Form-36 Physical Component Summary (SF-36 PCS)
Time Frame At the end of the three-month stable dose treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analysis was performed based on intent-to-treat population defined as all randomized patients who took at least one dose of double-blind study medication. All subjects with missing assessments at the end of the three-month stable dose treatment phase were considered non-responders (baseline value carried forward (BOCF)).
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description:
Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase
Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
Overall Number of Participants Analyzed 509 516
Measure Type: Number
Unit of Measure: Syndrome Responder Participants
56 103
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Milnacipran
Comments The test of no difference in the responder rate between milnacipran and placebo groups was performed using a logistic regression model with treatment group, baseline pain score, and baseline SF-36 PCS score as explanatory variables.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Closed testing procedure used to control overall type 1 error rate at 5%: fibromyalgia syndrome tested prior to fibromyalgia pain
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.06
Confidence Interval 95%
1.45 to 2.94
Estimation Comments [Not Specified]
2.Primary Outcome
Title Composite Pain Responder Status
Hide Description Composite Pain Responder Status is the number of responders based on two domains: (1) 30% reduction in pain (as recorded in the Patient Experience Diary [PED], electronic diary, during the morning report; 24 hour recall); and (2) Patient Global Impression of Change (PGIC) score of "very much improved" or "much improved."
Time Frame At the end of three-month stable dose treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analysis was performed based on intent-to-treat population defined as all randomized patients who took at least one dose of double-blind study medication. All subjects with missing assessments at the end of three-month stable dose treatment phase were considered non-responders (baseline value carried forward (BOCF)).
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description:
Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase
Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
Overall Number of Participants Analyzed 509 516
Measure Type: Number
Unit of Measure: Pain Responder Participants
90 147
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Milnacipran
Comments The test of no difference in the responder rate between milnacipran and placebo groups was performed using a logistic regression model with the treatment group and baseline pain score as explanatory variables.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Closed testing procedure was used to control overall type 1 error rate at 5%: fibromyalgia pain tested after statistically significant fibromyalgia syndrome test
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.86
Confidence Interval 95%
1.38 to 2.51
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time-Weighted Average of Patient Experience Diary (PED) Reported Morning 24-Hour Recall Pain Scores for Weeks 1-12 of the Stable Dose Phase
Hide Description

Time-weighted average (area under the curve [AUC]) of the weekly average Patient Experience Diary (PED)-reported morning recall pain scores for weeks 1 through 12 of the stable dose treatment phase is the area under the Patient Experience Diary (PED)-time curve estimated using the trapezoidal method and normalized by time.

PED is the Patient Experience Diary, an electronic diary system used for collection of patient self-reported pain data. Outcome measure is assessed using the VAS Pain Intensity Scale from 0-100 millimeters anchored at 0 mm (no pain) to 100 mm (worst possible pain).

Time Frame Weeks 1 through 12 of the stable dose treatment phase (Visit TX0-TX12)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed based on intent-to-treat population defined as all randomized patients who took at least one dose of double-blind study medication. For all subjects with missing assessments for weeks 1-12 of the stable dose treatment phase, values were imputed using last observation carried forward (LOCF).
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description:
Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase
Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
Overall Number of Participants Analyzed 509 516
Mean (Standard Error)
Unit of Measure: units on scale
48.0  (0.83) 41.2  (0.87)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Milnacipran
Comments This parameter was analyzed using an ANCOVA model with treatment group and study center as factors and baseline value as a covariate.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -6.38
Confidence Interval 95%
-8.56 to -4.19
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time-Weighted Average of Patient Global Impression of Change (PGIC) From Visit TX0-TX12.
Hide Description

Time-weighted average (area under the curve [AUC]) for Patient Global Impression of Change (PGIC) from Visit TX0-TX12 is the area under the PGIC-time curve estimated using the trapezoidal method and normalized by time.

