Arthritis, Systemic Lupus Erythematosus
Conditions
Keywords
lupus, arthritis, mycophenolate, biomarkers
Brief summary
We hypothesize that mycophenolate mofetil(Cellcept)is safe and effective for lupus arthritis. In this study, patients with lupus will be randomly assigned to receive mycophenolate mofetil or placebo (inert pills) for three months. At the end of three months all patients will receive mycophenolate mofetil for three additional months. The effectiveness on arthritis and other symptoms of lupus will be measured by joint counts and by the BILAG instrument (a measure of overall lupus disease activity. Additionally special blood tests aimed at understanding the biologic effects of mycophenolate mofetil will also be performed at some visits. The primary outcome measurement will be the safety and effectiveness of this treatment (as compared to placebo) at the three month point. The trial will continue in a blinded fashion (neither the investigator or the participants know who is getting mycophenolate and who is getting placebo) until 24 patients have completed the first three months of the protocol.
Detailed description
Patients and Methods: 27 patients with active BILAG B or A arthritis, with at least 6 swollen and 6 tender joints entered a six month study of MMF vs placebo for three months followed by open label MMF. 14 patients (12 women and 2 men) received placebo at baseline and 13 patients (11 women and 2 men) received MMF. Primary Outcome was Major Clinical Response at 3 months, then all patients received open label Cellcept for another 3 months. Blood was drawn for safety, lupus disease activity measures and exploratory Biomarkers, Joint counts were performed monthly. At baseline background DMARDs were stopped. Plaquenil was allowed. All patients received 160 mg depomedrol at baseline and were allowed 80 mg shots at subsequent months after blood draws and procedures had been completed. DEFINITION of RESPONSE Prespecified Primary Endpoint: Complete Clinical Response: BILAG C in musculoskeletal by Week 12 and decrease to 0.25 or less of tender +swollen jt counts Prespecified Secondary Endpoint: Partial response: One letter drop in musculoskeletal by Week 12 OR decrease to 0.5 or less tender + swollen jt counts Exploratory Measure (not prespecified): Major Clinical Response: BILAG C in musculoskeletal by Week 12 and decrease to 0.5 or less of tender +swollen jt counts. (In the primary analysis the one patient who met this endpoint was designated as a partial responder since those prespecified criteria were also met. Non response: Does not meet above criteria for complete or partial response Additional Measures: (prespecified secondary endpoints) included joint counts, changes in BILAG and SLEDAI and physician and patient global assessments.
Interventions
DRUGmycophenolate mofetil
First treatment month: mycophenolate mofetil ascending doses orally Second treatment month to end of study: mycophenolate mofetil 3 gms/day (or less if tolerance issues arise)
OTHERplacebo
oral placebo will be given in ascending doses during the first month and at full dose during the second and third month (or at lower dose if tolerance issues warrant). During the fourth month mycophenolate mofetil will be given in ascending doses to 3 gms/day (or less if tolerance issues arise) and continues until the end of the study at 6 months.
Sponsors
NYU Langone Health
Oklahoma Medical Research Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
14 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of SLE by the 1995 modification of revised ACR criteria (includes antiphospholipid antibodies) 2. BILAG A arthritis or BILAG B arthritis with at least 6 tender and 4 swollen joints at screening and baseline 3. Stable prednisone dose at 20 mg of less for one month at baseline. 4. If on antimalarials must be stable for at least one month at baseline 5. If on NSAIDS must be on a stable regimen for at least one month but can be prn dosing 6. Must be willing to withdraw from azathioprine or MTX at the time of screening. 7. Between ages 14 and 70 8. Women of childbearing potential must have a negative pregnancy test at screening and at each month during the study. 9. All participants (male and female) must, if fertile, agree to practice contraception during the entire course of the study. This may include barrier, oral contraceptives, depo-provera, intrauterine device and/or abstinence. \-
Exclusion criteria
