Rheumatoid Arthritis
Conditions
Keywords
Pain, Fatigue, Geriatric, Rheumatoid Arthritis, Milnacipran
Brief summary
The purpose of this study is to examine the effects of milnacipran for the treatment of pain in rheumatoid arthritis in older adults.
Detailed description
This is a 12-week open-label trial of milnacipran for the treatment of pain in rheumatoid arthritis in older adults. The investigators are interested in the relationship of chronic pain to inflammation, resilience, fatigue, and physical and mental functioning. The investigators anticipate that effective pain reduction will result in improved fatigue, resilience, physical and mental functioning and reduced levels of inflammation. The investigators are seeking to examine this directly in 30 older adults (55 years of age or older) with rheumatoid arthritis who will be using milnacipran for treatment of pain in the absence of clinical major depression. This proposed trial will serve as a pilot study to estimate the effect of the drug on pain and functional outcomes, as well as aid in dose-finding in this population.
Interventions
DRUGMilnacipran
All subjects will be free of antidepressant medications or opiates, or any other medications used to treat pain for at least 2 weeks prior to initiation of dose titration. Patients will be allowed to escalate up to 100 mg a day: Day 1: 12.5 mg once a day; Days 2-3: 25 mg/day (12.5 mg twice daily); Days 4-7: 50 mg/day (25 mg twice daily); After Day 7: 100 mg/day (50 mg twice daily). The stable-dose phase will be a 10-week period during which patients will take medications at the final dose achieved (either 100 mg per day in divided doses, or the maximum tolerated dose of less than 100 mg per day).
Sponsors
Forest Laboratories
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Diagnosis. RA subjects will be evaluated by a board certified rheumatologist using revised criteria established by the American College of Rheumatology (ACR). This requires at least four of the following seven criteria: 1) morning joint stiffness; 2) arthritis in 3 or more joint areas; 3) arthritis of hand joints; 4) symmetric arthritis; 5) rheumatoid nodules; 6) presence of serum rheumatoid factor and 7) changes on posteroanterior hand and wrist radiographs. In addition, criteria 1-4 must be present for at least four weeks. Individuals diagnosed with juvenile RA will be excluded. Inclusion Criteria: Medication Use for RA patients. RA subjects taking disease modifying anti-rheumatic drugs (DMARDs) must be on a stable regime for one month before study and stable throughout study. RA subjects using DMARDs will be categorized as follows: 1) no DMARDs; 2) DMARD monotherapy with sulfasalazine, hydroxychloroquine, minocycline, or azothioprine, 3) DMARD monotherapy with methotrexate or leflunomide, 4) biologic therapy with or without concomitant DMARDs.
Exclusion criteria
Medical conditions. Subjects will not be eligible for the study based on the following criteria: (1) presence of acute or uncontrolled co-morbid medical conditions not limited to but including cardiovascular (e.g., history of acute coronary event, stroke, uncontrolled HTN) and neurological diseases (e.g., Parkinson's disease), as well as pain disorders; (2) presence of co-morbid inflammatory disorders such as Crohn's disease and ulcerative colitis and other autoimmune disorders; (3) presence of an uncontrolled medical condition that is deemed by the investigators to interfere with the proposed study procedures, or put the study participant at undue risk; (4) presence of chronic infections (e.g. positive purified protein derivative (PPD) test)) due to contraindication of tumor necrosis factor (TNF) antagonist use in these individuals and also because chronic infection can produce elevations in proinflammatory cytokines; (5) presence of an acute infectious illness in the two weeks prior to an experimental session; (6) pregnancy or breast-feeding because of the effects on neuroendocrine systems and sleep; (7) in women, the presence of vasomotor symptoms due to the effects of such symptoms on measures of sleep; (8) use of hormone containing medications including steroids; (9) current and/or regular use of nonsteroidal anti-inflammatory drug (NSAID) medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Rating Index | Change score at baseline and 12 weeks | The Pain Rating Index ranked values associated with adjectives depicting the severity of pain from the McGill Pain Questionnaire (MPQ). The assessment is comprised of 15 adjectives, each of which is scored on a scale ranging from 0 (none) to 3 (severe) and summed to arrive at a score ranging from 0 (no pain) to 45 (worst possible pain), to measure the extent of pain/tenderness and swelling. The Pain Rating Index final scores were averaged to indicate an overall report of joint pain and stiffness. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analogue Scale to Evaluate Fatigue (VAS-F) | Change scores from Week 1 to Week 12 of energy and fatigue | The Visual Analogue Scale to Evaluate Fatigue (VAS-F) is an assessment of fatigue severity. The Visual Analogue Scale (VAS) measures a characteristic or attitude that ranges across a continuum of values from none (0) to an extreme amount of fatigue and energy (10). Scores fall between 0 and 10 anchored by word descriptors at each end and the patient marks on the line the point that they feel represents their perception of their current state. The scale consists of 18 items relating to the subjective experience of fatigue. Two subscales are summed separately and reported as follows: Items 1-5 and 11-18 represent fatigue from none (0) to extreme fatigue (10) and items 6-10 represent energy from none (0) to extreme energy (10). The outcome measures the change scores of energy and fatigue from Week 1 to Week 12. The VAS subscales for Fatigue Scale range: 0-130 and Energy Scale range: 0-50 with higher scores indicating greater energy and fatigue. |
| (UKU) Side Effects Rating Scale Profile | Weeks 1-4, 6, 8, 10, 12 | The UKU assessment will rate the number of participants with emerging adverse events. |
| Profile of Mood States (POMS) | Week 1 and 12 | Depressive symptoms: Repeated assessment of depressive symptoms severity will be made using the Profile of Mood States (POMS). The scale consisted of 65 adjectives rated on 5-point scale 0= not at all; 1=a little; 2=moderately; 3=quite a bit; 4=extremely. Five subscales were included in analysis: tension-anxiety (9 items, score range: 0-36), depression (15 items, range 0-60), friendliness (12 items, range 0-48), vigor-activity (8 items, range 0-32), and fatigue (7 items, range 0-28). Higher vigor-activity and friendliness scores reflect a good mood or emotion (high scores indicating better outcomes), and low scores in the other subscales (tension, depression, and fatigue) reflect a good mood or emotion (low scores indicating better outcomes). |
| Connor-Davidson Resilience Scale (CD-RISC) | Change Scores from Week 1 to Week 12 | Resilience: the Connor-Davidson Resilience scale (CD-RISC) quantifies stress coping ability. The CD-RISC is a 25-item self-administered scale, although where necessary, a staff professional could read out each question to the subject and record the answer. The subject is directed to respond to each question with reference to the previous month, understanding that if a particular situation has not arisen in this time, then the response should be determined by how the person thinks they would have reacted. Scoring of the full 25 item scale is based on summing the total of each item, which is scored from 0-4. The full range is therefore from 0 to 100, with higher scores reflecting greater resilience. The outcome measure is a change score from Week 1 to Week 12. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Milnacipran, Active Drug, Open-label All subjects will be free of antidepressant medications or opiates, or any other medications used to treat pain for at least 2 weeks prior to initiation of dose titration. Subjects will be allowed to escalate up to 100 mg a day or to their maximum tolerated dose in the course of the first week: Day 1: 12.5 mg once a day; Days 2-3: 25 mg/day (12.5 mg twice daily); Days 4-7: 50 mg/day (25 mg twice daily); After Day 7: 100 mg/day (50 mg twice daily). The stable-dose phase will be a 10-week period during which patients will take medications at the final dose achieved (either 100 mg per day in divided doses, or the maximum tolerated dose of less than 100 mg per day). Final efficacy assessments will be made at the termination visit, and the study medication will be tapered down following 12 weeks of drug treatment. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Milnacipran, Active Drug, Open-label |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 67.5 years |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 6 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Pain Rating Index
The Pain Rating Index ranked values associated with adjectives depicting the severity of pain from the McGill Pain Questionnaire (MPQ). The assessment is comprised of 15 adjectives, each of which is scored on a scale ranging from 0 (none) to 3 (severe) and summed to arrive at a score ranging from 0 (no pain) to 45 (worst possible pain), to measure the extent of pain/tenderness and swelling. The Pain Rating Index final scores were averaged to indicate an overall report of joint pain and stiffness.
Time frame: Change score at baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Milnacipran, Active Drug, Open-label | Pain Rating Index | -3.7 units on a scale | Standard Deviation 6.6 |
Secondary
Connor-Davidson Resilience Scale (CD-RISC)
Resilience: the Connor-Davidson Resilience scale (CD-RISC) quantifies stress coping ability. The CD-RISC is a 25-item self-administered scale, although where necessary, a staff professional could read out each question to the subject and record the answer. The subject is directed to respond to each question with reference to the previous month, understanding that if a particular situation has not arisen in this time, then the response should be determined by how the person thinks they would have reacted. Scoring of the full 25 item scale is based on summing the total of each item, which is scored from 0-4. The full range is therefore from 0 to 100, with higher scores reflecting greater resilience. The outcome measure is a change score from Week 1 to Week 12.
Time frame: Change Scores from Week 1 to Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Milnacipran, Active Drug, Open-label | Connor-Davidson Resilience Scale (CD-RISC) | -2.2 units on a scale | Standard Deviation 8 |
Secondary
Profile of Mood States (POMS)
Depressive symptoms: Repeated assessment of depressive symptoms severity will be made using the Profile of Mood States (POMS). The scale consisted of 65 adjectives rated on 5-point scale 0= not at all; 1=a little; 2=moderately; 3=quite a bit; 4=extremely. Five subscales were included in analysis: tension-anxiety (9 items, score range: 0-36), depression (15 items, range 0-60), friendliness (12 items, range 0-48), vigor-activity (8 items, range 0-32), and fatigue (7 items, range 0-28). Higher vigor-activity and friendliness scores reflect a good mood or emotion (high scores indicating better outcomes), and low scores in the other subscales (tension, depression, and fatigue) reflect a good mood or emotion (low scores indicating better outcomes).
Time frame: Week 1 and 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Friendliness Week 1 | 6.42 units on a scale | Standard Deviation 3.82 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Anxiety Week 1 | 5.75 units on a scale | Standard Deviation 5.12 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Depression Week 1 | 4.08 units on a scale | Standard Deviation 3.6 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Vigor Week 1 | 13.00 units on a scale | Standard Deviation 6.03 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Fatigue Week 1 | 6.67 units on a scale | Standard Deviation 6.27 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Anxiety Week 12 | 5.50 units on a scale | Standard Deviation 4.56 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Depression Week 12 | 3.92 units on a scale | Standard Deviation 6.64 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Vigor Week 12 | 16.83 units on a scale | Standard Deviation 5.92 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Fatigue Week 12 | 6.00 units on a scale | Standard Deviation 4.86 |
| Milnacipran, Active Drug, Open-label | Profile of Mood States (POMS) | POMS Friendliness Week 12 | 9.42 units on a scale | Standard Deviation 5.99 |
Secondary
(UKU) Side Effects Rating Scale Profile
The UKU assessment will rate the number of participants with emerging adverse events.
Time frame: Weeks 1-4, 6, 8, 10, 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Micturition Disturbances | 2 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Concentration difficulties | 1 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Asthenia / Lassitude / Increased Fatiguability | 6 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Sleepiness / Sedation | 2 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Failing Memory | 1 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Depression | 2 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Reduced Duration of Sleep | 1 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Nausea / Vomiting | 3 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Increased Tendency to Sweating | 3 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Ejaculatory Dysfunction | 1 Participants |
| Milnacipran, Active Drug, Open-label | (UKU) Side Effects Rating Scale Profile | Tension Headache | 2 Participants |
Secondary
Visual Analogue Scale to Evaluate Fatigue (VAS-F)
The Visual Analogue Scale to Evaluate Fatigue (VAS-F) is an assessment of fatigue severity. The Visual Analogue Scale (VAS) measures a characteristic or attitude that ranges across a continuum of values from none (0) to an extreme amount of fatigue and energy (10). Scores fall between 0 and 10 anchored by word descriptors at each end and the patient marks on the line the point that they feel represents their perception of their current state. The scale consists of 18 items relating to the subjective experience of fatigue. Two subscales are summed separately and reported as follows: Items 1-5 and 11-18 represent fatigue from none (0) to extreme fatigue (10) and items 6-10 represent energy from none (0) to extreme energy (10). The outcome measures the change scores of energy and fatigue from Week 1 to Week 12. The VAS subscales for Fatigue Scale range: 0-130 and Energy Scale range: 0-50 with higher scores indicating greater energy and fatigue.
Time frame: Change scores from Week 1 to Week 12 of energy and fatigue
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran, Active Drug, Open-label | Visual Analogue Scale to Evaluate Fatigue (VAS-F) | Fatigue Subscale | 15.2 units on a scale | Standard Deviation 18.9 |
| Milnacipran, Active Drug, Open-label | Visual Analogue Scale to Evaluate Fatigue (VAS-F) | Energy Subscale | 3.7 units on a scale | Standard Deviation 16.4 |