Graft Rejection, Immunosuppression, Kidney Transplantation
Conditions
Keywords
Transplants, Kidney Transplantation, Immunosuppression, HLA Antigens, Stem Cells, Bone Marrow
Brief summary
The purpose of this study is to attempt to eliminate the necessity of immunosuppressive therapy for HLA-identical sibling Kidney Transplants, examine cellular chimerism of donor hematopoietic stem cell (DHSC) lineages for pairs to demonstrate immunologic unresponsiveness, and to investigate the safety and efficacy of the treatment regimen including withdrawal of immunosuppression after one year post-transplant for those recipients having received DHSC infusions.
Detailed description
Primary Study Objectives: 1. To remove all immunosuppressive therapy from recipients of HLA-identical sibling renal transplants within 24 months of transplantation. 2. To detect and follow cellular (macro) chimerism of donor hematopoietic stem cell (DHSC) lineages and the generation of T-regulatory cells using specialized immunomonitoring assays for these donor/recipient pairs to demonstrate specific immunologic unresponsiveness. 3. To investigate the safety and efficacy of a treatment regimen consisting of induction therapy with Campath-1H and steroid-free low dose maintenance immunosuppression, consisting of mycophenolate mofetil (MMF) and tacrolimus converted to sirolimus. This is to be followed by complete withdrawal of immunosuppression beginning at one year, at a minimum, post transplant, in recipients who have also been given four infusions of purified donor hematopoietic Cluster of Differentiation (CD)34+ stem cells (DHSC).
Interventions
BIOLOGICALInfusion of Donor Hematopoietic Stem Cells and Campath-1H
Intervention: a four-dose (peri-operative and 3, 6, and 9-month boost) DHSC infusion protocol using two-dose Campath-1H induction combined with transient (conditioning) Tacrolimus/Sirolimus and MMF therapy will result in a high degree of macro-chimerism (\>10%), and a robust prolonged donor-specific (post-thymic) immunoregulatory condition that will allow renal transplant survival in the absence of permanent immunosuppression.
Sponsors
Northwestern University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Patient fully informed, signed dated Institutional Review Board (IRB)-approved informed consent form obtained directly by the P.I., Co-P.I., or Res. Nurse, and willing to follow study procedures for the duration of study (3 yrs). * Recipient: a hematocrit of ≥ 33%, and a hemoglobin of ≥ 11.0 g/dL. * Weight \> 40 kg. * Primary renal allograft: living related (HLA-identical donor-recipient sibling pairs) * Negative B-cell and T-cell cytotoxic cross-match, and a low (≤ 10%) Panel Reactive Antibody (PRA) using cytotoxicity. * Women of childbearing potential: negative qualitative serum pregnancy test. * Patients studied equivalently as available for transplant using criteria, w/out regard to gender, race, or ethnicity. * Normal echocardiogram w/ ejection fraction \>50%. * Male participants w/ reproductive potential agree to use approved methods of birth control during treatment w/ Campath-1H and for minimum of 6 months following last dose. Female participants of childbearing potential agree to use approved methods of birth control for duration of participation in study. * Patient agrees to follow-up every 2 months after year 3, up to 10 years.