1. Inability to understand informed consent 2. Drug or alcohol abuse within the past six months 3. In the opinion of the investigator, it is not likely the patient can comply with the protocol for any reason, or participation in the protocol is not in the patient's best interest. 4. Unstable medical condition that, in the opinion of the investigator would contraindicate study participation 5. History of malignancy (except for basal cell carcinoma at any time and/or cervical cancer or squamous cell cancer at least five years previous to screening). 6. Use of cyclosporine, leflunomide, cyclophosphamide or ay biologic agent within three months prior to screening. 7. Participation in any clinical study of an investigational agent within three months of screening -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arthritis Complete Response | 3 months | Complete response at three months (This is defined as \</= 0.25 of the total tender plus swollen joints observed at baseline and British Isles Lupus Assessment Group (BILAG) index C (mild) or D (no longer present) score in the Musculoskeletal system), comparing treatment to placebo group as complete responder or not complete responder. This was an intent to treat analysis so dropouts were counted as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Arthritis Response | 3 months | This is defined as at least a 50% reduction in tender + swollen joint counts and severity rated as mild as defined by the British Isles Lupus Assessment Group Index |
| Major and Partial Clinical Response | 3 Months | Those meeting the Criteria for Major or Complete Clinical Response as listed in the preceding endpoints or who meet criteria for partial response defined as at least a 25% decrease in tender and swollen joint count and improvement of at least one severity rating for arthritis as at least one level on the British Isles Lupus Assessment Group Index. |
Countries
United States
Participant flow
Recruitment details
A total of 27 patients with SLE and active arthritis (with or without other manifestations) were randomized 1:1 to receive mycophenolate mofetil (MMF) or placebo. A total of 13 received MMF and 14 received placebo for the first 3 months. For the second three months patients could elect to continue on open lable MMF
Pre-assignment details
Patients were excluded if they did not have arthritis sufficient to be treated with an aggressive immune suppressant. All patients were offered steroid rescue at baseline, those who required immediate treatment and/or who could not be given steroids were excluded from the study
Participants by arm
| Arm | Count |
|---|---|
| Patients Who Received MMF for the First 3 Months 13 patients were randomized to receive MMF for the first 3 months. MMF was (blindly) increased to maximal tolerated dose or 3 gms/daily whichever was lowest. | 13 |
| Patients Who Received Placebo for the First 3 Months 14 patients were randomized to placebo for the first three months | 14 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Final 3 Months | Withdrawal by Subject | 4 | 3 |
| First 3 Months | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Patients Who Received Placebo for the First 3 Months | Patients Who Received MMF for the First 3 Months | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 13 Participants | 27 Participants |
| Age, Continuous | 34.0 years STANDARD_DEVIATION 11.35 | 38.9 years STANDARD_DEVIATION 9.42 | 36.3 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 14 participants | 13 participants | 27 participants |
| Sex: Female, Male Female | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 14 |
| other Total, other adverse events | 12 / 13 | 12 / 14 |
| serious Total, serious adverse events | 2 / 24 | 2 / 14 |
Outcome results
Primary
Arthritis Complete Response
Complete response at three months (This is defined as \</= 0.25 of the total tender plus swollen joints observed at baseline and British Isles Lupus Assessment Group (BILAG) index C (mild) or D (no longer present) score in the Musculoskeletal system), comparing treatment to placebo group as complete responder or not complete responder. This was an intent to treat analysis so dropouts were counted as non-responders.
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Who Received MMF for the First 3 Months | Arthritis Complete Response | 4 participants |
| Patients Who Received Placebo for the First 3 Months | Arthritis Complete Response | 0 participants |
Secondary
Major and Partial Clinical Response
Those meeting the Criteria for Major or Complete Clinical Response as listed in the preceding endpoints or who meet criteria for partial response defined as at least a 25% decrease in tender and swollen joint count and improvement of at least one severity rating for arthritis as at least one level on the British Isles Lupus Assessment Group Index.
Time frame: 3 Months
Population: Patients who entered and were randomized to receive MMF vs Placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Who Received MMF for the First 3 Months | Major and Partial Clinical Response | 9 participants |
| Patients Who Received Placebo for the First 3 Months | Major and Partial Clinical Response | 5 participants |
Secondary
Major Arthritis Response
This is defined as at least a 50% reduction in tender + swollen joint counts and severity rated as mild as defined by the British Isles Lupus Assessment Group Index
Time frame: 3 months
Population: All those randomized to MMF or placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Who Received MMF for the First 3 Months | Major Arthritis Response | 5 participants |
| Patients Who Received Placebo for the First 3 Months | Major Arthritis Response | 0 participants |
Comparison: this is a categorical assessment. Prespecified. Fishers exact test. Significant is calculated as \< 0.05p-value: =0.041Fisher Exact