Arthritis, RheumatoidPhase 4NCT01207453
Milnacipran in the Treatment of Widespread, Non-Joint Pain in Rheumatoid Arthritis
A Phase 4 study testing Milnacipran in people with Arthritis, Rheumatoid, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 24 years and older
- Conditions the study is for
- Arthritis, Rheumatoid
- What is being tested?
- Milnacipran
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 49 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2011to Nov 2013
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 24 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 24 years or older
- Primary diagnosis of rheumatoid arthritis from a board-certified rheumatologist
- Willing to maintain stable doses of concurrent non-steroidal anti-inflammatory drugs or other acceptable medications or therapies for the duration of the study
- Brief Pain Inventory Average Pain >= 4 at the screening visit
- Widespread Pain Index >= 5 at the screening visit
- Able to give informed consent
Who cannot join
- 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.
Show all 19Show fewer
- 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)
- For patients 2-3 times the upper limit of normal, we will obtain enrollment permission from the patient's hepatologist and monitor values at each study visit. If values increase above 3 times the upper limit of normal, the patient will be discontinued from the study.
- For patients 1-2 times the upper limit of normal, we will obtain enrollment permission from the patient's physician and monitor per request of the physician.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham and Women's Hospital
Boston, Massachusetts, 02115
About this study
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.
Read the detailed description
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.
- Conditions
- Arthritis, Rheumatoid
- Being tested
- Milnacipran, Placebo
- Keywords
- Arthritis, Rheumatoid, Milnacipran, Pain
- Medical subject headings
- Arthritis, Rheumatoid, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MilnacipranDrug
Also called Savella
Milnacipran comes in 50 mg tablets and is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily.
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Milnacipran; Drug: Placebo |
| 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. Receives: Drug: Milnacipran; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to 6 weeks
Secondary outcomes (6)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline to 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Sep 2010 (estimated)
- Study startJan 2011
- Primary completionNov 2013
- Study completionNov 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Arthritis, RheumatoidStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 49 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Forest Laboratories, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- Responsible party
- Principal investigator, Yvonne C. Lee, Brigham and Women's Hospital
- Investigators
- Yvonne C Lee, MD, MMSc, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01207453
- Sponsor's protocol ID
- SAV-MD-16
- Other IDs
- K23AR057578
- Status last verified
- Nov 2014
- First submitted
- 21 Sep 2010
- Last updated
- 17 Nov 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 19874580Lee 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.
PubMed 26628607
Study at a glance
From the registry record, last updated by the sponsor on 17 Nov 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Milnacipran in the Treatment of Widespread, Non-Joint Pain in Rheumatoid Arthritis
- ClinicalTrials.gov ID
- NCT01207453
- Acronym / sponsor ID
- SAV-MD-16
- Conditions
- Arthritis, Rheumatoid
- Keywords
- Arthritis, Rheumatoid, Milnacipran, Pain
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 49 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Collaborators
- Forest Laboratories, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- Study start
- Jan 2011
- Primary completion
- Nov 2013 (actual)
- Study completion
- Nov 2013 (actual)
- First posted
- 23 Sep 2010 (estimated)
- Results
- Posted 17 Nov 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Milnacipran then placebo | Other | Drug: Milnacipran, Drug: PlaceboThis 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 | Drug: Milnacipran, Drug: PlaceboThis 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. |
Who may qualify
- Ages
- 24 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Age 24 years or older
- Primary diagnosis of rheumatoid arthritis from a board-certified rheumatologist
- Willing to maintain stable doses of concurrent non-steroidal anti-inflammatory drugs or other acceptable medications or therapies for the duration of the study
- Brief Pain Inventory Average Pain >= 4 at the screening visit
- Widespread Pain Index >= 5 at the screening visit
Key exclusion criteria (19 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MilnacipranAlso: SavellaMilnacipran comes in 50 mg tablets and is taken orally. Participants will gradually be increased to a target dose of 50 mg twice daily. | Drug | Milnacipran then placebo, Placebo then milnacipran |
| Placebo | Drug | Milnacipran then placebo, Placebo then milnacipran |
Primary outcome
Brief Pain Inventory (BPI) Change
Time frame: Baseline to 6 weeks
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.
6 secondary outcomes
Change in Conditioned Pain Modulation (CPM)
Time frame: Baseline to 6 weeks
Symptom Intensity Scale (SIS)
Time frame: Baseline to 6 weeks
Thumbnail Pain Threshold
Time frame: Baseline to 6 weeks
Trapezius Pain Threshold
Time frame: Baseline to 6 weeks
Wrist Pain Threshold
Time frame: Baseline to 6 weeks
Knee Pain Threshold
Time frame: Baseline to 6 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Nov 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19874580Lee 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.
- Derived from this study: PubMed 26628607Lee 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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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yvonne C Lee, MD, MMSc principal investigator
Brigham and Women's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Milnacipran in people with Arthritis, Rheumatoid, run by Brigham and Women's Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Nov 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Nov 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Brief Pain Inventory (BPI) Change (time frame: Baseline to 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01207453, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Nov 2014.