Rheumatoid Arthritis:Tolerance Induction by Mixed Chimerism

• ClinicalTrials.gov Identifier: NCT00282412
• Recruitment Status: Terminated
• First Posted: January 26, 2006
• Results First Posted: July 30, 2018
• Last Update Posted: July 30, 2018
• Sponsor: Northwestern University
• Information provided by (Responsible Party): Richard Burt, MD, Northwestern University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Biological: Hematopoietic Stem Cell Transplantation; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Campath 1H; Drug: GCSF; Drug: Cyclosporins; Drug: Mycophenolate Mofetil	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rheumatoid Arthritis: Tolerance Induction by Mixed Chimerism
• Study Start Date: September 2002
• Actual Primary Completion Date: June 2016
• Actual Study Completion Date: June 2016

Arms and Interventions

Arm

Intervention/treatment

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

Biological: Hematopoietic Stem Cell Transplantation; Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Fludarabine; inhibits DNA synthesis or repair; Other Name: Fludara; Drug: Cyclophosphamide; Causes prevention of cell division by forming adducts with DNA; Other Name: Cytoxan, Neosar; Drug: Campath 1H; humanized monoclonal antibody against CD52 antigen; Other Name: Alemtuzumab; Drug: GCSF; Hematopoietic growth factor; Other Name: Neupogen; Drug: Cyclosporins; immune suppressive drug; Other Name: CSA; Drug: Mycophenolate Mofetil; immune suppressive drug; Other Name: Cellcept

Outcome Measures

Primary Outcome Measures :

1. Survival [ Time Frame: up to 5 years ]
   The number of participants who survived treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Participant 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.

Participant 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.

Donor Exclusion Criteria

• 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.

Contacts and Locations

Locations

United States, Illinois

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, United States, 60611

Sponsors and Collaborators

Northwestern University

Investigators

• Principal Investigator: Richard Burt, MD; Northwestern University

More Information

• Responsible Party: Richard Burt, MD, MD, Northwestern University
• ClinicalTrials.gov Identifier: NCT00282412
• Other Study ID Numbers: DIAD RA ALLO
• First Posted: January 26, 2006
• Results First Posted: July 30, 2018
• Last Update Posted: July 30, 2018
• Last Verified: June 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Fludarabine; Alemtuzumab; Cyclosporins; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Enzyme Inhibitors; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Calcineurin Inhibitors; Antibiotics, Antineoplastic; Antibiotics, Antitubercular