Fibromyalgia
Conditions
Keywords
Milnacipran, Pain, Durability of Effect, Loss of Therapeutic Response, Fatigue, Forest Research Institute, Savella ®
Brief summary
The purpose of this study is to evaluate the durability of effect of milnacipran for the treatment of fibromyalgia in patients receiving long-term milnacipran treatment and to characterize the effects of milnacipran on multiple symptoms of fibromyalgia, as demonstrated by changes in symptoms following the discontinuation of milnacipran.
Interventions
DRUGPlacebo
Placebo tablets administered orally twice daily
DRUGMilnacipran
Milnacipran tablets administered orally twice daily
Sponsors
Cypress Bioscience, Inc.
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Currently participating in Study MLN-MD-06 * Receiving a stable dosage of milnacipran (50-200 mg/d) at Screening/Enrollment (Visit 1)
Exclusion criteria
* Significant risk of suicide * History of mania, bipolar disorder, psychotic disorder, schizophrenia, or a current episode of major depressive disorder * Myocardial infarction and/or stroke within the prior 12 months * Mean systolic blood pressure \> 180 mm Hg or mean diastolic blood pressure \> 110 mm Hg at Screening (Visit 1) * Active liver disease * Severe renal impairment * Platelet and bleeding disorders * Female patients who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Loss of Therapeutic Response (LTR) | From baseline Visit 3 (week 5) to Visit 7 (week 17) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Worsening in Patient Global Impression of Change (PGIC) | From baseline Visit 3 (week 5) to Visit 7 (week 17) | 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 to Worsening in Multidimensional Assessment of Fatigue (MAF) | From baseline Visit 3 (week 5) to Visit 7 (week 17) | 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). |
Countries
United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Responders: Placebo (Milnacipran Withdrawn) 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. | 50 |
| Responders: Milnacipran (Milnacipran Continued) Safety Population for Responders: milnacipran treatment assignment | 100 |
| Non-Responders: Placebo (Milnacipran Withdrawn) Safety Population for Non-Responders: placebo treatment assignment | 60 |
| Non-Responders: Milnacipran (Milnacipran Continued) 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. | 128 |
| Total | 338 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 1 | 3 |
| Overall Study | Withdrawn Due to Worsening Fibromyalgia | 18 | 23 | 22 | 22 |
Baseline characteristics
| Characteristic | Responders: Placebo (Milnacipran Withdrawn) | Responders: Milnacipran (Milnacipran Continued) | Non-Responders: Placebo (Milnacipran Withdrawn) | Non-Responders: Milnacipran (Milnacipran Continued) | Total |
|---|---|---|---|---|---|
| Age Continuous | 54.0 years STANDARD_DEVIATION 8.3 | 54.5 years STANDARD_DEVIATION 9.3 | 54.7 years STANDARD_DEVIATION 9.6 | 54.8 years STANDARD_DEVIATION 9.4 | 54.6 years STANDARD_DEVIATION 9.2 |
| Age, Customized >=60 years | 11 Years | 27 Years | 22 Years | 42 Years | 102 Years |
| Age, Customized Between 20 and 60 years | 39 Years | 73 Years | 38 Years | 86 Years | 236 Years |
| Region of Enrollment United States | 50 participants | 100 participants | 60 participants | 128 participants | 338 participants |
| Sex: Female, Male Female | 48 Participants | 96 Participants | 59 Participants | 122 Participants | 325 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 1 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 50 | 6 / 100 | 10 / 60 | 30 / 128 |
| serious Total, serious adverse events | 0 / 50 | 1 / 100 | 1 / 60 | 3 / 128 |
Outcome results
Primary
Time to Loss of Therapeutic Response (LTR)
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Responders: Placebo (Milnacipran Withdrawn) | Time to Loss of Therapeutic Response (LTR) | 56 Days |
| Responders: Milnacipran (Milnacipran Continued) | Time to Loss of Therapeutic Response (LTR) | NA Days |
p-value: 0.000495% CI: [0.27, 0.71]Log Rank
Secondary
Time to Worsening in Multidimensional Assessment of Fatigue (MAF)
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Responders: Placebo (Milnacipran Withdrawn) | Time to Worsening in Multidimensional Assessment of Fatigue (MAF) | NA Days |
| Responders: Milnacipran (Milnacipran Continued) | Time to Worsening in Multidimensional Assessment of Fatigue (MAF) | NA Days |
p-value: 0.410495% CI: [0.46, 1.38]Log Rank
Secondary
Time to Worsening in Patient Global Impression of Change (PGIC)
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Responders: Placebo (Milnacipran Withdrawn) | Time to Worsening in Patient Global Impression of Change (PGIC) | 86 Days |
| Responders: Milnacipran (Milnacipran Continued) | Time to Worsening in Patient Global Impression of Change (PGIC) | NA Days |
p-value: 0.000295% CI: [0.2, 0.63]Log Rank