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| ID | Type | Description | Link |
|---|---|---|---|
| K23AR057578 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Forest Laboratories | INDUSTRY |
| National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) | NIH |
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The purpose of this study is to determine whether milnacipran reduces widespread, non-joint pain in patients with rheumatoid arthritis (RA). The investigators will conduct a double-blind randomized crossover trial in subjects with RA to test the hypothesis that milnacipran improves widespread, non-joint pain. The investigators will also use data from the trial to determine whether response to milnacipran is associated with pain-modulating mechanisms from the central nervous system. The investigators hypothesize that response to milnacipran will be greater among patients with impaired central pain mechanisms than among patients with intact central pain modulating mechanisms.
Despite the development of effective medications to treat inflammation, pain remains a priority for rheumatoid arthritis (RA) patients. The pain that persists despite anti-inflammatory treatment is usually widespread and non-articular; it may lead to diminished quality of life and high medical, psychological and social costs. To develop better treatments for pain and prevent disability, it is critical to obtain a better understanding of widespread, non-joint pain in RA.
Milnacipran is a selective serotonin-norepinephrine reuptake inhibitor (SNRI). No studies have examined the effect of SNRIs on pain in RA. However, several studies have examined the role of SNRIs in fibromyalgia and related pain conditions. Treatment with milnacipran has been associated with improvements in clinical pain severity in Phase 2 and Phase 3 randomized placebo-controlled trials of fibromyalgia patients. In animal models, milnacipran appears to moderate the pain-inducing effects of inflammation and central sensitization. Thus milnacipran may be an ideal drug to treat pain in RA.
A clinical trial of an SNRI in the treatment of widespread, non-joint pain in RA will provide more information regarding pain mechanisms and may lead to more targeted, effective ways of treating pain in RA.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Milnacipran then placebo | Other | This arm of the study will contain half the study population after randomization. The participants in this arm will receive milnacipran for 6 weeks. They will undergo a one-week taper and a two week washout period and then crossover to a placebo for 6 weeks. |
|
| Placebo then milnacipran | Other | This arm of the study will contain half the study population after randomization. The participants in this arm will receive placebo for 6 weeks. They will undergo a one-week "taper" and a two week "washout" period and then crossover to milnacipran for 6 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Milnacipran | Drug | Milnacipran comes in 50 mg tablets and is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Brief Pain Inventory (BPI) Change | A measure of change in scores on the BPI short form, a "24-hr average pain" item, from baseline to 6 weeks, The BPI short form scores ranges from 0-10, with 10 being the worst pain. | Baseline to 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Conditioned Pain Modulation (CPM) | CPM is defined as the difference between pain threshold A (measured after a conditioning stimulus activates pathways that inhibit pain) and pain threshold B (measured before the conditioning stimulus is applied). The conditioning stimulus was immersion of the hand in a cold water bath. Pressure pain threshold was assessed at the trapezius muscle initially. Subjects were then instructed to immerse their hand in a water bath for 30 seconds. At 20 seconds, pressure pain threshold at the trapezius was assessed again. We defined the magnitude of subjects' CPM as the difference in pressure pain threshold between baseline and 20 seconds after cold water immersion. This difference was compared to that measured at 6 weeks. The scale for the difference in CPM ranged from 0-11 kg/cm^2, with 0 indicating no change in CPM between 6 weeks and baseline and 11 indicating the maximum possible change. A greater change in CPM between baseline and 6 weeks is indicative of improvements in CPM. |
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Inclusion Criteria:
Exclusion Criteria:
Diagnosis of primary fibromyalgia
Diagnosis of cold sensitive conditions such as Raynaud's syndrome, cryoglobulinemia and paroxysmal cold hemoglobinuria
Diagnosis of psychotic disorders, such as schizophrenia, schizoaffective disorder, delusional disorder and shared psychotic disorder
Patients being treated with SSRIs, MAO inhibitors or tricyclic, tetracyclic or atypical antidepressants for pain may participate in this study if they are washed off these medications before study entry. Patients currently receiving therapy with SSRIs or tricyclic, tetracyclic or atypical antidepressants for depression may be washed off these medications before study entry pending permission of the prescribing physician and if they have never received a diagnosis of major depressive disorder or had a history of suicidal ideation.
Patients on thioridazine or MAO inhibitors
Patients taking codeine or other opioids/opiates. Patients who are taking medications such as pregabalin (Lyrica) and gabapentin (Neurontin) for pain may be enrolled in this study.
Known hypersensitivity to milnacipran
Patients with a significant risk of suicide as assessed by the Beck depression inventory form
Patients with a history of suicide
Pregnant or breast-feeding women
Patients with an actively pending worker's compensation claim or auto no-fault claim; patients with current worker's compensation, auto no-fault compensation, or litigation; or any patient with significant secondary gain issues per discretion of the researchers.
Patients with myocardial infarction within the past 12 months, active cardiac disease (chest pain or evidence of ischemia on stress test), acute congestive heart failure requiring hospitalization in the past 12 months, clinically significant cardiac rhythm or conduction abnormalities requiring hospitalization in the past 12 months
Patients with severe liver impairment (AST or ALT > 3 times the upper limit of normal)
Patients with severe or end stage renal disease, defined as a GFR < 15 ml/min or on dialysis
Patients with a recent (≤ 12 months) history of seizures.
Patients with uncontrolled narrow-angle glaucoma.
Patients who have been treated with an experimental agent within the last three months.
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| Name | Affiliation | Role |
|---|---|---|
| Yvonne C Lee, MD, MMSc | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19874580 | Background | Lee YC, Chibnik LB, Lu B, Wasan AD, Edwards RR, Fossel AH, Helfgott SM, Solomon DH, Clauw DJ, Karlson EW. The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 2009;11(5):R160. doi: 10.1186/ar2842. Epub 2009 Oct 29. | |
| 26628607 | Derived | Lee YC, Massarotti E, Edwards RR, Lu B, Liu C, Lo Y, Wohlfahrt A, Kim ND, Clauw DJ, Solomon DH. Effect of Milnacipran on Pain in Patients with Rheumatoid Arthritis with Widespread Pain: A Randomized Blinded Crossover Trial. J Rheumatol. 2016 Jan;43(1):38-45. doi: 10.3899/jrheum.150550. Epub 2015 Dec 1. |
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49 patients signed the informed consent document. 8 patients did not meet inclusion criteria and failed screening. 41 patients were randomized and received >= 1 dose of the study drug/placebo. Seven patients stopped participation due to adverse events, and 2 were lost to follow-up. 32 patients completed the study and were analyzed.
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| ID | Title | Description |
|---|---|---|
| FG000 | Milnacipran and Then Placebo | Participants first received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). This was followed by a 3-week wash-out. Participants then received 6 weeks of placebo. |
| FG001 | Placebo and Then Milnacipran | Participants first received 6 weeks of placebo. This was followed by a 3-week wash-out. After the wash-out period, participants then received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
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| ||||||||||||||||||
| Washout |
| |||||||||||||||||||
| 2nd Intervention |
|
49 individuals signed the informed consent document. Of these individuals, 8 did not meet inclusion/exclusion criteria. 41 subjects were randomized and received study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Milnacipran and Then Placebo | Participants first received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). This was followed by a 3-week wash-out. Participants then received 6 weeks of placebo. |
| BG001 | Placebo and Then Milnacipran |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Brief Pain Inventory (BPI) Change | A measure of change in scores on the BPI short form, a "24-hr average pain" item, from baseline to 6 weeks, The BPI short form scores ranges from 0-10, with 10 being the worst pain. | Posted | Mean | Standard Deviation | units on a scale | Baseline to 6 weeks |
|
6 weeks for intervention with a period of 3 weeks of washout between each intervention period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Milnacipran | Participants received milnacipran for 6 weeks. The dose was titrated according to the following schedule: 1) Days 1-3: milnacipran 12.5 mg twice daily, 2) Days 4-6: milnacipran 25 mg twice daily, 3) Days 7-42: milnacipran 50 mg twice daily. If participants could not tolerate the full dose, the dose was decreased to the highest tolerated dose. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Colon Abscess | Gastrointestinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yvonne C Lee, MD, MMSc | Brigham and Women's Hospital | 617-732-8736 | ylee9@partners.org |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| D010146 | Pain |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| ID | Term |
|---|---|
| D000078764 | Milnacipran |
| ID | Term |
|---|---|
| D003521 | Cyclopropanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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|
| Placebo | Drug |
|
| Baseline to 6 weeks |
| Symptom Intensity Scale (SIS) | A measure of the change in SIS score from baseline to 6 weeks. The SIS score ranges from 0-9.75, with high scores being worse indicating more widespread pain and fatigue. | Baseline to 6 weeks |
| Thumbnail Pain Threshold | A measure of the change in thumbnail pain threshold from baseline to 6 weeks. Thumbnail pain threshold was determined by applying pressure to a subjectt's thumbnail until the subject felt pain. The difference between the average thumbnail pain threshold (an average for the right and left thumbs) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Baseline to 6 weeks |
| Trapezius Pain Threshold | A measure of the change in trapezius pain threshold from baseline to 6 weeks. Trapezius pain threshold was determined by applying pressure to a subject's trapezius muscle until the subject felt pain. The difference between the average trapezius pain threshold (an average for the right and left trapezii) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Baseline to 6 weeks |
| Wrist Pain Threshold | A measure of the change in wrist pain threshold from baseline to 6 weeks. Wrist pain threshold was determined by applying pressure to a subject's wrist until the subject felt pain. The difference between the average wrist pain threshold (an average for the right and left wrists) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Baseline to 6 weeks |
| Knee Pain Threshold | A measure of the change in knee pain threshold from baseline to 6 weeks. Knee pain threshold was determined by applying pressure to a subject's knee until the subject felt pain. The difference between the average knee pain threshold (an average for the right and left knees) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Baseline to 6 weeks |
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| NOT COMPLETED |
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Participants first received 6 weeks of placebo. This was followed by a 3-week wash-out. After the wash-out period, participants then received 6 weeks of milnacipran (titrated up to full dose of 50 mg twice daily). |
| BG002 | Total | Total of all reporting groups |
| Year |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Secondary | Change in Conditioned Pain Modulation (CPM) | CPM is defined as the difference between pain threshold A (measured after a conditioning stimulus activates pathways that inhibit pain) and pain threshold B (measured before the conditioning stimulus is applied). The conditioning stimulus was immersion of the hand in a cold water bath. Pressure pain threshold was assessed at the trapezius muscle initially. Subjects were then instructed to immerse their hand in a water bath for 30 seconds. At 20 seconds, pressure pain threshold at the trapezius was assessed again. We defined the magnitude of subjects' CPM as the difference in pressure pain threshold between baseline and 20 seconds after cold water immersion. This difference was compared to that measured at 6 weeks. The scale for the difference in CPM ranged from 0-11 kg/cm^2, with 0 indicating no change in CPM between 6 weeks and baseline and 11 indicating the maximum possible change. A greater change in CPM between baseline and 6 weeks is indicative of improvements in CPM. | Posted | Mean | Standard Deviation | kg/cm^2 | Baseline to 6 weeks |
|
|
|
|
| Secondary | Symptom Intensity Scale (SIS) | A measure of the change in SIS score from baseline to 6 weeks. The SIS score ranges from 0-9.75, with high scores being worse indicating more widespread pain and fatigue. | Posted | Mean | Standard Deviation | units on a scale | Baseline to 6 weeks |
|
|
|
|
| Secondary | Thumbnail Pain Threshold | A measure of the change in thumbnail pain threshold from baseline to 6 weeks. Thumbnail pain threshold was determined by applying pressure to a subjectt's thumbnail until the subject felt pain. The difference between the average thumbnail pain threshold (an average for the right and left thumbs) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Posted | Mean | Standard Deviation | kg/cm^2 | Baseline to 6 weeks |
|
|
|
|
| Secondary | Trapezius Pain Threshold | A measure of the change in trapezius pain threshold from baseline to 6 weeks. Trapezius pain threshold was determined by applying pressure to a subject's trapezius muscle until the subject felt pain. The difference between the average trapezius pain threshold (an average for the right and left trapezii) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Posted | Mean | Standard Deviation | kg/cm^2 | Baseline to 6 weeks |
|
|
|
|
| Secondary | Wrist Pain Threshold | A measure of the change in wrist pain threshold from baseline to 6 weeks. Wrist pain threshold was determined by applying pressure to a subject's wrist until the subject felt pain. The difference between the average wrist pain threshold (an average for the right and left wrists) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Posted | Mean | Standard Deviation | kg/cm^2 | Baseline to 6 weeks |
|
|
|
|
| Secondary | Knee Pain Threshold | A measure of the change in knee pain threshold from baseline to 6 weeks. Knee pain threshold was determined by applying pressure to a subject's knee until the subject felt pain. The difference between the average knee pain threshold (an average for the right and left knees) at baseline was compared to that at 6 months. Pain threshold was measured in kg/cm^2. The difference in threshold could range from 0-11 kg/cm^2. A higher difference between thresholds indicates improved pain sensitivity. | Posted | Mean | Standard Deviation | kg/cm^2 | Baseline to 6 weeks |
|
|
|
|
| 0 |
| 41 |
| 17 |
| 41 |
| EG001 | Placebo | Participants received placebo tablets for 6 weeks. The tablets were identical in appearance to the milnacipran tablets. | 1 | 41 | 8 | 41 |
| EG002 | Washout Period | This 3-week period occurred after the first 6 weeks (when participants either received milnacipran or placebo). During the washout period, participants down titrated from the full dosage of milnacipran/placebo to nothing. | 0 | 41 | 1 | 41 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | General disorders | Systematic Assessment |
|
| Sleep Problems | General disorders | Systematic Assessment |
|
| Loss of appetite | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Urinary Hesitation | Renal and urinary disorders | Systematic Assessment |
|
| Parathesthesias | Nervous system disorders | Systematic Assessment |
|
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| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| Change |
|
The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models. |
| Mixed Models Analysis |
| 0.96 |
Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was < 0.05. |
| 2-Sided |
| No |
| Superiority or Other |
| Change |
|
The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models. |
| Mixed Models Analysis |
| 0.83 |
Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was < 0.05. |
| 2-Sided |
| No |
| Superiority or Other |
| Change |
|
The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models. |
| Mixed Models Analysis |
| 0.04 |
Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was < 0.05. |
| 2-Sided |
| No |
| Superiority or Other |
| Change |
|
The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models. |
| Mixed Models Analysis |
| 0.44 |
Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was < 0.05. |
| 2-Sided |
| No |
| Superiority or Other |
| Change |
|
The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models. |
| Mixed Models Analysis |
| 0.34 |
Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was < 0.05. |
| 2-Sided |
| No |
| Superiority or Other |
| Change |
|
The difference between the change measured during placebo versus the change during milnacipran treatment. Calculated using linear mixed models. |
| Mixed Models Analysis |
| 0.82 |
Linear mixed models including treatment, crossover period and treatment sequence. Not adjusted for multiple comparisons. A priori threshold for statistical significance was < 0.05. |
| 2-Sided |
| No |
| Superiority or Other |