Rituximab for the Treatment of Refractory Adult and Juvenile Dermatomyositis (DM) and Adult Polymyositis (PM)

Rituximab for the Treatment of Refractory Adult and Juvenile Dermatomyositis (DM) and Adult Polymyositis (PM)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Genentech, Inc., Biogen

Rituximab is a man-made antibody used to treat certain types of cancer. This study will determine whether rituximab is an effective treatment for adult and pediatric patients with dermatomyositis or polymyositis. Study hypotheses: 1) The time to improvement in Group A patients (receiving rituximab first) will occur significantly earlier than in Group B patients (receiving rituximab later). 2) The proportion of patients improved at Week 8 of the treatment phase will be significantly greater in Group A than in Group B.

Rituximab is a chimeric, murine-human, genetically engineered monoclonal antibody directed against the CD20 (cluster of differentiation antigen 20) antigen found on the surface of B-lymphocytes and is known to deplete B cells when administered intravenously. It is approved to treat non-Hodgkin's lymphoma. Rituximab has been used for autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and immune-mediated hematologic disorders. It has also been studied and used in small numbers of patients with myositis. This study will evaluate the efficacy of rituximab in treating refractory adult and pediatric patients with dermatomyositis and adult polymyositis. A patient's participation in this study will last approximately 45 weeks. At screening, participants will have a physical exam, muscle strength assessment, an electrocardiogram, and blood and urine collection; they will also be asked to complete several questionnaires. All participants will receive 2 infusions of rituximab and 2 infusions of placebo. Participants will be randomly assigned to one of two groups. Group A will receive rituximab at Weeks 0 and 1 and placebo at Weeks 8 and 9. Group B will receive placebo at Weeks 0 and 1 and rituximab at Weeks 8 and 9. Each infusion will be given on an outpatient basis over a minimum of approximately 5 hours' time. There will be a total of 14 study visits. All participants will visit the outpatient clinic at selected time points for muscle strength testing, a physical exam, disease activity measurements, and blood collection. During the study, participants will be monitored closely for improvement or worsening of their disease and for serious drug related side effects. Some participants will be asked if they are willing to undergo 2 muscle biopsy procedures, 1 prior to receiving study medication and 1 after receiving study medication, to determine the effects of rituximab on muscle tissue. If a participant is unable to locate a near-by clinical center, the adult and pediatric centers at the National Institute of Health located in Bethesda, Maryland have funds available to assist with travel costs. NIH SUB-STUDY: "Rituximab to Treat Dermatomyositis and Polymyositis" This study is currently recruiting patients. Sponsored by: National Institute of Environmental Health Sciences (NIEHS) Information provided by: National Institutes of Health Clinical Center (CC) Expected Total Enrollment: 30 Study start: October 2006 Location and Contact Information: Patient Recruitment and Public Liaison Office;(800) 411-1222; prpl@mail.cc.nih.gov; Phone: 1-866-411-1010 The NIH sub-study will take advantage of the multi-center core RIM trial to identify changes in gene expression patterns in muscle, skin, and peripheral blood and the imaging features and immunopathology of muscle, skin, and peripheral cells before (week 0) and after (week 16) therapy. These changes will also be correlated with the large number of clinical, laboratory, and research variables already planned to be collected in the core RIM Study. Furthermore, knowing specifically which gene expression patterns are altered in resistant patients before rituximab, and which are changed after rituximab therapy - in conjunction with flow cytometry of peripheral cells and immunopathology of the tissues - will help in understanding more about the pathogenesis of myositis and the possible contribution of B lymphocytes and their subsets. Patients with dermatomyositis and polymyositis who meet the inclusion/exclusion criteria for the core RIM trial may be eligible for this sub-study. The following procedures will be conducted in addition to the core RIM trial procedures during the 13 clinic visits over a period of 44 weeks: Weeks 0, 16: Muscle and skin biopsy (adult only). Small samples of muscle and skin tissue will be surgically removed for examination under a microscope. Weeks 0, 8, 16, 44: Skin evaluation and photography. The effect of the disease on the skin will be thoroughly evaluated and photographs of any rashes and of the skin around the nails will be taken. Weeks 0, 8, 16, 44: Magnetic resonance imaging (MRI). All participants will have MRI scans of the skin and of the muscle in the legs. Adults will also have an MRI to examine blood flow in the muscle.

Refractory adult polymyositis patients who will receive rituximab at Weeks 0 and 1 followed by placebo at Weeks 8 and 9 (Treatment Group A)

Refractory adult polymyositis patients who will receive placebo at Weeks 0 and 1 followed by rituximab at Weeks 8 and 9 (Treatment Group B)

Adult dermatomyositis patients who will receive rituximab at Weeks 0 and 1 followed by placebo at Weeks 8 and 9 (Treatment Group A)

Adult dermatomyositis patients who will receive placebo at Weeks 0 and 1 followed by rituximab at Weeks 8 and 9 (Treatment Group B)

Refractory juvenile dermatomyositis patients who will receive rituximab at Weeks 0 and 1 followed by placebo at Weeks 8 and 9 (Treatment Group A)

Refractory juvenile dermatomyositis patients who will receive placebo at Weeks 0 and 1 followed by rituximab at Weeks 8 and 9 (Treatment Group B)

Treatment Group A - intravenous rituximab 750mg/m2 BSA (Body Surface Area) up to a maximum dose of 1 gram at Weeks 0 and 1 Group B - intravenous rituximab 750mg/m2 BSA (Body Surface Area) up to a maximum does of 1 gram at Weeks 8 and 9

Treatment Group A: placebo infusion at Weeks 8 and 9 Treatment Group B: placebo infusion at Weeks 0 and 1

Comparison Between the Time to Improvement Between the Two Groups of IIM (Idiopathic Inflammatory Myopathy) Patients

The Definition of Improvement for both adult and pediatric patients will be: 3 of any of the 6 core set measures improved by ≥ 20%, with no more than 2 of the core set measures worsening by ≥25% (worsening measure cannot include the MMT) at two consecutive visits. Of note, the MMT could not be one of the worsening measures. Core Set Measures Included: Manual Muscle Testing (MMT)- Muscle Strength Physician Global Disease Activity VAS Score Health Assessment Questionnaire Index Score - Physical Function Patient Global Assessment of Disease Activity VAS score Extramuscular Activity - Myositis Disease Activity Assessment Tool 2 or more elevated muscle enzymes (Aldolase, CK, AST, ALT, and LDH)

Response Rates (Proportion of Improved Patients) Between Groups A (Rituximab Wks 0 and 1) and B (Rituximab Wks 8 and 9) at Week 8

The Definition of Improvement for both adult and pediatric patients will be: 3 of any of the 6 core set measures improved by ≥ 20%, with no more than 2 of the core set measures worsening by ≥25% (worsening measure cannot include the MMT) at two consecutive visits. Of note, the MMT could not be one of the worsening measures. Core Set Measures Included: Manual Muscle Testing (MMT)- Muscle Strength Physician Global Disease Activity VAS Score Health Assessment Questionnaire Index Score - Physical Function Patient Global Assessment of Disease Activity VAS score Extramuscular Activity - Myositis Disease Activity Assessment Tool 2 or more elevated muscle enzymes (Aldolase, CK, AST, ALT, and LDH)

20% Improvement in Manual Muscle Testing (MMT) Over Baseline on Two Consecutive Time Points (Muscle is the Primary Organ of Involvement, and MMT is the One Objective Measurement of the Definition of Improvement [DOI])

Inclusion Criteria: Adults with definite or probable dermatomyositis or polymyositis and pediatric patients five years of age and over with definite or probable juvenile dermatomyositis (JDM) by Bohan and Peter criteria. Diagnosis of JDM based on an age of onset (i.e., first symptom of myositis or dermatomyositis rash) is less 18 years of age Refractory myositis, defined by intolerance to or inadequate response to corticosteroids plus an adequate regime of at least one other immunosuppressive agent. Intolerance is defined as side effects that require discontinuation of the medication or an underlying condition that precludes further use of the medication. Baseline manual muscle testing which is based on a maximum MMT-8 (Manual Muscle Test) score of 150:Adult subjects with dermatomyositis (DM) or polymyositis (PM) must have a score that is no greater than 125/150 in conjunction with 2 other abnormal core set measures. Subjects with a diagnosis of Juvenile Dermatomyositis (JDM) must meet either of the following criteria: An MMT-8 (Manual Muscle Test) score that is no greater than 125/150 in conjunction with 2 other abnormal core set measures. OR If MMT (Manual Muscle Test) score is greater than 125/150 the patient MUST meet at least 3 abnormal core set measures. Background therapy with at least 1 non-corticosteroid immunosuppressive agent at a stable dose for at least 6 weeks prior to screening Able and willing to complete self-report questionnaires. Parents of pediatric participants will be required to complete the questionnaires on behalf of their children. Willing to use acceptable forms of contraception for the duration of the study for patients of reproductive potential. Parent willing to provide informed consent, if applicable Willing to forgo immunization with a live vaccine for the duration of the study Exclusion Criteria: Drug-induced myositis. Patients who have myositis or myopathic syndromes caused by taking medications known to induce myositis-like syndromes, including but not limited to statin agents, fibric acid derivatives, colchicine, and hydroxychloroquine. Juvenile polymyositis Inclusion body myositis Cancer-associated myositis, defined as the diagnosis of myositis within 2 years of the diagnosis of cancer. Patients with basal or squamous cell skin cancer or carcinoma in situ of the cervix are not excluded, if it has been at least 5 years since excision. Myositis in overlap with another connective tissue disease that may preclude the accurate assessment of a treatment response Live viral vaccine within 4 weeks prior to study entry Any joint disease or other musculoskeletal condition that may interfere with muscle strength testing Known hypersensitivity to mouse proteins Any concomitant or life-threatening non-myositis illness that, in the opinion of the investigator, may interfere with the study Known or suspected history of drug or alcohol abuse within the last 6 months prior to study entry, as determined by medical record or patient interview Anticipated poor compliance with study requirements Participation in another clinical trial within 30 days prior to screening Any history or evidence of any severe illness or other condition that, in the opinion of the investigator, may interfere with the study Previously received rituximab Evidence of prior infection with hepatitis B or hepatitis C virus Initiation of an exercise program within 4 weeks of screening OR initiation of an exercise program during the study Consumed any creatine-containing, over-the-counter products in the form of dietary supplements 30 days prior to screening visit and for the duration of the study

Feldman B, Wang E, Willan A, Szalai JP. The randomized placebo-phase design for clinical trials. J Clin Epidemiol. 2001 Jun;54(6):550-7. doi: 10.1016/s0895-4356(00)00357-7.

Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum. 2005 Feb;52(2):601-7. doi: 10.1002/art.20849.

Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, Barohn RJ, Feldman BM, Harris-Love MO, Koontz DC, Fertig N, Kelley SS, Pryber SL, Miller FW, Rockette HE; RIM Study Group. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013 Feb;65(2):314-24. doi: 10.1002/art.37754.