A Study to Evaluate the Effects of Milnacipran on Pain Processing and Functional MRI in Patients With Fibromyalgia

Study Overview
=================
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.

Official Title
-----------------
A Randomized, Double-blind,Placebo-controlled, Two-way Crossover Study to Evaluate the Effect of Milnacipran on Pain Processing and Functional Magnetic Resonance Imaging Activation Patterns in Patients With Fibromyalgia

Conditions
-----------------
Fibromyalgia

Intervention / Treatment
-----------------
* Drug: milnacipran
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Milnacipran<br>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. | Drug: milnacipran<br>* 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.<br>* Other names: Savella;|
| Experimental: Placebo<br>Placebo will be given orally twice daily in tablet form at different times during the course of the study. | Drug: Placebo<br>* Placebo will be given orally twice daily in tablet form at different times during the course of the study.<br>* Other names: placebo/sugar pill;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baselines measured at week 0 and week 9 after washout from first assignment to treatment | 
| 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. | baseline compared with 6 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baselines measured at week 0 and week 9 after washout from first assignment to treatment | 
| 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. | baseline compared with 6 weeks of treatment | 
| Pain Tolerance at Baseline | The primary outcome parameter is the pressure pain tolerance (maximum tolerated pressure) at pre-treatment baseline. | Baselines measured at week 0 and week 9 after washout from first assignment to treatment | 
| 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. | baseline compared wtih 6 weeks of treatment |