Lupus Immunosuppressive/Immunomodulatory Therapy or Stem Cell Transplant (LIST)

• Status: Withdrawn
• Trial end date: 1969-12-31
• Target enrollment: 0
• Participant gender: All

Summary

Systemic lupus erythematosus, also known as lupus or SLE, is a chronic, multisystem, autoimmune disease in which the body's internal system of defense attacks its own normal tissues. This abnormal autoimmune response can result in damage to many parts of the body, especially the skin, joints, lungs, heart, brain, intestines, and kidneys. Both genetic and environmental risk factors are involved in the development of lupus, but these are poorly understood.

SLE has an overall 10-year survival between 80 and 90%. However, we estimate that severe lupus not responding to the usual available treatments has a 50% mortality rate in 10 years. Kidney problems occur in 30% to 50% of lupus patients and may progress to kidney failure. Kidney disease due to lupus occurs more frequently in African-Americans and Hispanics. Lupus can affect many parts of the body and cause damage, but the severe form can result in death from kidney disease; cardiovascular disease, specifically atherosclerosis; central nervous system disease; and infections.

Currently, no single standard therapy for treatment of severe SLE exists. Usually physicians prescribe an aggressive regimen of one or a combination of immunosuppressive/immunomodulatory treatments. This approach to therapy for all forms of severe SLE derives largely from studies of lupus nephritis. Current treatment, although effective in many people, are not effective in all patients and are associated with drug-induced morbidity. The design of the control arm for this study reflects the current status of treatment of SLE in the academic setting. Investigators may choose from a list of commonly used and currently available immunosuppressive/immunomodulatory treatments to optimize the treatment of their patients, based on their past treatment history and response to those treatments. Study treatments may consist of corticosteroids, cyclophosphamide (CTX), azathioprine, methotrexate, cyclosporine, mycophenolate mofetil (MMF), plasmapheresis, intravenous immunoglobulin (IVIG), rituximab, and leflunomide. Treatment may be changed as frequently and as necessary within the first year of the study to control the manifestations of SLE in each patient. New therapies that become available during the course of this trial may be added to the list of approved medications for this study.

In response to the absence of a uniformly effective treatment for severe lupus, autologous hematopoietic stem cell transplantation (HSCT) has been proposed as a potential therapy. Hematopoietic stem cells are immature blood cells that can develop into all of the different blood and immune cells the body uses. Researchers believe that resetting the immune system may stop or slow down the progression of the disease. The main purpose of this study is to compare two ways of treating SLE: 1) high-dose immunosuppressive therapy (HDIT) followed by HSCT and 2) currently available immunosuppressive/immunomodulatory therapies.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Antibodies; Antilymphocyte Serum; Azathioprine; gamma-Globulins; Immunoglobulins; Immunoglobulins, Intravenous; Immunosuppressive Agents; Leflunomide; Methotrexate; Methylprednisolone; Methylprednisolone acetate; Methylprednisolone Hemisuccinate; Mycophenolate mofetil; Mycophenolic Acid; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Rho(D) Immune Globulin; Rituximab; Sargramostim; Thymoglobulin

Criteria

Inclusion Criteria:

• Male or female subjects between the ages of 18 and 60 years, inclusive

• Meet at least 4 of 11 American College of Rheumatology (ACR) Revised Classification Criteria for SLE

• Have at least one of the following conditions defining severe steroid refractory disease:

a) Lupus nephritis - Subjects must have severe disease, defined as meeting criteria for BILAG renal category A, and be corticosteroid dependent while receiving at least 6 months of pulse CTX at doses of 500 to 1000 mg/m2 every 4 weeks or MMF at of 2 g/day or greater. If nephritis is to constitute the sole eligibility, a renal biopsy performed within 11 months of the date of screening must show ISN/RPS 2003 classification of lupus nephritis Class III or IV disease. A renal biopsy must demonstrate the potential of a reversible (non-fibrotic) component. b) Visceral organ involvement other than nephritis - Subjects must be without mesenteric vasculitis. The subject must be BILAG cardiovascular/respiratory category A, vasculitis category A, or neurologic category A, and be corticosteroid dependent while receiving at least 3 months of oral (2 to 3 mg/kg/day or greater) or IV CTX (500 mg/m2 or greater every 4 weeks). c) Cytopenias that are immune-mediated - Subjects must be BILAG hematologic category A and be corticosteroid dependent while receiving at least one of the following: azathioprine at 2 mg/kg/day or greater for at least 3 months, MMF at 2 g/day or greater for more than 3 months, CTX at 500 mg/m2 or greater intravenously every 4 weeks or 2 mg/kg/day orally for at least 3 months, cyclosporine at 3 mg/kg/day or greater for at least 3 months, or have had a splenectomy. d) Mucocutaneous disease

• Subjects must meet BILAG mucocutaneous category A and be corticosteroid dependent while receiving at least 1 of the following: azathioprine at 2 mg/kg/day or greater for at least 3 months; methotrexate at 15 mg/week or greater for at least 3 months; CTX at 500 mg/m2 or greater intravenously every 4 weeks or 2 mg/kg/day or greater orally for at least 3 months, cyclosporine at 3 mg/kg/day or greater for at least 3 months, or MMF at doses 2 g/day or greater for at least 3 months. e) Arthritis/myositis - Subjects must meet BILAG musculoskeletal category A and be corticosteroid dependent while receiving at least one of the following: azathioprine at 2 mg/kg/day or greater for at least 3 months, methotrexate at 15 mg/week or greater for at least 3 months, CTX at 500 mg/m2 or greater intravenously every 4 weeks or 2 mg/kg/day or greater orally for at least 3 months, MMF at 2 g/day or greater for at least 3 months, or cyclosporine at 3 mg/kg/day or greater for at least 3 months.

• Have the ability and willingness to provide written informed consent. In case of lupus cerebritis, a person designated by the subject may give consent.

• Must be ANA positive

Exclusion Criteria:

• HIV positive status

• Any active systemic infection

• Hepatitis B surface antigen positive

• Hepatitis C PCR positive

• Use of immunosuppressive agents for other indications other than SLE

• Any comorbid illness that in the opinion of the investigator would jeopardize the ability of the subject to tolerate therapy

• For lupus nephritis: renal biopsy, performed within 11 months of the screening date, showing Class I, II, or V disease or Class III or IV disease in conjunction with total sclerosis of 50% or more of the glomeruli

• Ongoing cancer. Patients with localized basal cell or squamous skin cancer are not excluded.

• Pregnancy, unwillingness to use acceptable means of birth control, or unwilling to accept or comprehend irreversible sterility as a side effect of therapy

• Psychiatric illness or mental deficiency not due to active lupus cerebritis making compliance with treatment or informed consent impossible

• Hemoglobin adjusted diffusion capacity test (DLCO) less than 30% at screening

• Resting left ventricular ejection fraction (LVEF) 40% or less as evaluated by echocardiogram

• History of an allergic reaction or hypersensitivity to Escherichia coli recombinant proteins, CTX, or any part of the investigative or control therapy

• SGOT/SGPT greater than 2 x the upper limit of normal, unless due to active lupus

• ANC 1000 or greater if not due to active SLE

• Subdural hematoma or any active intracranial bleeding documented within 30 days of the screening visit

• Failure to be approved for participation in this study by the SCSLE Protocol Eligibility Review Committee

• Positive tuberculin skin test

• Presence of mesenteric vasculitis