Using Donor Stem Cells and Alemtuzumab to Prevent Organ Rejection in Kidney Transplant Patients

Phase 1

Completed

Conditions: Kidney Transplantation
Kidney Disease
Kidney Failure

Interventions: Drug: Alemtuzumab
Drug: Mycophenolate mofetil
Drug: Sirolimus
Drug: Tacrolimus
Procedure: Donor bone marrow stem cell infusion
Procedure: Kidney transplant

Registration Number: NCT00183248

Lead Sponsor: University of Miami

Brief Summary: Alemtuzumab is a man-made antibody used to treat certain blood disorders. This study will evaluate treatment of kidney transplant recipients with alemtuzumab and other immune system suppressing medications with or without infusions of bone marrow stem cells from the kidney donor. The purpose of this study is to find out which strategy is more effective in preventing organ rejection and maintaining patient health.

Detailed Description: Organ transplantation is a common procedure in hospitals, but organ rejection and serious side effects are potential problems for the patient. Mycophenolate mofetil, sirolimus, and tacrolimus are drugs used to decrease immune system activity in people who have received organ transplants so that the new organ will not be rejected. Alemtuzumab is a monoclonal antibody that binds to and depletes excess T cells in the bone marrow of leukemia patients. In this study, alemtuzumab will be used to destroy the recipient's white blood cells (WBCs) at the time of transplantation. It is hoped that WBCs produced after alemtuzumab administration will recognize the transplanted liver as "self" and will not attack the new kidney.

To further assist the immune system in accepting the donor kidney, some patients in this study will also receive two infusions of bone marrow stem cells from the kidney donor. Bone marrow stem cells are adult blood cells from which other specialized blood cells, such as T cells, develop. Treatment with these cells is believed to create a state of "chimerism" in the body, where the immune cells of both the donor and recipient can coexist and tolerate the presence of a donor organ. This study will evaluate the safety and effectiveness of an antirejection regimen including alemtuzumab and other immunosuppressive medications and donor bone marrow stem cell infusions in patients undergoing kidney transplantation.

This study will last 3 years. Participants will be randomly assigned to receive either the full immunosuppressive therapy and donor bone marrow stem cell infusions (Group 1) or immunosuppressive therapy alone (Group 2). Patients will undergo kidney transplantation at the start of the study on Day 0. Patients will receive inpatient infusions of alemtuzumab on Days 0 and 4. Starting on Day 0, patients will begin taking mycophenolate mofetil; starting on Day 1, patients will also begin taking tacrolimus. On Day 5, patients in Group 1 will receive their first of 2 infusions of purified stem cells taken from the kidney donor's bone marrow; their second infusion of stem cells will occur sometime between Months 4 and 6 post-transplant.

Beginning between Months 4 and 6 post-transplant, all participants will begin receiving low-dose maintenance immunosuppressive therapy with sirolimus, as is typical for post-transplant antirejection therapy. One year post-transplant, patients will be evaluated for the potential to withdraw some or all of this maintenance immunotherapy. Participants will be monitored for 3 years post-transplant. Urine collection will occur at Week 1 and Months 1, 3, 6, and 9. At Months 12, 24, and 30, participants will undergo kidney biopsies. Blood collection will occur at regular intervals for laboratory tests to evaluate the immune system's response to the transplanted kidney.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 9

Inclusion Criteria

Weight greater than 40 kg (88.2 lbs)
Will be receiving a living-related (1-haplotype-matched donor/recipient) primary kidney allograft
Negative B-cell and T-cell cytotoxic and flow cytometry crossmatch (1-haplotype-matched donor/recipient pairs with a minimum of 1 HLA DR 1A and 1B locus in common and panel-reactive antibodies [PRA] of less than 10%)
Normal echocardiogram (ECG) with an ejection fraction of greater than 50%
Received full course of vaccination for hepatitis B virus (HBV), completed at least 6 weeks before transplantation, OR has naturally acquired immunity
Willing to comply with the study visits
Willing to use acceptable forms of contraception

Exclusion Criteria

Previously received or is receiving an organ transplant other than a kidney
Receiving an ABO (blood type) incompatible donor kidney
Human Immunodeficiency Virus (HIV) infected
Antibody positive for hepatitis C virus (HCV)
Surface antigen positive for hepatitis B virus (HBV)
Recipient or donor is positive for tuberculosis (TB), under treatment for suspected TB, or previously exposed to TB (positive Mantoux test)
Current cancer or a history of cancer within the 5 years prior to study entry. Patients who have had successfully treated nonmetastatic basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix are not excluded.
Significant liver disease, defined as having continuously elevated aspartate aminotransferase (AST SGOT) or alanine aminotransferase (ALT SGPT) levels greater than 3 times the upper value of the normal range within 28 days prior to study entry
Uncontrolled concomitant infections, severe diarrhea, vomiting, active upper gastrointestinal tract malabsorption, active peptic ulcer, or any other unstable medical condition that could interfere with this study
Currently receiving an investigational drug or received an investigational drug within 30 days prior to transplant
Currently receiving any immunosuppressive agent
Anticipated contraindication to taking medications orally or via nasogastric tube by the morning of Day 2 following completion of the transplant procedure
Require certain medications
Known hypersensitivity to any of the study medications, thymoglobulin daclizumab, or corticosteroids
Certain screening laboratory values. More information on this criterion can be found in the protocol.
Any form of substance abuse, psychiatric disorder, or other condition that, in opinion of the investigator, may interfere with the study
Anticipated contraindication to tacrolimus administration for longer than 5 days post-transplant
Currently undergoing peritoneal dialysis
PRA value less than 10% at any time prior to study entry
Graves disease. Patients with Graves disease adequately treated with radioiodine ablative therapy are not excluded.
Cytomegalovirus (CMV) or Epstein-Barr virus (EBV) negative kidney recipient receiving a kidney from a CMV or EBV positive donor
Pregnancy or breastfeeding

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
DBMCs	Sirolimus	Kidney transplantation, followed by immunotherapy given along with kidney donor Donor bone Bone marrow Marrow stem cell Cells (DBMCs) infusions
DBMCs	Donor bone marrow stem cell infusion	Kidney transplantation, followed by immunotherapy given along with kidney donor Donor bone Bone marrow Marrow stem cell Cells (DBMCs) infusions
DBMCs	Kidney transplant	Kidney transplantation, followed by immunotherapy given along with kidney donor Donor bone Bone marrow Marrow stem cell Cells (DBMCs) infusions
Control Group	Kidney transplant	Kidney transplantation, followed by immunotherapy
DBMCs	Tacrolimus	Kidney transplantation, followed by immunotherapy given along with kidney donor Donor bone Bone marrow Marrow stem cell Cells (DBMCs) infusions
DBMCs	Mycophenolate mofetil	Kidney transplantation, followed by immunotherapy given along with kidney donor Donor bone Bone marrow Marrow stem cell Cells (DBMCs) infusions
DBMCs	Alemtuzumab	Kidney transplantation, followed by immunotherapy given along with kidney donor Donor bone Bone marrow Marrow stem cell Cells (DBMCs) infusions
Control Group	Alemtuzumab	Kidney transplantation, followed by immunotherapy
Control Group	Mycophenolate mofetil	Kidney transplantation, followed by immunotherapy
Control Group	Sirolimus	Kidney transplantation, followed by immunotherapy
Control Group	Tacrolimus	Kidney transplantation, followed by immunotherapy

Primary Outcome Measures

Name	Time	Method
Overall Participant Survival at One Year Post Kidney Transplant	One year post kidney transplant
Overall Kidney Graft Survival at One Year Post-Transplant	One year post kidney transplant	Number of participants that did not experience kidney graft failure\[1\] at one year post-transplant \[1\]Graft failure is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation.

Secondary Outcome Measures

Name	Time	Method
Participant Survival at Three Years Post Kidney Transplant	Three years post kidney transplant
Graft Survival at Three Years Post-Transplant	Three years post kidney transplant	Number of participants that did not experience kidney graft failure\[1\] at three years post-transplant \[1\]Graft failure is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation.
Number of Kidney Biopsy-proven Acute Rejection	Three years post kidney transplant	Biopsy-proven acute renal (kidney) rejection\[1,2\]. 1. Diagnosis of acute rejection was made by renal biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection\[2\] 2. Ref: Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999
Number of Chronic Allograft Nephropathies	Three years post kidney transplant	Number of chronic allograft nephropathies\[1,2,3\] at 3 years post kidney transplant. 1. Chronic allograft nephropathy is defined as renal biopsies with Banff 97 Grade I or greater\[2\] with higher numeric scores indicating more severe nephropathy 2. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification\[3\] 3. Reference: Racusen LC, Solez K, Colvin RB et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999
Number of Graft-versus-host Disease (GVHD) Events	Three years post kidney transplant	A disease caused when cells from a donated stem cell graft attack the normal tissue of the transplant patient. Symptoms include jaundice, skin rash or blisters, a dry mouth, or dry eyes. Also called graft-versus-host disease.