An fMRI Study Of Brain Response In Patients With Fibromyalgia

Study Overview
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Brief Summary
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The purpose of this study is to explore how pregabalin works in patients with fibromyalgia by evaluating brain imaging signals. To find out whether fMRI (functional magnetic resonance imaging) is an efficient way to show whether new pain medications are effective in treating fibromyalgia.

Detailed Description
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Methodology study

Official Title
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A Double-Blind, Placebo-Controlled Cross-Over Study In Fibromyalgia Subjects To Examine Effects Of Pregabalin On Brain Response To Mechanical Pain As Assessed By Functional Magnetic Resonance Imaging, Proton Magnetic Resonance Spectroscopy And Subjective Ratings

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: Pregabalin, then placebo
* Drug: Placebo, then pregabalin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women must have pain due to fibromyalgia Fibromyalgia must have been diagnosed at least 6 months prior to be eligible for this study Exclusion Criteria: Patients with severe depression or other serious illness, who are left-handed, or who are pregnant or nursing are not eligible for this study.

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

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregabalin, then placebo<br> | Drug: Pregabalin, then placebo<br>* Placebo and pregabalin will be given orally twice daily in capsules at different times during the course of the study. The highest dose of pregabalin to be used in the study is 450 mg/day.<br>|
| Experimental: Placebo, then pregabalin<br> | Drug: Placebo, then pregabalin<br>* Placebo and pregabalin will be given orally twice daily in capsules at different times during the course of the study. The highest dose of pregabalin to be used in the study is 450 mg/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS) | Single voxel spectra obtained from the anterior and posterior right insula at rest to compare ratios for Gln/Cr, Glu/Cr, and combined Glutamate + Glutamine (Glx/Cr) for pregabalin and placebo. Gln, Glu, Glx calculated as ratios to the internal standard creatine. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers | BOLD fMRI imaging modality to assess brain activation signals across the whole brain in defined Region of Interest (ROI) brain regions in response to blunt pressure pain; acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kilograms [kg] pressure/equal stimulus conditions, and high pain pressure/up to 10 kg). Estimated as magnitude (percent change) of the betas representing brain signal activation associated with pressure induced pain. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli | BOLD fMRI imaging modality to assess brain activation signals across the whole brain in defined ROI brain regions in response to checkerboard visual stimuli (flashing at 8 hertz [Hz]). Reported as percent change between the pre-dose (baseline) and post-dose values. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions | Resting state brain activity assessed for correlation of brain seed region (pIns, anIns) to ROI connectivity at baseline (pre-dose) and post-dose (pre minus post) measured using z-score (mean of 0, standard deviation [SD] of 1); range approximately -3 to +3. Positive (+) z-scores reflect greater connectivity (+correlation between seed region and ROI). Negative (-) z-scores reflect -connectivity (anti-correlation between seed region and ROI). ROIs include PCC and IPL from within the default mode network (DMN). DMN is a constellation of regions in which connectivity is augmented in fibromyalgia. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Gracely Box Scales for Pain Intensity (GBSint) Including Outliers | Minimum and maximum pain intensity acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kg pressure/equal stimulus conditions, and high pain pressure/up to 10 kg) measured during fMRI and scored from 0 (no pain sensation) to 20 (extremely intense). Baseline and Post-dose data for Period 1 and Period 2 summarized as Least Squares Mean (LS Mean). Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers | Minimum and maximum pain unpleasantness acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kg pressure/equal stimulus conditions, and high pain pressure/up to 10 kg) measured during fMRI and scored from 0 (neutral) to 20 (very intolerable). Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline/Pre-dose (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 7 Day Average Pain Score Including Outliers | The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The 7 day average pain score was defined as the mean daily pain NRS value for the last 7 days prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 3 Day Average Pain Score Including Outliers | The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The 3 day average pain score was defined as the mean daily pain NRS value for the last 3 days prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: Individual Daily Pain Score Including Outliers | The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The individual daily pain score was defined as the final score recorded in the last pain diary of the treatment period 24 hours prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Total Score Including Outliers | SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12); higher scores indicated higher pain/impact. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Total Score Including Outliers | SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12); higher scores indicated higher pain/impact. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Short-Form McGill Pain Questionnaire (SF-MPQ): Overall Score Including Outliers | SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by the participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12). Total (overall) score was sum of items 1 to 15, range 0 to 45; higher scores indicated higher pain/impact. Any observation with a studentized residual >3 or <-3 was considered an outlier. | Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51) | 
| Sphygmomanometry Evoked Allodynia in Relation to the Blood Pressure (BP) Value at Which Allodynia Was Evoked | BP cuff evoked allodynia assessed based on participant response to the following question When I take your blood pressure, tell me if the cuff's pressure is painful. A standard BP cuff was inflated at approximately 10 millimeters of mercury (mm Hg) per second up to 180 mm Hg or to point when participant experienced pain; performed 3 times on each arm whether or not pain was reported. If no pain elicited at 180 mm Hg, it was recorded that no sphygmomanometry-evoked allodynia occurred. If pain was reported, value (in mm Hg) at which pain first occured was recorded for each of the assessments. | Day 58 | 
| Pain at the Bilateral Epicondyle Tender Points Assessed Using American College of Rheumatology (ACR) Classification Criteria | Participant rated severity of pain upon application of 4 kilograms (kg) pressure via dolorimeter at the bilateral epicondyle tender points (2 tender points, 2 centimeters distal to the epicondyles) described in the American College of Rheumatology (ACR) classification criteria and scored on a 0 (no pain) to 10 (worst possible pain) rating scale. Each arm was to be assessed for any pain (one point on each arm) with the application of pressure. | Day 58 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibromyalgia; fMRI; pain; pregabalin; Lyrica; imaging