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Delayed Blood Stem Transplantation in HLA Matched Kidney Transplant Recipients to Eliminate Immunosuppressive Drugs.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03591302
Recruitment Status : Recruiting
First Posted : July 19, 2018
Last Update Posted : April 4, 2019
Information provided by (Responsible Party):
Stephan Busque, Stanford University

Tracking Information
First Submitted Date  ICMJE June 18, 2018
First Posted Date  ICMJE July 19, 2018
Last Update Posted Date April 4, 2019
Actual Study Start Date  ICMJE September 13, 2018
Estimated Primary Completion Date October 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 9, 2018)
Percentage of patients no longer dependent on immunosuppressive drugs to maintain normal renal function. [ Time Frame: six months to up to five years post stem cell transplant ]
A patient will be considered no longer dependent if able to maintain normal renal function after coming off immunosuppressive medications.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03591302 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2018)
  • Percentage of patients experiencing biopsy proven rejection episodes requiring treatment requiring corticosteroids. [ Time Frame: One year to five years ]
  • Percentage of patients experiencing graft loss. [ Time Frame: One year to five years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Delayed Blood Stem Transplantation in HLA Matched Kidney Transplant Recipients to Eliminate Immunosuppressive Drugs.
Official Title  ICMJE Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T-cell Transfusion to Withdraw Immunosuppressive Drugs From Recipients of a Previous HLA Matched Living Donor Kidney Transplantation .
Brief Summary The study will determine whether patients with functioning Human Leukocyte Antigen (HLA) matched kidney transplants for at least one year and who want to discontinue immunosuppressive drugs can be treated with Total Lymphoid Irradiation (TLI) and rabbit Anti-Thymocyte Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.
Detailed Description

This is a single-center, open-label study in adult renal transplant patients.Twenty five patients with functioning HLA matched living donor kidney transplants will receive TLI, rATG and an infusion of cluster of differentiation (CD)34+ (Stem/Progenitor cells) selected granulocyte colony-stimulating factor (G-CSF) mobilized blood cells combined with CD3+ T cells (Stem/ Progenitor cells) from their transplant donors.Transplant recipients will have their maintenance Immunosuppressive drugs adjusted for four weeks before starting the TLI and ATG conditioning regimen. Mycophenolate Mofetil (MMF) will be maintained at 0.5 gm twice a day per day during this four week period during TLI and ATG treatments, and increased to 1 gram twice a day immediately after the completion of TLI at day 14.

MMF will be tapered starting 6 (six) months later. Tacrolimus levels will be targeted to blood trough levels of 4-6 ng/ml in the month before the start of the conditioning regimen. This target would be increased to 8-10 ng/ml at the start of the TLI and ATG conditioning regimen. At serial time points (1) graft function will be monitored. (2) chimerism will be measured in recipient white blood cell subsets, (3) protocol biopsies of the graft will be obtained. An attempt will be made to discontinue Tacrolimus at 12 months if (1) chimerism is detectable for least 180 days after the CD34+ and CD3+ cell infusion, (2) there is no Graft Versus Host Disease (GVHD), (3) there is stable graft function without clinical rejection episodes and (4) lack of histological rejection on protocol biopsies.

Recipients will be given the target dose of ≥ 8 x 10^6 CD 34 + cells/Kg and a dose of 5x10^6 CD3+ cells/Kg.The dose would be sequentially increased to 10, 15 and 25 x 10^6 CD3+ cells/Kg if fewer than 4 of 5 consecutive patients achieve whole blood chimerism of ≥ 30 % at 60 days. If 4 of 5 patients achieve this level of chimerism, then all subsequent enrolled patients will receive this dose.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T Cell Transfusion in previous HLA Matched Living Donor Kidney Transplantation
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Immune Tolerance
Intervention  ICMJE
  • Biological: Hematopoietic cell transplantation
    Transplantation of hematopoietic stem cells from living donor.
  • Radiation: Total Lymphoid irradiation
    Total lymphoid irradiation is used as part of the conditioning regimen for the hematopoietic stem cell transplant.
Study Arms  ICMJE Experimental: Immune tolerance, Kidney transplantation
Intervention: HLA matched living donor recipients of a functioning kidney transplant graft at one year will receive hematopoietic cell transplantation and Total lymphoid irradiation. The intervention is intended to induce immune tolerance such as to allow withdrawal of the immunosuppressive drugs. Immune tolerance is achieved through the development of donor/recipient mixed chimerism following combined kidney and hematopoietic stem cell transplantation from the living donor.
  • Biological: Hematopoietic cell transplantation
  • Radiation: Total Lymphoid irradiation
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 9, 2018)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2025
Estimated Primary Completion Date October 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. All consenting adults of age 18 years and older with previous HLA matched sibling living donor renal transplants who still have their HLA- matched kidney donor available, and who have no history of acute or chronic rejection.
  2. Patients who agree to participate in the study and sign an Informed Consent
  3. The HLA-matched donor meets the Stanford Bone Marrow Transplant criteria for stem cell donation, agrees to participate and has signed an Informed Consent.
  4. The pair is confirmed to be HLA-matched (2 haplo type match) as determined by the histocompatibility laboratory at Stanford.
  5. Patients who have no known contraindication to the administration of rabbit ATG or radiation
  6. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 18 months post transplant.

Exclusion Criteria:

  1. Known allergy to ATG or a known allergy to rabbit proteins.
  2. History of malignancy with the exception of non-melanoma skin malignancies.
  3. Pregnant women or nursing mothers.
  4. Serological evidence of HIV, Hepatitis B (HepBsAg+) or Hepatitis C infection.
  5. Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (platelet count < 100,000/mm3)
  6. Previous history of acute or chronic rejection of the kidney transplant or recurrence of the original disease.
  7. Screening kidney biopsy demonstrating acute or chronic rejection, recurrence of original disease or interstitial fibrosis/Tubular Atrophy (IF/TA) score greater than 1.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Asha Shori, CCRP 6507360245
Contact: Stephan Busque, MD,MS 6504986189
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03591302
Other Study ID Numbers  ICMJE 46787
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Stephan Busque, Stanford University
Study Sponsor  ICMJE Stephan Busque
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Samuel Md Strober, MD Stanford University
PRS Account Stanford University
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP