Fibromyalgia
Conditions
Brief summary
Evaluation of the effect of combinatorial treatment of fibromyalgia patients (standard of care + minocycline + N-acetylcysteine (NAC) relative to standard of care on subjective pain measurement Revised Fibromyalgia Impact Questionnaire (FIQR).
Interventions
DRUGminocycline (200 mg daily) and NAC (1200 mg daily) followed by placebo
minocycline (200 mg daily) and NAC (1200 mg daily) followed by placebo
DRUGPlacebo followed by minocycline (200 mg daily) and NAC (1200 mg daily)
Placebo followed by minocycline (200 mg daily) and NAC (1200 mg daily)
Sponsors
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
• A simple randomization method will be used to assign the initial treatment and then the opposite treatment will ensure for the second treatment period. Patients will be randomized to (i) 8 weeks of placebo, minimum 2 week washout period, and then 8 weeks of a combination minocycline (200 mg daily) and NAC (1200 mg daily) followed by a final 2 week washout or (ii) 8 weeks of a combination minocycline (200 mg daily) and NAC (1200 mg daily), minimum 2 week washout period, and then 8 weeks of placebo followed by a final 2 week washout.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Female * Age 18 years or older * Diagnosis of fibromyalgia for at least 6 months (confirmed by the modified 2010 ACR Diagnostic Criteria for Fibromyalgia Widespread Pain Inventory and Symptom Severity Scale) * Currently on birth control or unable to become pregnant * Willingness to avoid taking opioid and opiate medications during the duration of the study (5-6 months)
Exclusion criteria
* Known hypersensitivity to minocycline or tetracycline antibiotics or to N-acetylcysteine * Current opioid therapy or planned initiation of opioid therapy * Active pregnancy, lactation or plans to become pregnant in the next 6 months * Significant hepatic disease as indicated by an AST or ALT greater than twice the upper limits of normal or bilirubin greater than twice the upper limits of normal * Significant renal disease as indicated by an estimated glomerular filtration rate less than 60 mL/min/1.73m2 at baseline or during the first washout period * History of autoimmune syndromes (systemic lupus erythematosus, myasthenia gravis, rheumatoid arthritis, * History of intracranial hypertension or pseudotumor cerebri * History of IBD (Crohns disease, ulcerative colitis), Clostridium difficile infection * History of esophagitis, esophageal obstruction, achalasia or esophageal dysmotility * History of GI hemorrhage or known risk factors for GI hemorrhage, such as esophageal varices, peptic ulcer disease, etc. * Subjects taking divalent and trivalent cations such as oral iron supplements, certain dietary supplements (multivitamins) that contain manganese or zinc, or antacids that contain aluminum, calcium, or magnesium, which would decrease minocycline absorption * Subjects taking anticoagulant medication since minocycline can decrease plasma prothrombin activity * Subjects taking isotretinoin * Subject taking ergot alkaloids for migraines * Subjects taking penicillin antibiotics * Subjects taking methoxyflurane containing products * Subjects who work outdoors or otherwise have prolonged exposure to UV light and sunlight * Lack of access to reliable technology to be able to complete emailed REDCap questionnaires * Cognitive deficits that may make it difficult to adhere to the medication regimen or provide consistent and timely completion of questionnaires * Inability or unwillingness to give informed consent * Unwillingness to use two forms of birth control for the entire duration of participation in the study (if capable of becoming pregnant) * Unwillingness to complete home pregnancy tests throughout the study (if capable of becoming pregnant) * Inability to swallow large pills
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Revised Fibromyalgia Impact Questionnaire (FIQR) Score From Baseline to After Treatment Occurring at Weeks 8 and 18 | Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18 | The FIQR (Revised Fibromyalgia Impact Questionnaire) is comprised of 21 questions spread across 3 domains: function, overall impact, symptoms, scored on an 11-point numeric rating scale. The questions are framed with the context of the past 7 days. The instructions ask the patient to rate the difficulty on a scale of 0-10 (0 = No difficulty, and 10 = Very difficult) which indicates how much difficulty they have experienced in doing the specified activity during the past 7 days. Each item is rated on a scale from 0 - 10, and the raw scores on each subscale. Then, the score on the function subscale is divided by 3, the overall impact subscale divided by 1, and the symptoms subscale divided by 2. These final scores from each subscale are then added up for the total FIQR score The total score can range from 0 -100. The total FIQR score is the sum of each section. A lower score means a better outcome. Higher scores indicate more severe impact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain, Enjoyment of Life and General Activity (PEG) Scale From Baseline to After Treatment Occurring at Weeks 8 and 18 | Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18 | In the PEG score, a higher score indicates more severe pain and pain-related interference. The PEG has 3 separate numerical scales. Each has ratings 0-10.The first scale asks individuals to rate their pain, on average, over the past week, the second asks to rate how pain has interfered with their enjoyment of life in the past week, the third asks individuals to rate how pain has interfered with general activities. The PEG scale is scored by averaging the three numbers. The final score helps to track and monitor pain levels over time. The PEG score should decrease when treatment is effective. |
| Change in Patient Health Questionnaire (PHQ-2) From Baseline to After Treatment Occurring at Weeks 8 and 18 | Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18 | The change in depression scale (PHQ-2) by evaluating the number of days the participant feels down, depressed or hopeless and has little interest or pleasure in doing things rated as not at all (0), several days (1), more than half the days (2), or nearly every day (3) by scoring the 2 questions from 0-3 as indicated. Scores range from 0-6, with the higher score meaning the patient experiencing more severe symptoms. |
| Change in General Anxiety Disorder (GAD-2) Score From Baseline to After Treatment Occurring at Weeks 8 and 18 | Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18 | The Generalized Anxiety Disorder 2-item (GAD-2) screens for generalized anxiety disorder 1. Two questions are asked, with the scoring of each ranging from 0-3, then both numbers added together, with possible scores ranging from 0-6. A total score of at least 3 points indicates possible anxiety disorder. The higher the score, the more severe anxiety. |
| Patient Global Impression of Change (PGIC) | immediately after each treatment at week 8 (first intervention) and week 18 (second intervention) | Patient Global Impression of Change (PGIC) has the subject will reporting whether there was a change in their activity, limitations, symptoms, emotions and overall quality of life by rating no change, almost the same, a little better, somewhat better, moderately better, better or a great deal better. Participants will also rate degrees of change from much better (0), 5 (no change), to much worse (10). The higher the score, the worse their impression of their health status was worse than previously. Scores will range from no change to a great deal better, and from 0 (much better) to 10 (much worse). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Modified 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (Modified ACR 2010) | Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18 | Participants will rate change using modified 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (modified ACR 2010) by answering questions related to their areas of pain, amount of medication required for pain, and symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Followed by Minocycline (200 mg Daily) and NAC (1200 mg Daily) Participants will be randomized to 8 weeks of placebo, minimum 2 week washout period, and then 8 weeks of a combination minocycline (200 mg daily) and NAC (1200 mg daily) followed by a final 2 week washout
Placebo followed by minocycline (200 mg daily) and NAC (1200 mg daily): Placebo followed by minocycline (200 mg daily) and NAC (1200 mg daily) | 7 |
| Minocycline (200 mg Daily) and NAC (1200 mg Daily) Followed by Placebo Participants will be randomized to 8 weeks of a combination minocycline (200 mg daily) and NAC (1200 mg daily), minimum 2 week washout period, and then 8 weeks of placebo followed by a final 2 week washout
minocycline (200 mg daily) and NAC (1200 mg daily) followed by placebo: minocycline (200 mg daily) and NAC (1200 mg daily) followed by placebo | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (8 Weeks) | Lost to Follow-up | 0 | 3 |
| First Intervention (8 Weeks) | Withdrawal by Subject | 0 | 1 |
| Second Intervention (8 Weeks) | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo Followed by Minocycline (200 mg Daily) and NAC (1200 mg Daily) | Minocycline (200 mg Daily) and NAC (1200 mg Daily) Followed by Placebo | Total |
|---|---|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 17.2 | 51.6 years STANDARD_DEVIATION 9.98 | 48.4 years STANDARD_DEVIATION 13.9 |
| Duration of Formal Diagnosis 0-1 years | 0 participants | 2 participants | 2 participants |
| Duration of Formal Diagnosis >10 years | 1 participants | 1 participants | 2 participants |
| Duration of Formal Diagnosis 1-2 years | 1 participants | 1 participants | 2 participants |
| Duration of Formal Diagnosis 3-5 years | 1 participants | 0 participants | 1 participants |
| Duration of Formal Diagnosis 5-10 years | 4 participants | 3 participants | 7 participants |
| Duration of Symptoms >10 years | 4 participants | 5 participants | 9 participants |
| Duration of Symptoms 1-2 years | 1 participants | 0 participants | 1 participants |
| Duration of Symptoms 3-5 years | 1 participants | 0 participants | 1 participants |
| Duration of Symptoms 5-10 years | 1 participants | 2 participants | 3 participants |
| Fibromyalgia Impact Questionnaire (FIQR) Score | 67.6 units on a scale STANDARD_DEVIATION 12.9 | 58.4 units on a scale STANDARD_DEVIATION 16.2 | 63.0 units on a scale STANDARD_DEVIATION 14.9 |
| Generalized Anxiety Disorder 2 (GAD-2) Score | 2 units on a scale | 2 units on a scale | 2 units on a scale |
| Patient Health Questionnaire-2 (PHQ-2) Score | 4 units on a scale | 2 units on a scale | 2 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Symptom Severity Score (SS score) - Part 2a | 7 units on a scale | 5 units on a scale | 6 units on a scale |
| Symptom Severity (SS) 2b Score | 1 units on a scale | 2 units on a scale | 1.5 units on a scale |
| The Pain, Enjoyment of Life and General Activity (PEG) Score | 7.29 units on a scale STANDARD_DEVIATION 1.2 | 6.90 units on a scale STANDARD_DEVIATION 1.74 | 7.10 units on a scale STANDARD_DEVIATION 1.41 |
| Total Symptom Severity (SS) Score | 8.57 units on a scale STANDARD_DEVIATION 1.9 | 7.14 units on a scale STANDARD_DEVIATION 2.34 | 7.86 units on a scale STANDARD_DEVIATION 2.18 |
| Widespread Pain Index (WPI) Score | 14.3 units on a scale STANDARD_DEVIATION 3.9 | 10.6 units on a scale STANDARD_DEVIATION 4.12 | 12.4 units on a scale STANDARD_DEVIATION 4.31 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 14 |
| other Total, other adverse events | 5 / 10 | 8 / 14 |
| serious Total, serious adverse events | 0 / 10 | 0 / 14 |
Outcome results
Primary
Change in Revised Fibromyalgia Impact Questionnaire (FIQR) Score From Baseline to After Treatment Occurring at Weeks 8 and 18
The FIQR (Revised Fibromyalgia Impact Questionnaire) is comprised of 21 questions spread across 3 domains: function, overall impact, symptoms, scored on an 11-point numeric rating scale. The questions are framed with the context of the past 7 days. The instructions ask the patient to rate the difficulty on a scale of 0-10 (0 = No difficulty, and 10 = Very difficult) which indicates how much difficulty they have experienced in doing the specified activity during the past 7 days. Each item is rated on a scale from 0 - 10, and the raw scores on each subscale. Then, the score on the function subscale is divided by 3, the overall impact subscale divided by 1, and the symptoms subscale divided by 2. These final scores from each subscale are then added up for the total FIQR score The total score can range from 0 -100. The total FIQR score is the sum of each section. A lower score means a better outcome. Higher scores indicate more severe impact.
Time frame: Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Treatment Period | Change in Revised Fibromyalgia Impact Questionnaire (FIQR) Score From Baseline to After Treatment Occurring at Weeks 8 and 18 | 4.37 Score |
| Minocycline (200 mg Daily) and NAC (1200 mg Daily) Treatment Period | Change in Revised Fibromyalgia Impact Questionnaire (FIQR) Score From Baseline to After Treatment Occurring at Weeks 8 and 18 | 12.1 Score |
Secondary
Change in General Anxiety Disorder (GAD-2) Score From Baseline to After Treatment Occurring at Weeks 8 and 18
The Generalized Anxiety Disorder 2-item (GAD-2) screens for generalized anxiety disorder 1. Two questions are asked, with the scoring of each ranging from 0-3, then both numbers added together, with possible scores ranging from 0-6. A total score of at least 3 points indicates possible anxiety disorder. The higher the score, the more severe anxiety.