Exclusion criteria
* Patient previously received/receiving transplant other than kidney. * Patient receiving ABO (blood type) incompatible donor kidney. * Recipient/donor is ELISA positive for human immunodeficiency virus (HIV), antibody positive for hep. C, or surface antigen positive for hep. B. * Patient has current malignancy or history of malignancy (within past 5 years), except non-metastatic basal or squa¬mous cell carcinoma of the skin, or carcinoma in situ of the cervix that has been treated successfully. * Patients w/ significant liver disease, defined as having during past 28 days continuously elevated aspartate aminotransferase (AST (SGOT)) and/or Alanine Aminotransferase (ALT (SGPT)) levels greater than 3 times the upper value of the normal range at this center. * Patient has uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or active peptic ulcer or other unstable medical condition that could interfere w/ study objectives. * Patient currently receiving investigational drug or received an investigational drug within 30 days pre-transplant. * Patient currently receiving immunosuppressive agent. * In investigator's judgment, anticipated that patient unable to take medications orally or via nasogastric tube by morning of second day (i.e., skin closure). * Concurrent use of warfarin, fluvastatin, astemizole, pimozide, cisapride, terfenadine, or ketoconazole. * Patient hypersensitivity to tacrolimus, Campath-1H, Thymoglobulin, daclizumab (Zenapax®), sirolimus, MMF or corticosteroids. * Patient pregnant or lactating. * Patients w/ screening/baseline total white blood cell count \<4000/mm3; platelet count \<100,000/mm3; fasting triglycerides \>400 mg/dl (\>4.6 mmol/L); fasting total cholesterol \>300 mg/dl (\>7.8 mmol/L); fasting HDL-cholesterol \<30 mg/dl; fasting LDL-cholesterol \>200 mg/dl. * Patient unlikely to comply w/ visits. * Patient w/ any form of substance abuse, psychiatric disorder or condition that, in investigator's opinion, may invalidate communication. * Expected that tacrolimus cannot be instituted for over 5 days post-operatively. * Patients w/ cytotoxic PRA value \>10% any time pre-enrollment. * Patients w/ Graves disease, unless previously treated w/ radioiodine ablative therapy. * History of idiopathic thrombocytopenic purpura (ITP) or thrombotic thrombocytopenic purpura (TTP)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Ability to Withdraw Immunosuppression as Above 24 Months Post-transplant | 24 months post-transplant with follow-up to 10 years | The ability to withdraw immunosuppression as above 24 months post-transplant with follow-up to 10 years. |
| Patient and Graft Survival | One Year | Patient and graft survival measured at the one-year timepoint post-transplant. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoseph Leventhal, MD
Northwestern University
Participant flow
Recruitment details
Subject enrollment 2008-2012. Subjects were recruited at the Northwestern University Medical Center, in the comprehensive Transplant Center. Enrollment has been completed since 2012
Pre-assignment details
1 subject did not did not receive the DHSC infusions due to the immediate pre-operative cross-match again the donor that was unexpectedly found to be positive
Participants by arm
| Arm | Count |
|---|---|
| Recipients Recipient of kidney transplant | 20 |
| Donor Donating kidney to sibling | 20 |
| Healthy Controls The control subjects (not having the disease or problem being studied) either have a one time bone marrow aspiration (taking bone marrow out of one or both hip bones) and/or having blood taken for the study. | 19 |
| Parents of Recipients/Donors The subjects in this group are the parents of donors and recipients of kidney transplant | 29 |
| Total | 88 |
Baseline characteristics
| Characteristic | Healthy Controls | Parents of Recipients/Donors | Total | Recipients | Donor |
|---|---|---|---|---|---|
| Age, Continuous | 36.034 years | 53.379 years | 36.034 years | 39.625 years | 39.241 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 6 Participants | 11 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 23 Participants | 73 Participants | 17 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 4 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 12 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 15 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 8 Participants | 20 Participants | 55 Participants | 14 Participants | 13 Participants |
| Sex: Female, Male Female | 9 Participants | 17 Participants | 41 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 10 Participants | 12 Participants | 47 Participants | 16 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 20 | 0 / 20 | 0 / 19 | 0 / 29 |
| other Total, other adverse events | 4 / 20 | 0 / 20 | 0 / 19 | 0 / 29 |
| serious Total, serious adverse events | 8 / 20 | 0 / 20 | 0 / 19 | 0 / 29 |
Outcome results
Primary
Patient and Graft Survival
Patient and graft survival measured at the one-year timepoint post-transplant.
Time frame: One Year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Kidney Transplant Recipients Who Received Infusion of Donor Hematopoietic Stem Cells and Campath-1H | Patient and Graft Survival | 20 Participants |
Primary
The Ability to Withdraw Immunosuppression as Above 24 Months Post-transplant
The ability to withdraw immunosuppression as above 24 months post-transplant with follow-up to 10 years.
Time frame: 24 months post-transplant with follow-up to 10 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Kidney Transplant Recipients Who Received Infusion of Donor Hematopoietic Stem Cells and Campath-1H | The Ability to Withdraw Immunosuppression as Above 24 Months Post-transplant | 6 Participants |