Lupus Immunosuppressive/Immunomodulatory Therapy or Stem Cell Transplant (LIST)
Information source: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Systemic Lupus Erythematosus
Intervention: Leukapheresis (Procedure); Non-myeloablative high dose immunosuppressive therapy conditioning (HDIT) (Procedure); Autologous CD34+HPC transplantation (HSCT) (Procedure); Plasmapheresis (Procedure); Rabbit anti-thymocyte globulin (Drug); Methylprednisolone (Drug); Growth colony stimulating factor (G-CSF) (Drug); Corticosteroids (Drug); Mycophenolate mofetil (Drug); Azathioprine (Drug); Intravenous immunoglobulin (Drug); Methotrexate (Drug); Rituximab (Drug); Leflunomide (Drug)
Phase: Phase 2
Status: Withdrawn
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID) Official(s) and/or principal investigator(s): Richard Burt, MD, Study Chair, Affiliation: Division of Immunotherapy, Northwestern University Bevra Hahn, MD, Study Chair, Affiliation: Division of Rheumatology, Department of Medicine, University of California, Los Angeles Kenneth Kalunian, MD, Study Chair, Affiliation: Division of Rheumatology, Allergy, and Immunology, University of California, Los Angeles Ann Traynor, MD, Study Chair, Affiliation: Division of Hematology and Oncology, University of Massachusetts Medical School Keith Sullivan, MD, Study Chair, Affiliation: Division of Cellular Therapy, Department of Medicine, Duke University Betty Diamond, MD, Study Chair, Affiliation: Department of Medicine, Columbia University
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.
Clinical Details
Official title: 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
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Mortality resulting from treatment, underlying disease, or unrelated causes
Detailed description:
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.
1. 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.
Participants assigned to the first treatment group will undergo mobilization with CTX
and granulocyte colony stimulating factor (G-CSF) beginning 2 weeks after
randomization. In preparation for the transplant process. a central venous line
(plastic tube) will be inserted into the neck or chest vein; this tube will be used to
administer stem cells and medications and for drawing blood. IV CTX, followed by G-CSF,
will be given injected under the skin beginning 3 days after CTX. G-CSF will be given
for about 4 to 7 days, to boost the body's production of blood precursor cells. These
precursor cells will be collected through the central venous line through apheresis.
In this process, whole blood is collected through a needle in an arm vein and directed
to a cell-separating machine, where the white cells are separated and saved. The rest
of the blood is returned to the patient through the same needle. Several apheresis
procedures will be required to collect enough cells for the autologous transplant.
Within 3 weeks of the apheresis stem cell collection, the first group's participants
will be admitted to the hospital and will undergo a five-day conditioning regimen
consisting of IV CTX and rabbit anti-thymocyte globulin (rATG). This regimen will
suppress the malfunctioning immune system and prepare the patient's body to receive the
precursor cells previously collected during apheresis. The stem cells will be infused
after the five-day conditioning regimen. The return of the precursor cells is called
autologous stem cell transplantation. During the hospitalization a specialized team of
transplant physicians and nurses will closely monitor the participants until their bone
marrow recovers and the participants are well enough to be discharged. The hospital
stay will be approximately 21 days after the autologous stem cell transplant. Upon
discharge, the patient will return home and will follow-up at the treatment center at
Weeks 1 and 3 post-transplantation for close monitoring by the transplant team.
Participants will also be followed by the study rheumatologist monthly at the treatment
center for 30 months.
2. The other group of study participants will receive immunosuppressive/immunomodulatory
therapy as prescribed by the study rheumatologist, based on the organ systems affected
and prior treatment history. Therapy may include one or a combination of the following
treatments: corticosteroids, azathioprine, methotrexate, cyclosporine, MMF,
plasmapheresis, IVIG, rituximab, and leflunomide. As new drugs become available and a
part of the usual medications for the treatment of SLE, they may be approved for use in
this study. Treatment may be changed as frequently as necessary within the first year
of the study to control the manifestations of SLE in each patient. Treatment for the
second group will begin 1 week after randomization; patients will be seen monthly at
the treatment center for 30 months.
Corticosteroid dosage tapering will be monitored closely; the schedule for tapering will be
the same in both groups. To reduce the possibility of disease flare. a slow tapering of 10%
per month will occur for the first six months. Tapering will continue in a prescribed manner
to achieve a dose equivalent of 10 mg/day of prednisone or less by one year post-treatment.
All participants will have monthly follow-up visits for 30 months after treatment has been
initiated. Study visits will include a physical exam, clinical assessments, rheumatology
evaluations, and blood and urine collections. Participants will be asked to complete
questionnaires assessing their lupus disease. Neuropsychiatric assessments, echocardiogram,
CT scan of brain, renal biopsy, pulmonary function test, dual-energy x-ray absorptiometry
scan (DEXA scan), magnetic resonance imagery scan, electromyograph scan (EMG), bone marrow
biopsy and aspiration and lumbar puncture may occur at selected visits, based on each
individual's manifestations of lupus and clinical indication. Participants will also receive
certain vaccinations at selected visits. Participants will be contacted by phone each and
every week throughout the study. There will be an extension period for those patients that
have completed their treatment and follow-up visits during the study's 5-year duration.
Participants will be contacted via telephone, e-mail, or visit every 3 months to assess
their use of concomitant medications and immunosuppressive/immunomodulatory therapy and
corticosteroids.
Five treatment centers across the United States, all leaders in the fields of
transplantation and rheumatology, are participating in this research study.
Eligibility
Minimum age: 18 Years.
Maximum age: 60 Years.
Gender(s): Both.
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
Locations and Contacts
UCSD, Thornton Hospital, La Jolla, California 92037-0943, United States
UCLA, Rehabilitation Center, Los Angeles, California 90095-1670, United States
Northwestern University, Chicago, Illinois 60611, United States
Feinstein Institute for Medical Research NS-LIJ Health System, Manhassat, New York 11030, United States
Duke University Medical Center, Durham, North Carolina 27709, United States
Additional Information
Related publications: Burt RK, Marmont A, Arnold R, Heipe F, Firestein GS, Carrier E, Hahn B, Barr W, Oyama Y, Snowden J, Kalunian K, Traynor A. Development of a phase III trial of hematopoietic stem cell transplantation for systemic lupus erythematosus. Bone Marrow Transplant. 2003 Aug;32 Suppl 1:S49-51. Openshaw H, Nash RA, McSweeney PA. High-dose immunosuppression and hematopoietic stem cell transplantation in autoimmune disease: clinical review. Biol Blood Marrow Transplant. 2002;8(5):233-48. Review. Traynor AE, Barr WG, Rosa RM, Rodriguez J, Oyama Y, Baker S, Brush M, Burt RK. Hematopoietic stem cell transplantation for severe and refractory lupus. Analysis after five years and fifteen patients. Arthritis Rheum. 2002 Nov;46(11):2917-23.
Starting date: September 2005
Last updated: January 31, 2013
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