Kidney Transplantation, Kidney Failure, Chronic
Conditions
Keywords
renal allograft tolerance, mixed chimerism, kidney transplant, bone marrow transplant, antirejection, immunosuppression
Brief summary
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
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.
Interventions
PROCEDUREKidney Transplantation
Surgical transplantation of donor kidney
PROCEDUREBone 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
BIOLOGICALMEDI-507
0.1 mg/kg on day -2; 0.6 mg/kg on days -1,0,1
DRUGcyclophosphamide
60 mg/kg infusion on days -5, -4
BIOLOGICALrituximab
375 mg/m\^2 infusion on days -7, -2, 5, and 12
DRUGTacrolimus
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
DRUGcorticosteroids
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
RADIATIONthymic irradiation
700 cGy of thymic irradiation administered in a single dose on day -1
Sponsors
Immune Tolerance Network (ITN)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Successfully Withdrawn Off of Immunosuppressant Medication for 104 Weeks | 48 months post-transplant | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Renal Function | Transplantation until study completion or participant termination (up to five years) | 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 | Transplantation until week 156 | 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 | Transplantation until week 156 | 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. |
| Percentage of Participants Experiencing Acute Rejection | Transplantation until study completion or participant termination (up to five years) | 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. |
| Time to Platelet Recovery Following Transplant | Transplantation until study completion or participant termination (participants followed up to five years) | 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 | Transplantation until study completion or participant termination (participants followed up to five years) | Clinically significant invasive or resistant opportunistic infections include cytomegalovirus, herpes zoster, and candida. |
| Time to Neutrophil Recovery Following Transplant | Transplantation until study completion or participant termination (participants followed up to five years) | 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. |
Countries
United States
Participant flow
Recruitment details
Participants with end-stage renal disease and no evidence of prior sensitization were enrolled between December 2008 and September 2009.
Participants by arm
| Arm | Count |
|---|---|
| MEDI-507 Recipients received a conditioning treatment that started with rituximab (375 mg/m\^2 infusion) on days -7, -2, 5 and 12. Cyclophosphamide (60 mg/kg) on days -5 and -4, followed by hemodialysis. MEDI-507, a T-cell-depleting agent, was given at 0.1 mg/kg on day -2 and 0.6 mg/kg on days -1, 0 and 1. Thymic irradiation (700 cGy) was given on day -1. Recipients underwent surgical transplantation of a donor kidney on day 0. During kidney transplant, bone marrow cells donated by the same donor as the kidney were given through a plastic tube placed in a vein in the chest, underneath the collarbone. Prednisone was started at 2 mg/kg/day on day 4 and tapered off by day 20. A steroid pulse (methylprednisolone 500 mg) was given on days 10, 11, and 12. Tacrolimus (0.05 mg/kg twice a day, adjusted to trough level of 10-15 ng/mL) was given starting on day -1. When the subject met weaning criteria, tacrolimus was tapered over a period of no less than 8 weeks beginning 60 days post-transplant. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Re-transplant | 1 |
Baseline characteristics
| Characteristic | MEDI-507 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 32.8 years STANDARD_DEVIATION 8.6 |
| Baseline Creatinine Level | 1.9 mg/dL STANDARD_DEVIATION 1.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 5 / 5 |
Outcome results
Primary
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.
Time frame: 48 months post-transplant
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-507 | Number of Participants Successfully Withdrawn Off of Immunosuppressant Medication for 104 Weeks | 3 participants |
95% CI: [14.7, 94.7]
Secondary
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.
Time frame: Transplantation until study completion or participant termination (up to five years)
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MEDI-507 | Change in Renal Function | Baseline Serum Creatinine | 1.9 mg/dL | Standard Deviation 1.2 |
| MEDI-507 | Change in Renal Function | Study Termination/Completion | 3.2 mg/dL | Standard Deviation 2.7 |
| MEDI-507 | Change in Renal Function | Change from Baseline | 1.2 mg/dL | Standard Deviation 1.9 |
p-value: 0.215t-test, 2 sided
Secondary
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.
Time frame: Transplantation until study completion or participant termination (participants followed up to five years)
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-507 | Percentage of Participants Experiencing a Clinically Significant Invasive or Resistant Opportunistic Infection | 0 Percentage of Participants |
Secondary
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.
Time frame: Transplantation until study completion or participant termination (up to five years)
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-507 | Percentage of Participants Experiencing Acute Rejection | 40 Percentage of Participants |
Secondary
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.
Time frame: Transplantation until week 156
Population: Participants who were followed at least three years after transplantation or experienced death prior to week 156
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-507 | Percentage of Participants Surviving Through 156 Weeks | 100 Percentage of Participants |
Secondary
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.
Time frame: Transplantation until week 156
Population: Participants who were followed at least three years after transplantation or experienced graft loss prior to week 156
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-507 | Percentage of Participants With Graft Survival Through 156 Weeks | 80 Percentage of Participants |
Secondary
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.
Time frame: Transplantation until study completion or participant termination (participants followed up to five years)
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-507 | Time to Neutrophil Recovery Following Transplant | 14.0 days | Standard Deviation 4.1 |
Secondary
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.
Time frame: Transplantation until study completion or participant termination (participants followed up to five years)
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-507 | Time to Platelet Recovery Following Transplant | 1.0 days | Standard Deviation 0 |