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Rheumatoid Arthritis:Tolerance Induction by Mixed Chimerism

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ClinicalTrials.gov Identifier: NCT00282412
Recruitment Status : Terminated (No participant enrolled for three years. No plan to continue study.)
First Posted : January 26, 2006
Results First Posted : July 30, 2018
Last Update Posted : July 30, 2018
Sponsor:
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University

Tracking Information
First Submitted Date  ICMJE January 24, 2006
First Posted Date  ICMJE January 26, 2006
Results First Submitted Date  ICMJE June 8, 2017
Results First Posted Date  ICMJE July 30, 2018
Last Update Posted Date July 30, 2018
Study Start Date  ICMJE September 2002
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 24, 2017)
Survival [ Time Frame: up to 5 years ]
The number of participants who survived treatment
Original Primary Outcome Measures  ICMJE
 (submitted: January 24, 2006)
  • 1. Tender joint count
  • 2. Swollen joint count
  • 3. Patient’s assessment of pain
  • 4. Patient’s global assessment of disease
  • 8. Physician global assessment
  • 9. Patient’s assessment of physical activity (Health Assessment Questionnaire [HAQ])
  • 7. Acute phase reactant value (erythrocyte sedimentation rate).
Change History Complete list of historical versions of study NCT00282412 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rheumatoid Arthritis:Tolerance Induction by Mixed Chimerism
Official Title  ICMJE Rheumatoid Arthritis: Tolerance Induction by Mixed Chimerism
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE
  • 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
Study Arms  ICMJE Experimental: Hematopoietic Stem Cell Transplantation
Allogeneic Hematopoietic Stem Cell Transplantation will be performed on eligible patients diagnosed with RA
Interventions:
  • Biological: Hematopoietic Stem Cell Transplantation
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
  • Drug: Campath 1H
  • Drug: GCSF
  • Drug: Cyclosporins
  • Drug: Mycophenolate Mofetil
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 11, 2016)
4
Original Enrollment  ICMJE
 (submitted: January 24, 2006)
12
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00282412
Other Study ID Numbers  ICMJE DIAD RA ALLO
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Richard Burt, MD, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Richard Burt, MD Northwestern University
PRS Account Northwestern University
Verification Date June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP