Combined Kidney and Bone Marrow Transplantation to Prevent Kidney Transplant Rejection

Study Overview
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Brief Summary
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In small initial studies, combined kidney and bone marrow transplants from the same donor have permitted some individuals to stop taking anti-rejection medicines without rejecting their transplant. This clinical trial will study this method in a greater number of people to determine if it is indeed effective and safe.

Detailed Description
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All patients receiving an organ or tissue transplant must take special medicines known as immunosuppressive drugs in order to prevent the immune system from rejecting the transplant. These drugs can be very effective, but they leave the patient at an increased risk of serious infections and certain types of cancer. New methods of preventing transplant rejection are needed. Researchers have found that transplanting both bone marrow and a kidney from the same donor can create what is called mixed chimerism. This means that the transplant recipient has a mixture of the donor and recipient's immune systems. It is believed that this mixture of immune cells can prevent rejection of the kidney. In a small prior study, performing a kidney transplant together with a bone marrow transplant from the same donor allowed 4 of 5 patients to stop taking immunosuppressive drugs altogether, without rejecting their transplant. This clinical trial will study more patients to confirm if the technique is safe and effective. Patients eligible for this study must be candidates for a living kidney transplant, and have an eligible donor identified. The transplant recipient and donor must both consent to participate in this study. Transplant recipients enrolled in the study will receive both kidney and bone marrow transplants from the same living donor. Prior to the transplant procedure, the transplant recipient will undergo a conditioning regimen that prepares their immune system for the recipient's immune (bone marrow) cells. This conditioning regimen is a combination of chemotherapy, radiation, immunosuppressive drugs and specialized medications called rituximab and MEDI-507. MEDI-507 is an investigational medication that has not been approved by the FDA. After the transplant procedure, transplant recipients will be prescribed steroids for several weeks and immunosuppressive drugs. After 2 months, the dose of the immunosuppressive drugs will slowly be decreased to zero in patients whose immune system and kidney function meet certain criteria. Transplant recipients enrolled into the study will be hospitalized for 1 week prior to the transplant procedure. After the transplant, patients will remain in the hospital until the doctor feels they are well enough to go home. Recipients will receive approximately monthly checkups over a period of 2 years after transplant, plus a checkup at 2 ½, 3, 3 ½ , 4, and 5 years after transplant. Checkups will include physical exams, and blood and urine tests to assess immune system and kidney function. At four of these checkups, a kidney biopsy will be requested. Transplant donors enrolled in the study will attend a screening visit, which will include a physical exam, blood tests and chest x-ray. Eligible donors will be admitted to the hospital for 3-5 days, where bone marrow will be collected prior to removal of the kidney. Transplant donors may be asked at a later date to donate additional blood samples for research purposes.

Official Title
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Renal Allograft Tolerance Through Mixed Chimerism

Conditions
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Kidney Transplantation, Kidney Failure, Chronic

Intervention / Treatment
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* Procedure: Kidney Transplantation
* Procedure: Bone marrow transplantation
* Biological: MEDI-507
* Drug: cyclophosphamide
* Biological: rituximab
* Drug: Tacrolimus
* Drug: corticosteroids
* Radiation: thymic irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Awaiting first or second transplant with a living donor or first transplant with a cadaveric donor For living-donor transplants, must have one or more HLA antigen-mismatched donors identified Serologic evidence of prior exposure to Epstein-Barr virus (EBV) Exclusion Criteria: ABO blood group-incompatibility for a kidney graft of tissue from a donor Decreased circulating white blood cell count Positive for HIV-1, hepatitis B and C viruses Have had prior radiation therapy that could limit dose Lung capacity <50% of predicted normal Evidence of insufficient cardiac capacity Unwilling to use adequate contraception until 2 years after transplant Lactation or pregnancy Presence of antibody against the donor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kidney and Marrow Recipients<br>Combined kidney and bone marrow transplant | Procedure: Kidney Transplantation<br>* Surgical transplantation of donor kidney<br>* Other names: Renal Transplantation;Procedure: Bone marrow transplantation<br>* During kidney transplant, bone marrow cells donated by the same donor as the kidney are given through a plastic tube placed in a vein in the chest, underneath the collarbone<br>Biological: MEDI-507<br>* 0.1 mg/kg on day -2; 0.6 mg/kg on days -1,0,1<br>* Other names: anti-CD2 monoclonal antibody;Drug: cyclophosphamide<br>* 60 mg/kg infusion on days -5, -4<br>* Other names: Cytoxan;Biological: rituximab<br>* 375 mg/m^2 infusion on days -7, -2, 5, and 12<br>* Other names: Rituxan;Drug: Tacrolimus<br>* 0.05 mg/kg intravenously twice daily starting on day -1, adjusted to trough level of 10-15ng/ml, then tapered (if eligible) on days 1, 7, 14, 21, 28, 42, and 56<br>* Other names: PROGRAF®;Drug: corticosteroids<br>* 2 mg/kg prednisone on day 4, with an additional 500-mg pulse of methylprednisolone given on days 10, 11, and 12, and then tapered off by day 20<br>* Other names: prednisone;Radiation: thymic irradiation<br>* 700 cGy of thymic irradiation administered in a single dose on day -1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Successfully Withdrawn Off of Immunosuppressant Medication for 104 Weeks | A participant was considered a success if they were off immunosuppressive therapy for 104 consecutive weeks leading up to study week 208 (48 months post-transplant) or study termination, whichever occurred first. | 48 months post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Acute Rejection | The percentage of participants who experience an acute rejection. Acute rejection is defined as a biopsy with findings of Banff score of grade IA or higher. The Banff classification is as follows: grade IA is >25% of parenchyma affected and foci of moderate tubulitis; Grade IB is >25% of parenchyma affected and foci of severe tubulitis; Grade IIA is mild to moderate intimal arteritis; Grade IIB is severe intimal arteritis comprising >25% of the luminal area; Grade III is transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation. | Transplantation until study completion or participant termination (up to five years) | 
| Change in Renal Function | Change in renal function as seen in serum creatinine values from baseline until study completion or participant termination. Baseline is defined as the lowest serum creatinine collected during stabilization period or in the four weeks following the end of the stabilization period. The stabilization period is defined as four consecutive creatinine values close in value (not differing more than 0.3 mg/dL). Higher results indicate poorer kidney function, as creatinine is removed from the body by the kidneys. | Transplantation until study completion or participant termination (up to five years) | 
| Percentage of Participants With Graft Survival Through 156 Weeks | The percentage of participants with graft survival from transplantation through 156 weeks. Participants who terminated from the study prior to Week 156 without meeting the event were excluded. Graft survival is defined as the time to week 156 or graft loss. Graft loss is defined as the day on which a graft is deemed irreversibly nonfunctional and dialysis is begun, a transplantectomy is performed, or the participant is re-transplanted, whichever comes first. Six consecutive weeks of dialysis are required for the diagnosis of graft loss, though the date of graft loss will be defined as the date of first dialysis. | Transplantation until week 156 | 
| Percentage of Participants Surviving Through 156 Weeks | The percentage of participants who survived from transplantation through 156 weeks. Participants who terminated from the study prior to Week 156 without meeting the event were excluded. | Transplantation until week 156 | 
| Time to Neutrophil Recovery Following Transplant | Time (in days) until neutrophil recovery following transplant. Neutrophil recovery is defined as an absolute neutrophil count (ANC) > 500/mm^3 at three consecutive assessments on different days post-transplant. Time to recovery is time from transplantation until the first assessment date used to confirm the recovery. | Transplantation until study completion or participant termination (participants followed up to five years) | 
| Time to Platelet Recovery Following Transplant | Time (in days) until platelet recovery following transplant. Platelet recovery is defined as a platelet count >20,000 /mm^3 and where no transfusion is required. Time to recovery is time from transplantation until platelet value recovers. | Transplantation until study completion or participant termination (participants followed up to five years) | 
| Percentage of Participants Experiencing a Clinically Significant Invasive or Resistant Opportunistic Infection | Clinically significant invasive or resistant opportunistic infections include cytomegalovirus, herpes zoster, and candida. | Transplantation until study completion or participant termination (participants followed up to five years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal allograft tolerance, mixed chimerism, kidney transplant, bone marrow transplant, antirejection, immunosuppression