PGIC is an efficacy assessment on a scale of 1-7 taken at visits TX0-TX12. 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 Weeks 1-12 (Visit TX0-TX12) of the stable dose treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed based on intent-to-treat population defined as all randomized patients who took at least one dose of double-blind study medication. For all subjects with missing assessments from weeks 1-12 of the stable dose treatment phase, values were imputed using last observation carried forward (LOCF).
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description:
Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase
Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
Overall Number of Participants Analyzed 486 495
Mean (Standard Error)
Unit of Measure: units on scale
3.4  (0.06) 2.9  (0.06)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Milnacipran
Comments This parameter was analyzed using an ANOVA model with treatment group and study center as factors.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.53
Confidence Interval 95%
-0.69 to -0.38
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in the Multi-Dimensional Fatigue Inventory (MFI) Total Score at Visit TX12.
Hide Description

Change from Baseline in the Multi-Dimensional Fatigue Inventory (MFI) total score at TX12. Negative differences indicate decrease of fatigue.

MFI is a subjective report of fatigue symptoms consisting of 20 items that can be scored to produce 5 dimensions: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. The MFI is a 1-5 scale with 1="yes, that is true" and 5="no, that is not true."

Time Frame Baseline through end of week 12 (Visit TX12)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed based on intent-to-treat population defined as all randomized patients who took at least one dose of double-blind study medication. For all subjects with missing assessments at the end of week 12 (Visit TX12), values were imputed using Last Observation Carried Forward (LOCF).
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description:
Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase
Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
Overall Number of Participants Analyzed 502 508
Mean (Standard Error)
Unit of Measure: units on scale
-3.96  (0.549) -5.50  (0.599)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Milnacipran
Comments This parameter was analyzed using an ANCOVA model with treatment group and study center as factors and baseline value as a covariate.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.69
Confidence Interval 95%
-3.27 to -0.11
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time-Weighted Average of the Short Form-36 Physical Component Summary (SF-36 PCS) Score From Visit TX0-TX12
Hide Description

Short Form-36 (SF-36): pt. questionnaire (36 questions) which give rise to 8 domains & 2 component summaries (mental and physical); assessing quality of life, health & functional status.

SF-36 PCS: weighted summary of physical function using all 8 domains.

Scores are standardized so that the range for all domains and component summaries is 0 (worst possible score) to 100 (best possible score). Higher scores indicate better health or functional status.

SF-36 PCS AUC (Area under the Curve): estimated using trapezoidal method, normalized by time.