Time frame: Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Treatment Period | Change in General Anxiety Disorder (GAD-2) Score From Baseline to After Treatment Occurring at Weeks 8 and 18 | -0.02 score on a scale |
| Minocycline (200 mg Daily) and NAC (1200 mg Daily) Treatment Period | Change in General Anxiety Disorder (GAD-2) Score From Baseline to After Treatment Occurring at Weeks 8 and 18 | 0.72 score on a scale |
Secondary
Change in Pain, Enjoyment of Life and General Activity (PEG) Scale From Baseline to After Treatment Occurring at Weeks 8 and 18
In the PEG score, a higher score indicates more severe pain and pain-related interference. The PEG has 3 separate numerical scales. Each has ratings 0-10.The first scale asks individuals to rate their pain, on average, over the past week, the second asks to rate how pain has interfered with their enjoyment of life in the past week, the third asks individuals to rate how pain has interfered with general activities. The PEG scale is scored by averaging the three numbers. The final score helps to track and monitor pain levels over time. The PEG score should decrease when treatment is effective.
Time frame: Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Treatment Period | Change in Pain, Enjoyment of Life and General Activity (PEG) Scale From Baseline to After Treatment Occurring at Weeks 8 and 18 | 0.64 score on a scale |
| Minocycline (200 mg Daily) and NAC (1200 mg Daily) Treatment Period | Change in Pain, Enjoyment of Life and General Activity (PEG) Scale From Baseline to After Treatment Occurring at Weeks 8 and 18 | 1.24 score on a scale |
Secondary
Change in Patient Health Questionnaire (PHQ-2) From Baseline to After Treatment Occurring at Weeks 8 and 18
The change in depression scale (PHQ-2) by evaluating the number of days the participant feels down, depressed or hopeless and has little interest or pleasure in doing things rated as not at all (0), several days (1), more than half the days (2), or nearly every day (3) by scoring the 2 questions from 0-3 as indicated. Scores range from 0-6, with the higher score meaning the patient experiencing more severe symptoms.
Time frame: Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Treatment Period | Change in Patient Health Questionnaire (PHQ-2) From Baseline to After Treatment Occurring at Weeks 8 and 18 | 0.12 score on a scale |
| Minocycline (200 mg Daily) and NAC (1200 mg Daily) Treatment Period | Change in Patient Health Questionnaire (PHQ-2) From Baseline to After Treatment Occurring at Weeks 8 and 18 | 0.23 score on a scale |
Secondary
Patient Global Impression of Change (PGIC)
Patient Global Impression of Change (PGIC) has the subject will reporting whether there was a change in their activity, limitations, symptoms, emotions and overall quality of life by rating no change, almost the same, a little better, somewhat better, moderately better, better or a great deal better. Participants will also rate degrees of change from much better (0), 5 (no change), to much worse (10). The higher the score, the worse their impression of their health status was worse than previously. Scores will range from no change to a great deal better, and from 0 (much better) to 10 (much worse).
Time frame: immediately after each treatment at week 8 (first intervention) and week 18 (second intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Treatment Period | Patient Global Impression of Change (PGIC) | 1.6 units on a scale | Standard Error 0.72 |
| Minocycline (200 mg Daily) and NAC (1200 mg Daily) Treatment Period | Patient Global Impression of Change (PGIC) | 2.8 units on a scale | Standard Error 0.79 |
Other Pre-specified
Modified 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (Modified ACR 2010)
Participants will rate change using modified 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (modified ACR 2010) by answering questions related to their areas of pain, amount of medication required for pain, and symptoms.
Time frame: Evaluated at baseline (prior to intervention) then again after treatment which occurs at week 8 and week 18