Fibromyalgia
Conditions
Brief summary
Fibromyalgia is a condition that includes pain, tenderness, stiff muscle, and fatigue. Researchers want to find out if a drug called milnacipran can help people with fibromyalgia. milnacipran (Savella) is approved by the FDA for the management of fibromyalgia. In this study, milnacipran will be given to find out more about how it affects pain and thinking in people with fibromyalgia.
Detailed description
The objective of this study is to evaluate the effect of milnacipran on pain processing in patients with fibromyalgia and to assess the correlation between this effect and neural activation patterns during functional Magnetic Resonance Imaging (fMRI). NOTE regarding Changes in Outcome Measures In this Crossover Study, participants were involved for approximately 16 weeks in this sequence: a week of preparing for the initial assessments, baseline measurements (Week 0), 6 weeks on placebo or study drug followed by measurements for effect of drug or placebo (Week 6); a week of titration off of drug, if appropriate (or continued placebo, if on placebo), two weeks of washout, a new baseline assessment (Week 9), six weeks of study drug (or placebo), another set of measurements for effect of drug or placebo (Week 15), and a final titration period to maintain masking of assignment to drug or placebo. Of 17 participants who completed both sequences, data was analyzed for the 15 whose values for all measurement variables were usable. When Outcome measure data was originally and accurately posted for baseline and change after treatment, the time frames listed were 0 and 15 weeks, because the last assessment was gathered at approximately week 15 for each person whose data is in the data set. However, given the crossover design, it seems more accurate and understandable, to show the time frame for the outcome measure as 6 because the participants were each administered drug or placebo for six weeks total. (Of course for the Placebo then Study Drug arm, the placebo data was collected at week 6, and for the Study Drug then Placebo arm, the drug data was collected at week 6, and similarly for the first group the drug data was collected at week 15 (first assignment, plus 1 week titration, 2 weeks washout, new baseline at week 9, and final collection at week 15), and for the second group the placebo data was collected at week 15. Thus, outcome measures originally listed for 6 and 9 weeks, which were previously shown as Data Not Reported were effectively already included within the data presented for change from baseline shown in Week 15 in this fashion: 9 week data for the second assignment is part of the week 0 data for the first assignment, to get pre-treatment baseline for each treatment shown. Week 6 data is the post-treatment data which was shown as week 15, but is now recategorized as 6 week data. There is no, and never was, any data that could represent assignment to drug or placebo for 9 or 15 weeks. Additionally, several outcome measures based on fMRI values were always listed in the protocol as other outcomes (not secondary outcomes), but had been incorrectly posted in the earlier listings on ClinicalTrials.gov. They have been accurately reclassified in the 2017 resubmission.
Interventions
DRUGmilnacipran
Milnacipran will be given orally twice daily in tablet form at different times during the course of the study. The highest dose of milnacipran to be used in the study is 200mg/day.
DRUGPlacebo
Placebo will be given orally twice daily in tablet form at different times during the course of the study.
Sponsors
Forest Laboratories
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* You may be eligible to take part in this study if the following are true: * You are between the age of 18 and 70 years * If you are female * If you are right handed * You have a diagnosis of fibromyalgia for at least 3 months, as defined by the American College of Rheumatology 1990 Criteria * You are willing to stop taking certain medicines that you may be taking on a regular basis. The researchers will discuss these medications with you in detail
Exclusion criteria
* You may not be eligible take part in this study if any of the following are true for you: * You have problems with your heart or cardiovascular system * You have problems with your liver or kidneys * You have an autoimmune disease, or a whole-body infection like HIV or hepatitis * You have cancer * You are pregnant or breastfeeding * You abuse drugs or alcohol * You have suicidal thoughts or wishes * You have taken milnacipran or another study drug within the last 30 days * You have a medical problem not listed here that would make it unsafe for you to take part in the study * The research team feels that you will be unable to complete all phases of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Threshold at Baseline | Baselines measured at week 0 and week 9 after washout from first assignment to treatment | The primary outcome parameter is the medium pressure pain threshold at pre-treatment baseline (pressure that evokes a perceived pain intensity of 40-50 out of 100 on a numerical rating scale). Measured in kg/cm\^2. |
| Change in Pain Threshold From Baseline to End of Treatment. | baseline compared with 6 weeks of treatment | The primary outcome parameter is the change in medium pressure pain threshold (pressure that evokes a perceived pain intensity of 40-50 out of 100 on a numerical rating scale) from baseline to end of treatment. Measured in kg/cm\^2. Lower values represent a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Diffuse Noxious Inhibitory Control (DNIC) Effect From Baseline to End of Treatment. | baseline compared with 6 weeks of treatment | 0-100 numerical rating scale. 0 on the numerical scale represents a better outcome. 100 represents a worse outcome. |
| Diffuse Noxious Inhibitory Control (DNIC) Effect at Baseline. | Baselines measured at week 0 and week 9 after washout from first assignment to treatment | 0-100 numerical rating scale. 0 on the numerical scale represents a better outcome. 100 represents a worse outcome. |
| Pain Tolerance at Baseline | Baselines measured at week 0 and week 9 after washout from first assignment to treatment | The primary outcome parameter is the pressure pain tolerance (maximum tolerated pressure) at pre-treatment baseline. |
| Change in Pain Tolerance From Baseline to End of Treatment | baseline compared wtih 6 weeks of treatment | The primary outcome parameter is the change in pressure pain tolerance (maximum tolerated pressure) from baseline to end of treatment. Measured in kg/cm\^2. Lower values represent a worse outcome. |
Other
| Measure | Time frame |
|---|---|
| Change in Descending Pain Modulation From Baseline to End of Treatment (as Assessed by Changes in fMRI Brainstem Activation Patterns) | Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later |
| Change in fMRI Brain Activation Patterns During Pressure Stimulation From Baseline to End of Treatment | Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later |
| Change in fMRI Activation Patterns During N-back Procedure From Baseline to End of Treatment. | Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later |
Countries
United States
Participant flow
Pre-assignment details
Participants enrolled in the study received placebo for 1 week (Day -7 to 0) then began the double blinded treatment sequence.
Participants by arm
| Arm | Count |
|---|---|
| Milnacipran First, Then Placebo Milnacipran and placebo will be given orally twice daily in tablet form at different times during the course of the study. The highest dose of milnacipran to be used in the study is 200mg/day.
milnacipran, then placebo: Milnacipran and placebo will be given orally twice daily in tablet form at different times during the course of the study. The highest dose of milnacipran to be used in the study is 200mg/day. | 6 |
| Placebo First, Then Milnacipran Milnacipran and placebo will be given orally twice daily in tablet form at different times during the course of the study. The highest dose of milnacipran to be used in the study is 200mg/day.
Placebo, then milnacipran: Milnacipran and placebo will be given orally twice daily in tablet form at different times during the course of the study. The highest dose of milnacipran to be used in the study is 200mg/day. | 9 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 - Day 1 to 49 | Withdrawal by Subject | 2 | 2 |
| Period 2 - Day 64 to 112 | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Milnacipran First, Then Placebo | Placebo First, Then Milnacipran | Total |
|---|---|---|---|
| Age, Customized Fibromyalgia | 46.83 years STANDARD_DEVIATION 9.83 | 36.67 years STANDARD_DEVIATION 8.64 | 40.73 years STANDARD_DEVIATION 10.187 |
| Region of Enrollment United States | 6 participants | 9 participants | 15 participants |
| Sex/Gender, Customized Female | 6 participants | 9 participants | 15 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 20 | 11 / 20 |
| serious Total, serious adverse events | 1 / 20 | 0 / 20 |
Outcome results
Primary
Change in Pain Threshold From Baseline to End of Treatment.
The primary outcome parameter is the change in medium pressure pain threshold (pressure that evokes a perceived pain intensity of 40-50 out of 100 on a numerical rating scale) from baseline to end of treatment. Measured in kg/cm\^2. Lower values represent a worse outcome.
Time frame: baseline compared with 6 weeks of treatment
Population: Of 17 participants who completed both sequences, data was analyzed for the 15 whose values for all measurement variables were usable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | Change in Pain Threshold From Baseline to End of Treatment. | Pre-Treatment (Week 0 or 9) | 2.7333 kg/cm^2 | Standard Deviation 0.83166 |
| Milnacipran | Change in Pain Threshold From Baseline to End of Treatment. | Post-Treatment (Week 6 or 15) | 2.650 kg/cm^2 | Standard Deviation 1.05982 |
| Placebo | Change in Pain Threshold From Baseline to End of Treatment. | Pre-Treatment (Week 0 or 9) | 2.583 kg/cm^2 | Standard Deviation 0.84339 |
| Placebo | Change in Pain Threshold From Baseline to End of Treatment. | Post-Treatment (Week 6 or 15) | 2.70 kg/cm^2 | Standard Deviation 0.99642 |
Primary
Pain Threshold at Baseline
The primary outcome parameter is the medium pressure pain threshold at pre-treatment baseline (pressure that evokes a perceived pain intensity of 40-50 out of 100 on a numerical rating scale). Measured in kg/cm\^2.
Time frame: Baselines measured at week 0 and week 9 after washout from first assignment to treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Milnacipran | Pain Threshold at Baseline | 2.7333 kg/cm^2 | Standard Deviation 0.83166 |
| Placebo | Pain Threshold at Baseline | 2.583 kg/cm^2 | Standard Deviation 0.84339 |
Secondary
Change in Diffuse Noxious Inhibitory Control (DNIC) Effect From Baseline to End of Treatment.
0-100 numerical rating scale. 0 on the numerical scale represents a better outcome. 100 represents a worse outcome.
Time frame: baseline compared with 6 weeks of treatment
Population: Of 17 participants who completed both sequences, data was analyzed for the 15 whose values for all measurement variables were usable. On the placebo, side one additional participant did not have data for this variable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | Change in Diffuse Noxious Inhibitory Control (DNIC) Effect From Baseline to End of Treatment. | Pre-Treatment (Week 0 or 9) | 8.134 units on a scale | Standard Deviation 17.51978 |
| Milnacipran | Change in Diffuse Noxious Inhibitory Control (DNIC) Effect From Baseline to End of Treatment. | Post-Treatment (Week 6 or 15) | 11.0355 units on a scale | Standard Deviation 17.16822 |
| Placebo | Change in Diffuse Noxious Inhibitory Control (DNIC) Effect From Baseline to End of Treatment. | Pre-Treatment (Week 0 or 9) | 12.0240 units on a scale | Standard Deviation 20.80824 |
| Placebo | Change in Diffuse Noxious Inhibitory Control (DNIC) Effect From Baseline to End of Treatment. | Post-Treatment (Week 6 or 15) | 8.50 units on a scale | Standard Deviation 19.6678 |
Secondary
Change in Pain Tolerance From Baseline to End of Treatment
The primary outcome parameter is the change in pressure pain tolerance (maximum tolerated pressure) from baseline to end of treatment. Measured in kg/cm\^2. Lower values represent a worse outcome.
Time frame: baseline compared wtih 6 weeks of treatment
Population: Of 17 participants who completed both sequences, data was analyzed for the 15 whose values for all measurement variables were usable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | Change in Pain Tolerance From Baseline to End of Treatment | Pre-Treatment (Week 0 or 9) | 4.2667 kg/cm^2 | Standard Deviation 1.39983 |
| Milnacipran | Change in Pain Tolerance From Baseline to End of Treatment | Post-Treatment (Week 6 or 15) | 3.8667 kg/cm^2 | Standard Deviation 1.43261 |
| Placebo | Change in Pain Tolerance From Baseline to End of Treatment | Pre-Treatment (Week 0 or 9) | 3.80 kg/cm^2 | Standard Deviation 1.17716 |
| Placebo | Change in Pain Tolerance From Baseline to End of Treatment | Post-Treatment (Week 6 or 15) | 3.8667 kg/cm^2 | Standard Deviation 1.20218 |
Secondary
Diffuse Noxious Inhibitory Control (DNIC) Effect at Baseline.
0-100 numerical rating scale. 0 on the numerical scale represents a better outcome. 100 represents a worse outcome.
Time frame: Baselines measured at week 0 and week 9 after washout from first assignment to treatment
Population: One participant did not complete this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Milnacipran | Diffuse Noxious Inhibitory Control (DNIC) Effect at Baseline. | 8.134 units on a scale | Standard Deviation 17.51978 |
| Placebo | Diffuse Noxious Inhibitory Control (DNIC) Effect at Baseline. | 12.0240 units on a scale | Standard Deviation 20.80824 |
Secondary
Pain Tolerance at Baseline
The primary outcome parameter is the pressure pain tolerance (maximum tolerated pressure) at pre-treatment baseline.
Time frame: Baselines measured at week 0 and week 9 after washout from first assignment to treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Milnacipran | Pain Tolerance at Baseline | 4.2667 kg/cm^2 | Standard Deviation 1.39983 |
| Placebo | Pain Tolerance at Baseline | 3.80 kg/cm^2 | Standard Deviation 1.17716 |
Other Pre-specified
Change in Descending Pain Modulation From Baseline to End of Treatment (as Assessed by Changes in fMRI Brainstem Activation Patterns)
Time frame: Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later
Other Pre-specified
Change in fMRI Activation Patterns During N-back Procedure From Baseline to End of Treatment.
Time frame: Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later
Other Pre-specified
Change in fMRI Brain Activation Patterns During Pressure Stimulation From Baseline to End of Treatment
Time frame: Baselines measured at week 0 and week 9 after washout from first assignment to treatment; treatment effect measures collected 6 weeks later