Time Frame Weeks 1-12 (Visit TX0-TX12) of the stable dose treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed based on intent-to-treat population defined as all randomized patients who took at least one dose of double-blind study medication. For all subjects with missing assessments from weeks 1-12 (Visit TX0-TX12) of the stable dose treatment phase, values were imputed using the Last Observation Carried Forward (LOCF) approach.
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description:
Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase
Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
Overall Number of Participants Analyzed 509 516
Mean (Standard Error)
Unit of Measure: units on scale
36.4  (0.37) 37.9  (0.37)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Milnacipran
Comments This parameter was analyzed using an ANCOVA model with treatment group and study center as factors and baseline value as a covariate.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 1.65
Confidence Interval 95%
0.86 to 2.44
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Milnacipran
Hide Arm/Group Description Placebo administered orally BID (twice a day) for 12 weeks of stable dose treatment phase Milnacipran 100 mg per day, administered orally (BID [twice a day]) for 12 weeks of stable dose treatment phase
All-Cause Mortality
Placebo Milnacipran
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Milnacipran
Affected / at Risk (%) Affected / at Risk (%)
Total   7/509 (1.38%)   10/516 (1.94%) 
Blood and lymphatic system disorders     
Haemorrhagic Anaemia  1  1/509 (0.20%)  0/516 (0.00%) 
General disorders     
Chest Pain  1  0/509 (0.00%)  2/516 (0.39%) 
Non-cardiac Chest Pain  1  0/509 (0.00%)  1/516 (0.19%) 
Hepatobiliary disorders     
Cholecystitis  1  0/509 (0.00%)  1/516 (0.19%) 
Cholelithiasis  1  0/509 (0.00%)  1/516 (0.19%) 
Infections and infestations     
Apendicitis  1  1/509 (0.20%)  0/516 (0.00%) 
Lobar Pneumonia  1  0/509 (0.00%)  2/516 (0.39%) 
Injury, poisoning and procedural complications     
Fall  1  2/509 (0.39%)  0/516 (0.00%) 
Humerus Fracture  1  1/509 (0.20%)  0/516 (0.00%) 
Radius Fracture  1  1/509 (0.20%)  0/516 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  0/509 (0.00%)  1/516 (0.19%) 
Hyponatraemia  1  0/509 (0.00%)  1/516 (0.19%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal Chest Pain  1  0/509 (0.00%)  1/516 (0.19%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast Cancer  1  1/509 (0.20%)  0/516 (0.00%) 
Nervous system disorders     
Embolic Cerebral Infarction  1  1/509 (0.20%)  0/516 (0.00%) 
Grand Mal Convlusion  1  0/509 (0.00%)  1/516 (0.19%) 
Presyncope  1  0/509 (0.00%)  1/516 (0.19%) 
Psychiatric disorders     
Anxiety  1  0/509 (0.00%)  1/516 (0.19%) 
Confusional State  1  0/509 (0.00%)  1/516 (0.19%) 
Reproductive system and breast disorders     
Menorrhagia  1  1/509 (0.20%)  0/516 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Milnacipran
Affected / at Risk (%) Affected / at Risk (%)
Total   382/509 (75.05%)   434/516 (84.11%) 
Cardiac disorders     
Palpitations  1  15/509 (2.95%)  38/516 (7.36%) 
Tachycardia  1  5/509 (0.98%)  28/516 (5.43%) 
Gastrointestinal disorders     
Constipation  1  20/509 (3.93%)  76/516 (14.73%) 
Diarrhoea  1  26/509 (5.11%)  23/516 (4.46%) 
Dyspepsia  1  31/509 (6.09%)  25/516 (4.84%) 
Nausea  1  106/509 (20.83%)  189/516 (36.63%) 
General disorders     
Fatigue  1  22/509 (4.32%)  31/516 (6.01%) 
Infections and infestations     
Upper Respiratory Tract Infection  1  27/509 (5.30%)  19/516 (3.68%) 
Nervous system disorders     
Dizziness  1  26/509 (5.11%)  54/516 (10.47%) 
Headache  1  80/509 (15.72%)  92/516 (17.83%) 
Psychiatric disorders     
Insomnia  1  41/509 (8.06%)  51/516 (9.88%) 
Skin and subcutaneous tissue disorders     
Hyperhidrosis  1  7/509 (1.38%)  40/516 (7.75%) 
Vascular disorders     
Hot Flush  1  18/509 (3.54%)  56/516 (10.85%) 
Hypertension  1  5/509 (0.98%)  27/516 (5.23%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.0
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.
Sponsor can review results communications prior to public release & can embargo communications re: results for 90 days from time submitted to sponsor for review. PI shall not disclose sponsor’s confidential info. Upon sponsor’s request, PI shall delete any proprietary info & shall not include raw data in pub. On sponsor’s request, PI shall delay submission for any pub while sponsor files patent apps. If trial is multi-center, PI agrees that first publication shall be a multi-center pub.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Robert Palmer, MD
Organization: Forest Research Institute, a subsidiary of Forest Laboratories, Inc.
Phone: 1-201-427-8218
EMail: robert.palmer@frx.com
Layout table for additonal information
Responsible Party: Robert Palmer, MD, Forest Research Institute, a subsidiary of Forest Laboratories, Inc.
ClinicalTrials.gov Identifier: NCT00314249     History of Changes
Other Study ID Numbers: MLN-MD-03
First Submitted: April 11, 2006
First Posted: April 13, 2006
Results First Submitted: June 30, 2009
Results First Posted: November 2, 2009
Last Update Posted: January 20, 2010