Biomarker-Linked Outcomes of Cellcept in Lupus Arthritis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Biomarker-Linked Outcomes of Cellcept in Lupus Arthritis

Conditions
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Systemic Lupus Erythematosus, Arthritis

Intervention / Treatment
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* Drug: mycophenolate mofetil
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of SLE by the 1995 modification of revised ACR criteria (includes antiphospholipid antibodies) BILAG A arthritis or BILAG B arthritis with at least 6 tender and 4 swollen joints at screening and baseline Stable prednisone dose at 20 mg of less for one month at baseline. If on antimalarials must be stable for at least one month at baseline If on NSAIDS must be on a stable regimen for at least one month but can be prn dosing Must be willing to withdraw from azathioprine or MTX at the time of screening. Between ages 14 and 70 Women of childbearing potential must have a negative pregnancy test at screening and at each month during the study. 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: Inability to understand informed consent Drug or alcohol abuse within the past six months 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. Unstable medical condition that, in the opinion of the investigator would contraindicate study participation 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). Use of cyclosporine, leflunomide, cyclophosphamide or ay biologic agent within three months prior to screening. Participation in any clinical study of an investigational agent within three months of screening -

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I:<br>Participants randomly assigned to Arm I will receive mycophenolate mofetil in ascending doses during Month 1, and 3 grams/day (or less if there are tolerance issues) for Months 2 through 6. During Month 1 these participants receive the same number of pills as every other month, but with ascending doses of mycophenolate mofetil and descending numbers of placebo pills. Week one for a total of 1.5 gm/day of mycophenolate mofetil, Week two 2.0 gm/day, Week three 2.5 gm/day and Week 4 3 gm/day. Dose can be held or decreased for tolerance issues at any time. | Drug: mycophenolate mofetil<br>* 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)<br>* Other names: Cellcept;|
| Placebo Comparator: Arm 2<br>Patients Randomly Assigned to Arm 2 will receive a placebo comparator. The placebo treatment will be structured so that they will undergo the same type of dosing in Month 1 that the ascending dose patient from Arm 1 undergo, but will have placebo in both bottles of pills. At the end of three months, after assessment of primary outcome, these patients enter open label treatment for three more months. During the fourth month this group continues to receive the same number of pills as they received before, with ascending doses of mycophenolate mofetil given vs descending placebo pills so that their induction is the same as those in Arm 1 at the first month. | Other: placebo<br>* 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.<br>* Other names: oral placebo pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 3 months | 
| 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. | 3 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lupus, arthritis, mycophenolate, biomarkers