A Randomized, Open Label, Phase II Multicenter Study of Non-Myeloablative Autologous Transplantation With Auto-CD34+HPC Versus Currently Available Immunosuppressive/Immunomodulatory Therapy for Treatment of Systemic Lupus Erythematosus
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 5
- 主要终点
- Mortality resulting from treatment, underlying disease, or unrelated causes
研究概览
简要总结
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.
详细描述
SLE is a chronic, multisystem, inflammatory autoimmune disease in which the body's immune cells wrongly attack its own tissues. It is defined by the presence of circulating antinuclear antibodies that are directed against nucleosomal DNA-histone complexes, native double-stranded DNA (dsDNA), small nuclear ribonucleoproteins (Sm and RNP), single-stranded DNA, and phospholipids moieties on platelets and other tissues, indicating a failure of the regulatory systems involved in maintenance of immunologic tolerance to self-antigens. Despite use of currently available therapies, patients experience relapses of their lupus. Over time, patients develop significant morbidity from the disease as well as from medications, including glucocorticoids, used for treatment. 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.
- One group of study participants will undergo autologous hematopoietic stem cell transplantation. With this treatment, they will first undergo mobilization, a process that removes hematopoietic stem cells from their blood. Then they will receive high doses of chemotherapy to suppress their abnormal immune systems, followed by the reintroduction of the purified stem cells to re-establish their immune systems.
Medications are used to mobilize (i.e., encourage) blood cell precursors to multiply and move from the bone marrow to the bloodstream. These precursors (or autologous stem cells) can be harvested (collected) from the bloodstream during a process called apheresis and then transplanted (infused) back into the patient's body after chemotherapy has been given. HDIT can suppress the immune system, reducing the effectiveness or perhaps eliminating most of the immune cells that cause the progression of SLE. Autologous hematopoietic stem cell transplantation (HSCT) following HDIT hastens the return of the body's ability to produce blood cells. HDIT with HSCT has been identified as a potential treatment alternative to standard chemotherapy treatments.
One group of study participants will undergo autologous hematopoietic stem cell transplantation. With this treatment, they will first undergo mobilization, a process that removes hematopoietic stem cells from their blood. Then they will receive high doses of chemotherapy to suppress their abnormal immune systems, followed by the reintroduction of the purified stem cells to re-establish their immune systems.
Medications are used to mobilize (i.e., encourage) blood cell precursors to multiply and move from the bone marrow to the bloodstream. These precursors (or autologous stem cells) can be harvested (collected) from the bloodstream during a process called apheresis and then transplanted (infused) back into the patient's body after chemotherapy has been given. HDIT can suppress the immune system, reducing the effectiveness or perhaps eliminating most of the immune cells that cause the progression of SLE. Autologous hematopoietic stem cell transplantation (HSCT) following HDIT hastens the return of the body's ability to produce blood cells. HDIT with HSCT has been identified as a potential treatment alternative to standard chemotherapy treatments.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
1
high dose immunosuppressie therapy (HDIT) followed by HSCT (hemopoietic stem cell transplantation).
干预措施: Leukapheresis (Procedure)
1
high dose immunosuppressie therapy (HDIT) followed by HSCT (hemopoietic stem cell transplantation).
干预措施: Non-myeloablative high dose immunosuppressive therapy conditioning (HDIT) (Procedure)
1
high dose immunosuppressie therapy (HDIT) followed by HSCT (hemopoietic stem cell transplantation).
干预措施: Autologous CD34+HPC transplantation (HSCT) (Procedure)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Plasmapheresis (Procedure)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Corticosteroids (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Rabbit anti-thymocyte globulin (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Methylprednisolone (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Growth colony stimulating factor (G-CSF) (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Mycophenolate mofetil (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Azathioprine (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Intravenous immunoglobulin (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Methotrexate (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Rituximab (Drug)
2
Currently available immunosuppressive/immunomodulatory therapy
干预措施: Leflunomide (Drug)
结局指标
主要结局
Mortality resulting from treatment, underlying disease, or unrelated causes
时间窗: At Month 30
次要结局
未报告次要终点