Clinical trial NCT00619528: HLA-Identical Sibling Renal Transplant Tolerance
Official title: HLA-Identical Sibling Renal Transplant Tolerance With Donor Hematopoietic Stem Cells and Campath-1H
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Immunosuppression
Kidney Transplantation
Graft Rejection
Keywords: Transplants
Kidney Transplantation
Immunosuppression
HLA Antigens
Stem Cells
Bone Marrow
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2008-02-21
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

Eligibility criteria: 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)

Primary outcomes:
measure: The ability to withdraw immunosuppression as above 24 months post-transplant with follow-up to 10 years.
timeFrame: 24 months post-transplant with follow-up to 10 years.
measure: Patient and graft survival measured at the one-year timepoint post-transplant.
timeFrame: One Year
Secondary outcomes:
measure: Patient and graft survival measured at the three year timepoint post-transplant..
timeFrame: Three years post-transplant.
measure: Incidence rate of biopsy-proven acute rejection, defined as a renal biopsy demonstrating acute cellular or humoral rejection of Banff Grade IA or greater.
timeFrame: Up to 5 years Post-Transplant
measure: Incidence of chronic allograft nephropathy, determined using renal biopsies and laboratory values, including 24 hour urine protein excretion.
timeFrame: Up to 5 years post transplant
measure: Incidence of graft versus host disease (GVHD).
timeFrame: Up to 5 years Post-Transplant
measure: Incidence of adverse events associated w/ renal transplantation and immunosuppression, including infections, malignancies, post transplant lymphoproliferative disease (PTLD), thromboembolic events, hyperlipidemia, leukopenia, thrombocytopenia, GI toxic
timeFrame: Up to 5 years Post-Transplant
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
Study officials:
affiliation: Northwestern University
name: Joshua Miller, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Leventhal JR, Mathew JM, Salomon DR, Kurian SM, Friedewald JJ, Gallon L, Konieczna I, Tambur AR, Charette J, Levitsky J, Jie C, Kanwar YS, Abecassis MM, Miller J. Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers. Am J Transplant. 2016 Jan;16(1):221-34. doi: 10.1111/ajt.13416. Epub 2015 Jul 30.