免费获得国外相关药品，最快 1 个工作日回馈药物信息

出境医 / 临床实验 / TLI, ATG & Hematopoietic Stem Cell Transplantation and Recipient T Regs Therapy in Living Donor Kidney Transplantation

TLI, ATG & Hematopoietic Stem Cell Transplantation and Recipient T Regs Therapy in Living Donor Kidney Transplantation

Study Description
Brief Summary:
This study will determine whether a preparatory regimen including total lymphoid irradiation (TLI), anti-thymocyte globulin (ATG) and infusion of the donor hematopoietic stem cells when given along with recipient regulatory T cells (Tregs) will allow for eventual discontinuation of anti-rejection drugs after living donor kidney transplantation.

Condition or disease Intervention/treatment Phase
Living Donor Kidney Transplantation Biological: Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs Phase 1

Detailed Description:
It has been demonstrated that hematopoietic mixed chimerism or the coexistence of both donor and recipient immune cells can lead to tolerance to the graft in absence of graft versus host disease (GVHD). The goal of this pilot study is to determine if recipients of living donor kidney transplant can be successfully withdraw from immunosuppressive drugs. The patients will receive a preparatory regimen consisting of TLI and ATG following their kidney transplantation. Two weeks later, they will receive purified hematopoietic stem cells (CD34+) and Tcells that have been collected 6 weeks prior from their kidney donor. Regulatory T cells (Tregs) that have been collected from the recipient prior to the transplantation and expanded in vitro will be infuse the following day to enhance the chance of engraftment of the donor bone marrow cells. If chimerism develops and persists, the immunosuppressive drug will be tapered and stop. Mycophenolate mofetil (MMF) will be stopped 12 months after transplantation and if the chimerism remains stable, tacrolimus will be stopped 6 months later. The dose of Tregs will be escalated if the % of donor chimerism is not at least 25% during the first 60 days.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: In this phase 1 study, a conditioning regimen of Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donr CD34+, T cell and Recipient T regulatory Cell Transfusion in Human Leukocyte Antigen Mismatched Living Donor Kidney Transplantation will be studied
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+, T-cell and Recipient T Regulatory Cell Transfusion in Human Leukocyte Antigen Mismatched Living Donor Kidney Transplantation
Actual Study Start Date : February 1, 2020
Estimated Primary Completion Date : August 1, 2024
Estimated Study Completion Date : October 1, 2024
Arms and Interventions
Arm Intervention/treatment
Experimental: Combined kidney/stem cell transplants and recipient's Tregs
Preparatory regimen including TLI, ATG after kidney transplantation followed by infusion of donor CD34+, T cell and recipient Tregs
 Biological: Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs
Living donor kidney transplant recipients will receive after a preparatory regimen of total lymphoid irradiation and and anti-thymocyte globulin an infusion of purified donor CD34+ of >10 x10^6 cells /Kg, 100 x 10^6 donor T cell/ Kg and and an escalated dose of recipient Tregs starting at 25 x10^6/Kg.
Outcome Measures
Primary Outcome Measures :
  1. Count of participants with sustained mixed chimerism of >25% at 18 months [ Time Frame: Month 18 ]
    Chimerism is defined as the co-existence of the immune cell from both the donor and the recipient.

  2. Count of participants able to withdraw from immunosuppressive drugs without evidence of rejection at 18 months [ Time Frame: Month 18 ]

Secondary Outcome Measures :
  1. Count of participants with adverse events associated with the infusion of the Tregs cell product [ Time Frame: up to 2 years ]
  2. Count of participants with bacterial, viral, or fungal infections [ Time Frame: up to 2 years ]

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All consenting adults who are 18 to 65 years, living donor renal transplant recipients at Stanford University Medical Center or Northwestern Medicine who have a haplotype matched (minimum single Human Leukocyte Antigen - DR locus (HLA-DR) and HLA-A or B match) living related or unrelated donor.
  2. Patients who agree to participate in the study and sign an Informed Consent.
  3. Patients who have no known contraindication to administration of rabbit ATG or radiation.
  4. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 1 year posttransplant

