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Combined Kidney and Bone Marrow Transplantation to Prevent Kidney Transplant Rejection

This study has been completed.
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00801632
First received: December 2, 2008
Last updated: November 6, 2015
Last verified: November 2015
  Purpose
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.

Condition Intervention Phase
Kidney Transplantation
Kidney Failure, Chronic
Procedure: Kidney Transplantation
Procedure: Bone marrow transplantation
Biological: MEDI-507
Drug: cyclophosphamide
Biological: rituximab
Drug: Tacrolimus
Drug: corticosteroids
Radiation: thymic irradiation
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Renal Allograft Tolerance Through Mixed Chimerism

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Number of Participants Successfully Withdrawn Off of Immunosuppressant Medication for 104 Weeks [ Time Frame: 48 months post-transplant ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants Experiencing Acute Rejection [ Time Frame: Transplantation until study completion or participant termination (up to five years) ] [ Designated as safety issue: No ]
    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.

  • Change in Renal Function [ Time Frame: Transplantation until study completion or participant termination (up to five years) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Graft Survival Through 156 Weeks [ Time Frame: Transplantation until week 156 ] [ Designated as safety issue: Yes ]
    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.

  • Percentage of Participants Surviving Through 156 Weeks [ Time Frame: Transplantation until week 156 ] [ Designated as safety issue: Yes ]
    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.

  • Time to Neutrophil Recovery Following Transplant [ Time Frame: Transplantation until study completion or participant termination (participants followed up to five years) ] [ Designated as safety issue: No ]
    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.

  • Time to Platelet Recovery Following Transplant [ Time Frame: Transplantation until study completion or participant termination (participants followed up to five years) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Experiencing a Clinically Significant Invasive or Resistant Opportunistic Infection [ Time Frame: Transplantation until study completion or participant termination (participants followed up to five years) ] [ Designated as safety issue: Yes ]
    Clinically significant invasive or resistant opportunistic infections include cytomegalovirus, herpes zoster, and candida.


Enrollment: 5
Study Start Date: December 2008
Study Completion Date: November 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Kidney and Marrow Recipients
Combined kidney and bone marrow transplant
Procedure: Kidney Transplantation
Surgical transplantation of donor kidney
Other Name: Renal Transplantation
Procedure: Bone marrow transplantation
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
Biological: MEDI-507
0.1 mg/kg on day -2; 0.6 mg/kg on days -1,0,1
Other Names:
  • siplizumab
  • anti-CD2 monoclonal antibody
Drug: cyclophosphamide
60 mg/kg infusion on days -5, -4
Other Name: Cytoxan
Biological: rituximab
375 mg/m^2 infusion on days -7, -2, 5, and 12
Other Name: Rituxan
Drug: Tacrolimus
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
Other Name: PROGRAF®
Drug: corticosteroids
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
Other Names:
  • methylprednisolone
  • prednisone
Radiation: thymic irradiation
700 cGy of thymic irradiation administered in a single dose on day -1

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00801632

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Investigators
Principal Investigator: David Sachs, MD Massacusetts General Hospital
Principal Investigator: Ben Cosimi, MD Massachusetts General Hospital
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00801632     History of Changes
Other Study ID Numbers: DAIT ITN036ST 
Study First Received: December 2, 2008
Results First Received: April 21, 2015
Last Updated: November 6, 2015
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
renal allograft tolerance
mixed chimerism
kidney transplant
bone marrow transplant
antirejection
immunosuppression

Additional relevant MeSH terms:
Renal Insufficiency
Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Cyclophosphamide
Tacrolimus
Rituximab
Prednisone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on August 23, 2016