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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

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Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.

Condition or disease Intervention/treatment Phase
Immune Tolerance Biological: Hematopoietic cell transplantation Radiation: Total Lymphoid irradiation Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
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
Official Title: 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 .
Actual Study Start Date : September 13, 2018
Estimated Primary Completion Date : October 1, 2021
Estimated Study Completion Date : October 1, 2025

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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
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.

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Percentage of patients experiencing biopsy proven rejection episodes requiring treatment requiring corticosteroids. [ Time Frame: One year to five years ]
  2. Percentage of patients experiencing graft loss. [ Time Frame: One year to five years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03591302

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Contact: Asha Shori, CCRP 6507360245
Contact: Stephan Busque, MD,MS 6504986189

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United States, California
Stanford University Medical Center Recruiting
Palo Alto, California, United States, 94304
Contact: Asha Shori, CCRP    650-736-0245   
Contact: Stephan Busque, MD, MS    650-498-6189   
Principal Investigator: John Scandling, MD         
Sub-Investigator: Everett Meyer, MD         
Sub-Investigator: Judith Shizuru, MD         
Sub-Investigator: Robert Lowsky, MD         
Sub-Investigator: Hoppe Richard, MD         
Sub-Investigator: Thomas Pham, MD         
Principal Investigator: Samuel Strober, MD         
Principal Investigator: Stephan Busque, MD         
Sponsors and Collaborators
Stephan Busque
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Study Chair: Samuel Md Strober, MD Stanford University

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Responsible Party: Stephan Busque, Professor for Surgery, Stanford University Identifier: NCT03591302    
Other Study ID Numbers: 46787
First Posted: July 19, 2018    Key Record Dates
Last Update Posted: April 4, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Stephan Busque, Stanford University:
Kidney Transplantation
Blood Stem Cell Transplantation
Additional relevant MeSH terms:
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Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs