Rheumatoid Arthritis:Tolerance Induction by Mixed Chimerism

NCT ID: NCT00282412

Last Updated: 2018-07-30

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 4 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-09-30
• Study Completion Date: 2016-06-30

Brief Summary

Rheumatoid arthritis disease is believed to be due to immune cells, cells that normally protect the body and are now causing damage to the body. Risk of death is highest in people with twenty or more joints actively involved with disease, positive rheumatoid factor, an elevated sedimentation rate (laboratory measures of active inflammation), and patients with limitation of daily activities (trouble doing simple things like opening a carton of milk). In these high risk patients, life is significantly shortened. Death is usually from heart disease, kidney failure, neck dislocation, broken hip bones, or blood clots to the lung. In this study we use moderate dose chemotherapy (cyclophosphamide and fludarabine) and CAMPATH-1H (a protein that kills the immune cells that are thought to be causing the disease), followed by infusion of blood stem cells that have been collected from the patient's brother or sister (allogeneic stem cell transplant). The purpose of the moderate dose chemotherapy and CAMPATH-1H is to destroy the cells in the immune system and to allow the cells from the patient's brother or sister to grow. The purpose of the stem cell infusion is to restore blood cell production, which will be severely impaired by the moderate dose chemotherapy and CAMPATH-1H, and to produce a normal immune system that will no longer attack the body.

Detailed Description

Peripheral blood stem cell mobilization (PBSC)

PBSC will be mobilized with G-CSF (dose may be adjusted down to 5-10 ug/kg/day by PI for toxicity, e.g. flu-like symptoms) with stem cell collection beginning on day 4 or 5. Leukapheresis may be repeated up to four consecutive days.

Conditioning Regimen Immune Ablation:

Fludarabine 25 mg/m2/d x 5 days (dosage should be based on adjusted body weight) will be given IV over 30 minutes in 100 cc of normal saline.

Cyclophosphamide 50 mg/kg/d x 4 days (dosage should be based on adjusted body weight) will be given IV over 1 hour in 500 cc of normal saline.

CAMPATH-1H 30 mg/day x 3 days (no dose adjustment) will be given IV over 2 hours in 100 cc of normal saline. Premedication with acetaminophen 650mg & benadryl 25-50mg PO/IV will be given 30-60min before infusion. These medications can be repeated as needed.

Hydration approximately 200 cc /hour beginning 6 hours before cyclophosphamide and continued until 24 hours after the last cyclophosphamide dose.

G-CSF will be continued until absolute neutrophil count reaches 1,000 cells/ml for three days.

Cyclosporine will be started at 200 mg po BID and adjusted by HPLC levels to between 150-250 or by toxicity (e.g. tremor, renal insufficiency, TTP, etc.). CSA will be continued for 6 months unless stopped for toxicity

Mycophenolate Mofetil (Cellcept) will be given 1 gram po BID and may be adjusted by toxicity (e.g. cytopenia). Cellcept will be continued for 6 months unless stopped for toxicity.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hematopoietic Stem Cell Transplantation

Allogeneic Hematopoietic Stem Cell Transplantation will be performed on eligible patients diagnosed with RA

Group Type: EXPERIMENTAL

Hematopoietic Stem Cell Transplantation

Intervention Type: BIOLOGICAL

Allogeneic Hematopoietic Stem Cell Transplantation

Fludarabine

Intervention Type: DRUG

inhibits DNA synthesis or repair

Cyclophosphamide

Intervention Type: DRUG

Causes prevention of cell division by forming adducts with DNA

Campath 1H

Intervention Type: DRUG

humanized monoclonal antibody against CD52 antigen

GCSF

Intervention Type: DRUG

Hematopoietic growth factor

Cyclosporins

Intervention Type: DRUG

immune suppressive drug

Mycophenolate Mofetil

Intervention Type: DRUG

immune suppressive drug

Interventions

Hematopoietic Stem Cell Transplantation

Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: BIOLOGICAL

Fludarabine

inhibits DNA synthesis or repair

Intervention Type: DRUG

Cyclophosphamide

Causes prevention of cell division by forming adducts with DNA

Intervention Type: DRUG

Campath 1H

humanized monoclonal antibody against CD52 antigen

Intervention Type: DRUG

GCSF

Hematopoietic growth factor

Intervention Type: DRUG

Cyclosporins

immune suppressive drug

Intervention Type: DRUG

Mycophenolate Mofetil

immune suppressive drug

Intervention Type: DRUG

Other Intervention Names

Fludara; Cytoxan, Neosar; Alemtuzumab; Neupogen; CSA; Cellcept

Eligibility Criteria

Inclusion Criteria

• Age > 18 and < 60 years at time of pre-transplant evaluation.
• An established clinical diagnosis of rheumatoid arthritis by American College of Rheumatology criteria.
• Patients must have failed an autologous hematopoietic transplant or have failed to respond to either methotrexate or leflunomide in combination with a TNF inhibitor. Failure is defined as an inability to tolerate treatment with at least 6 swollen joints and 20 involved joints or inability to answer at least 70% of HAQ questions with "no difficulty" despite 2 or more months of treatment.

• Ability to give informed consent.
• Patient must have a HLA matched sibling donor at the A, B, C, and DR loci to proceed or HLA matched cord blood donor.
• If donor is HLA matched cord blood, cord blood stem cells will be obtained from the NMDP (1-800-548-1375) and one or two units of HLA matched cord blood will be infused on day zero.

Exclusion Criteria

• History of coronary artery disease, or documented congestive heart failure.
• HIV positive.
• Uncontrolled diabetes mellitus, or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemoradiotherapy.
• Prior history of malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as head and neck cancer, or stage I breast cancer will be considered on an individual basis.
• Positive pregnancy test, inability or unwillingness to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
• Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
• FEV1/FVC < 70% of predicted, DLCO < 40% of predicted.
• Resting LVEF < 45 %.
• Bilirubin > 2.0 mg/dl (unless due to Gilberts), transferase (AST) > 2.5 x upper limit of normal.
• Serum creatinine > 2.0 mg/dl.

• Age < 18 years.
• Positive for HIV-1, HIV-2, HTLV-I, HTLV-II.
• Active hepatitis B or C.
• History of a malignancy except for a localized cancer such as skin cancer that is deemed cured.
• History of myocardial infarction or congestive heart failure.
• Inability to give informed consent.
• Current pregnancy.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Richard Burt, MD

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard Burt, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, United States

Countries

United States

Other Identifiers

DIAD RA ALLO

Identifier Type: -

Identifier Source: org_study_id