Exclusion Criteria:

  1. Previous treatment with rabbit 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 surface antigen positive (HBsAg+), or Hepatitis C infection. Epstein Barr Virus (EBV) positive to EBV negative.
  5. Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (with a platelet count < 100,000/mm3).
  6. Panel Reactive Antibody (PRA) greater than 80% or demonstration of historic and/or current donor specific antibody (DSA)
  7. Prior organ transplantation
  8. High risk of primary kidney disease recurrence
  9. Advanced coronary or vascular disease.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Asha Shori, CCRP 650-736-0245 ashas@stanford.edu
Contact: Stephan Busque, MD 650-498-6189 sbusque@stanford.edu

Locations
Layout table for location information
United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94305
Contact: Asha Shori, CCRP    650-736-0245    ashas@stanford.edu   
Contact: Stephan Busque, MD    650-498-6189    sbusque@stanford.edu   
Principal Investigator: Everett Meyer, MD         
Sub-Investigator: Lowsky Robert, MD         
Sub-Investigator: Hoppe Richard, MD         
Sub-Investigator: Scandling John, MD         
Sub-Investigator: Strober Samuel, MD         
Sub-Investigator: Kent Jensen, PhD         
Principal Investigator: Stephan Busque, MD         
United States, Illinois
Nothwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Diane Stare, RN    312-694-0240    diane.stare@northwestern.edu   
Contact: Joseph Leventhal, MD    312-695-8900    jleventh@nm.org   
Sub-Investigator: Jayesh Mehta, MD         
Sub-Investigator: James Mathew, PhD         
Sub-Investigator: Lorenzo Gallon, MD         
Principal Investigator: Joseph Leventhal, MD         
Sponsors and Collaborators
Stanford University
California Institute for Regenerative Medicine (CIRM)
Northwestern University
Investigators
Layout table for investigator information
Study Director: Everett Meyer, MD Stanford University
Tracking Information
First Submitted Date  ICMJE May 7, 2019
First Posted Date  ICMJE May 9, 2019
Last Update Posted Date March 24, 2020
Actual Study Start Date  ICMJE February 1, 2020
Estimated Primary Completion Date August 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
  • Count of participants with sustained mixed chimerism of >25% at 18 months [ Time Frame: Month 18 ]
    Chimerism is defined as the co-existence of the immune cell from both the donor and the recipient.
  • Count of participants able to withdraw from immunosuppressive drugs without evidence of rejection at 18 months [ Time Frame: Month 18 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
  • Count of participants with adverse events associated with the infusion of the Tregs cell product [ Time Frame: up to 2 years ]
  • Count of participants with bacterial, viral, or fungal infections [ Time Frame: up to 2 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 TLI, ATG & Hematopoietic Stem Cell Transplantation and Recipient T Regs Therapy in Living Donor Kidney Transplantation
Official Title  ICMJE Phase 1 Study of Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+, T-cell and Recipient T Regulatory Cell Transfusion in Human Leukocyte Antigen Mismatched Living Donor Kidney Transplantation
Brief Summary This study will determine whether a preparatory regimen including total lymphoid irradiation (TLI), anti-thymocyte globulin (ATG) and infusion of the donor hematopoietic stem cells when given along with recipient regulatory T cells (Tregs) will allow for eventual discontinuation of anti-rejection drugs after living donor kidney transplantation.
Detailed Description It has been demonstrated that hematopoietic mixed chimerism or the coexistence of both donor and recipient immune cells can lead to tolerance to the graft in absence of graft versus host disease (GVHD). The goal of this pilot study is to determine if recipients of living donor kidney transplant can be successfully withdraw from immunosuppressive drugs. The patients will receive a preparatory regimen consisting of TLI and ATG following their kidney transplantation. Two weeks later, they will receive purified hematopoietic stem cells (CD34+) and Tcells that have been collected 6 weeks prior from their kidney donor. Regulatory T cells (Tregs) that have been collected from the recipient prior to the transplantation and expanded in vitro will be infuse the following day to enhance the chance of engraftment of the donor bone marrow cells. If chimerism develops and persists, the immunosuppressive drug will be tapered and stop. Mycophenolate mofetil (MMF) will be stopped 12 months after transplantation and if the chimerism remains stable, tacrolimus will be stopped 6 months later. The dose of Tregs will be escalated if the % of donor chimerism is not at least 25% during the first 60 days.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
In this phase 1 study, a conditioning regimen of Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donr CD34+, T cell and Recipient T regulatory Cell Transfusion in Human Leukocyte Antigen Mismatched Living Donor Kidney Transplantation will be studied
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Living Donor Kidney Transplantation
Intervention  ICMJE Biological: Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs
Living donor kidney transplant recipients will receive after a preparatory regimen of total lymphoid irradiation and and anti-thymocyte globulin an infusion of purified donor CD34+ of >10 x10^6 cells /Kg, 100 x 10^6 donor T cell/ Kg and and an escalated dose of recipient Tregs starting at 25 x10^6/Kg.
Study Arms  ICMJE Experimental: Combined kidney/stem cell transplants and recipient's Tregs
Preparatory regimen including TLI, ATG after kidney transplantation followed by infusion of donor CD34+, T cell and recipient Tregs
Intervention: Biological: Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs
Publications *
  • Leventhal JR, Ildstad ST. Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell Infusion: The importance of durable chimerism. Hum Immunol. 2018 May;79(5):272-276. doi: 10.1016/j.humimm.2018.01.007. Epub 2018 Mar 2. Review.
  • Ildstad ST, Leventhal J, Wen Y, Yolcu E. Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance. Chimerism. 2015 Apr 3;6(1-2):33-9. doi: 10.1080/19381956.2015.1130780. Epub 2016 Jan 8.
  • Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, Dejbakhsh-Jones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB, Engleman EG, Strober S. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant. 2015 Mar;15(3):695-704. doi: 10.1111/ajt.13091.
  • Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011 Oct 6;365(14):1359-60. doi: 10.1056/NEJMc1107841.
  • Scandling JD, Busque S, Lowsky R, Shizuru J, Shori A, Engleman E, Jensen K, Strober S. Macrochimerism and clinical transplant tolerance. Hum Immunol. 2018 May;79(5):266-271. doi: 10.1016/j.humimm.2018.01.002. Epub 2018 Jan 9. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 7, 2019) 		22
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2024
Estimated Primary Completion Date August 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. All consenting adults who are 18 to 65 years, living donor renal transplant recipients at Stanford University Medical Center or Northwestern Medicine who have a haplotype matched (minimum single Human Leukocyte Antigen - DR locus (HLA-DR) and HLA-A or B match) living related or unrelated donor.
  2. Patients who agree to participate in the study and sign an Informed Consent.
  3. Patients who have no known contraindication to administration of rabbit ATG or radiation.
  4. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 1 year posttransplant

Exclusion Criteria:

  1. Previous treatment with rabbit 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 surface antigen positive (HBsAg+), or Hepatitis C infection. Epstein Barr Virus (EBV) positive to EBV negative.
  5. Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (with a platelet count < 100,000/mm3).
  6. Panel Reactive Antibody (PRA) greater than 80% or demonstration of historic and/or current donor specific antibody (DSA)
  7. Prior organ transplantation
  8. High risk of primary kidney disease recurrence
  9. Advanced coronary or vascular disease.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Asha Shori, CCRP 650-736-0245 ashas@stanford.edu
Contact: Stephan Busque, MD 650-498-6189 sbusque@stanford.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03943238
Other Study ID Numbers  ICMJE 50540
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 Everett Meyer, Stanford University
Study Sponsor  ICMJE Stanford University
Collaborators  ICMJE
  • California Institute for Regenerative Medicine (CIRM)
  • Northwestern University
Investigators  ICMJE
Study Director: Everett Meyer, MD Stanford University
PRS Account Stanford University
Verification Date March 2020

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

治疗医院

新药特效药

治疗案例

前沿医讯