Primary Fibromyalgia
Conditions
Keywords
Fibromyalgia, Pediatric Fibromyalgia, Adolescent Fibromyalgia, milnacipran, Savella, loss of therapeutic response, Forest Research Institute, Pain, Fatigue, Serotonin Norepinephrine Reuptake Inhibitors, Randomized Withdrawal
Brief summary
The purpose of this study is to evaluate the safety, tolerability, efficacy, and pharmacokinetics of milnacipran in pediatric patients aged 13 to 17 years with primary fibromyalgia.
Detailed description
* 8 weeks open-label treatment period with milnacipran. * Followed by randomization to 8-weeks double blind treatment period for eligible patients
Interventions
DRUGMilnacipran
Maximum tolerated dose (50, 75, or 100 mg/day tablets) was determined during the open label phase of the study. Oral administration, twice daily dosing
DRUGPlacebo
matching placebo tablets 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
Age
13 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of primary fibromyalgia * 13-17 years of age * To be eligible for screening, have average pain rating in the previous week of at least 3 but no more than 9 on an 11-point numeric rating scale * To be eligible to enter into the open-label treatment period, have a 1-week mean of daily pain ratings of at least 3 but no more than 9 (11-point numeric rating scale) in the week before Baseline (Visit 2) * To be eligible for randomization and entry into the double-blind treatment period, have a decrease of at least 50% in 1-week mean of daily pain ratings (11-point numeric rating scale) before Randomization (Visit 7) compared with the 1-week mean of daily pain ratings, in the week before Baseline (Visit 2) * Unsatisfactory response to nonpharmacologic fibromyalgia treatment.
Exclusion criteria
* Severe psychiatric illness * Severe renal impairment * Evidence of active liver disease * Pregnant or breastfeeding * Significant risk of suicidality * Unable, unwilling or inadvisable to discontinue prohibited medications * History of alcohol abuse or drug abuse or dependence, within previous year * Current systemic infection * Autoimmune disease * History of seizure disorder (other than febrile seizures)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Loss of Therapeutic Response (LTR) Following Randomization to Milnacipran or Placebo. | Change from Visit 7 (Week 8) to Visit 10 (Week 16) | During the open-label period, 20 patients out of 116 enrolled had a reduction from baseline (Visit 2) of at least 50% in their pain, were classified as responders and were randomized (Visit 7). A Loss of Therapeutic Response was said to occur if, during the double-blind treatment period, any of the following occurred: • A worsening of fibromyalgia requiring an alternate treatment OR • An increase in 1-week mean of daily pain ratings (11-point numeric rating scale) to greater than 70% of Baseline (Visit 2) OR • Withdrawal from the study for any reason except withdrawals due to extenuating circumstances |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Global Impression of Severity (PGIS) | Change from Visit 7 (Week 8) to Visit 10 (Week 16) | The wording of the PGIS assessment was as follows: Considering all aspects of your illness, how do you evaluate the severity of your fibromyalgia? The possible responses to this question were 1. Normal, not at all ill 2. Borderline ill 3. Mildly ill 4. Moderately ill 5. Severely ill 6. Extremely ill |
Countries
United States
Participant flow
Recruitment details
Participants were recruited over a 12 month period from April of 2011 to April of 2012 at 47 study sites in the United States.
Pre-assignment details
116 patients took at least 1 dose of open-label investigational product; 20 patients were randomized to receive double-blind treatment.
Participants by arm
| Arm | Count |
|---|---|
| Open-Label Milnacipran Maximum tolerated dose (50, 75, or 100 mg/day tablets) determined during the open label treatment phase. Oral administration, twice daily dosing | 116 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Period | Adverse Event | 1 | 0 |
| Double-Blind Period | Lack of Efficacy | 1 | 0 |
| Open-Label Period | Adverse Event | 8 | 0 |
| Open-Label Period | Inclusion/exclusion criteria not met | 66 | 0 |
| Open-Label Period | Lack of Efficacy | 3 | 0 |
| Open-Label Period | Lost to Follow-up | 6 | 0 |
| Open-Label Period | Other Reason | 2 | 0 |
| Open-Label Period | Protocol Violation | 2 | 0 |
| Open-Label Period | Withdrawal by Subject | 9 | 0 |
Baseline characteristics
| Characteristic | Open-Label Milnacipran |
|---|---|
| Age, Continuous | 15.6 years STANDARD_DEVIATION 1.4 |
| Age, Customized 13 years old | 10 Participants |
| Age, Customized 14 years old | 21 Participants |
| Age, Customized 15 years old | 21 Participants |
| Age, Customized 16 years old | 23 Participants |
| Age, Customized 17 years old | 41 Participants |
| Region of Enrollment United States | 116 Participants |
| Sex: Female, Male Female | 98 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 62 / 116 | 4 / 6 | 6 / 14 |
| serious Total, serious adverse events | 0 / 116 | 0 / 6 | 1 / 14 |
Outcome results
Primary
Time to First Loss of Therapeutic Response (LTR) Following Randomization to Milnacipran or Placebo.
During the open-label period, 20 patients out of 116 enrolled had a reduction from baseline (Visit 2) of at least 50% in their pain, were classified as responders and were randomized (Visit 7). A Loss of Therapeutic Response was said to occur if, during the double-blind treatment period, any of the following occurred: • A worsening of fibromyalgia requiring an alternate treatment OR • An increase in 1-week mean of daily pain ratings (11-point numeric rating scale) to greater than 70% of Baseline (Visit 2) OR • Withdrawal from the study for any reason except withdrawals due to extenuating circumstances
Time frame: Change from Visit 7 (Week 8) to Visit 10 (Week 16)
Population: The Open-Label Safety Population consists of 116 patients who took at least 1 dose of open-label milnacipran. 20 patients who were randomized to a treatment group (Randomized Population) took at least 1 dose of double-blind treatment (Double-blind Safety Population) and were analyzed as randomized (Double-blind Intent-to-Treat \[ITT\] Population).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to First Loss of Therapeutic Response (LTR) Following Randomization to Milnacipran or Placebo. | NA Days | — |
| Milnacipran | Time to First Loss of Therapeutic Response (LTR) Following Randomization to Milnacipran or Placebo. | 7.0 Days | Standard Deviation 1.4 |
Secondary
Patient Global Impression of Severity (PGIS)
The wording of the PGIS assessment was as follows: Considering all aspects of your illness, how do you evaluate the severity of your fibromyalgia? The possible responses to this question were 1. Normal, not at all ill 2. Borderline ill 3. Mildly ill 4. Moderately ill 5. Severely ill 6. Extremely ill
Time frame: Change from Visit 7 (Week 8) to Visit 10 (Week 16)
Population: The Open-Label Safety Population consists of 116 patients who took at least 1 dose of open-label milnacipran. 20 patients were randomized to a treatment group (Randomized Population) took at least 1 dose of double-blind treatment (Double-blind Safety Population) and were analyzed as randomized (Double-blind Intent-to-Treat \[ITT\] Population).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Patient Global Impression of Severity (PGIS) | 0.5 units on a scale | Standard Deviation 0.8 |
| Milnacipran | Patient Global Impression of Severity (PGIS) | 0.4 units on a scale | Standard Deviation 0.9 |