Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (ARTEMIS)

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.
ClinicalTrials.gov Identifier: NCT02474199
Recruitment Status : Recruiting
First Posted : June 17, 2015
Last Update Posted : January 7, 2019
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation in Children
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE June 15, 2015
First Posted Date  ICMJE June 17, 2015
Last Update Posted Date January 7, 2019
Actual Study Start Date  ICMJE June 6, 2016
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 15, 2016)
  • Incidence of >/=Grade 3 Adverse Events (AEs) [ Time Frame: Week 24 post darTregs infusion ]
    All >/=Grade 3 AEs attributable to darTregs infusion (infusion reaction, cytokine release syndrome). Reference: NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
  • Incidence of Study Defined Grade 3 or Higher Infections [ Time Frame: Week 24 post darTregs infusion ]
    The following grading system will apply to AEs of infection:
    • Grade 1:asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required
    • Grade 2:symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required
    • Grade 3:any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection
    • Grade 4: life-threatening infection
    • Grade 5:death resulting from infection
  • Incidence of Any Malignancy [ Time Frame: Week 24 post darTregs infusion ]
    Number of participants with any malignancy, including Post -Transplant Lymphoproliferative Disorder (PTLD)
  • Number and Proportion of Liver Transplant Subjects Who Are Able to Reduce Calcineurin Inhibitor (CNI) Dosing by 75 Per Cent (%) and Discontinue a Second IS Drug (if applicable) with Stable Liver Function Tests (LFTs) for >/=12 weeks [ Time Frame: Week 24 post darTregs infusion ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 15, 2015)
  • Incidence of >/=Grade 3 Adverse Events (AEs) [ Time Frame: Week 24 post darTregs infusion ]
    All >/=Grade 3 AEs attributable to darTregs infusion (infusion reaction, cytokine release syndrome). Reference: NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
  • Incidence of Study Defined Grade 3 or Higher Infections infections [ Time Frame: Week 24 post darTregs infusion ]
    The following grading system will apply to AEs of infection:
    • Grade 1:asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required
    • Grade 2:symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required
    • Grade 3:any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection
    • Grade 4: life-threatening infection
    • Grade 5:death resulting from infection
  • Incidence of Any Malignancy [ Time Frame: Week 24 post darTregs infusion ]
    Number of participants with any malignancy, including Post -Transplant Lymphoproliferative Disorder (PTLD)
  • Number and Proportion of Liver Transplant Subjects Who Are Able to Reduce Calcineurin Inhibitor (CNI) Dosing by 75 Per Cent (%) and Discontinue a Second IS Drug (if applicable) with Stable Liver Function Tests (LFTs) for >/=12 weeks [ Time Frame: Week 24 post darTregs infusion ]
Change History Complete list of historical versions of study NCT02474199 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2015)
  • Rate of Composite Outcome Measure [ Time Frame: 52 weeks after darTregs infusion ]
    This measure includes refractory acute rejection (AR), chronic rejection, re-transplantation, and death
  • Incidence of Biopsy Proven or Clinical Acute Rejection (AR) and/or Chronic Rejection [ Time Frame: 52 weeks after darTregs infusion ]
  • Severity of Biopsy Proven Acute Rejection (AR) and/or Chronic Rejection [ Time Frame: 52 weeks after darTregs infusion ]
  • Efficacy of a Single Intravenous (IV) dose of Donor Alloantigen Reactive Regulatory T cells (darTregs) [ Time Frame: 52 weeks after darTregs infusion ]
    Assessed by determining the number and percentage of participants who have received darTregs infusion and are identified as operationally tolerant, defined by maintaining stable allograft function (assessed by liver tests) and histology (determined by central pathologist reading in comparison to screening liver biopsy at study entry) in the absence of immunosuppression for one year.
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 Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction
Official Title  ICMJE Safety of Donor Alloantigen Reactive Tregs to Facilitate Minimization and/or Discontinuation of Immunosuppression in Adult Liver Transplant Recipients (CTOTC-12)
Brief Summary

This research study is for liver transplant recipients and their respective living donors.

The purpose of this study is:

  1. To see if it is safe for liver recipients to receive one dose of donor reactive T regulatory cells (Tregs)
  2. To see if the Tregs allows a liver recipient to take less, or completely stop medications normally taken after receiving an organ transplant.
Detailed Description

Doctors give drugs called immunosuppressants (IS) to people who receive a liver transplant. IS must be taken every day to prevent the body from injuring the transplanted liver by a process called rejection. Liver transplant recipients usually have to take these drugs for the rest of their lives. These drugs have harmful side effects. Researchers are looking for ways to keep a transplanted liver working normally with as little IS medications as possible. Finding a way to lower and then stop these medications will allow the liver recipient to avoid unwanted side effects.

Another area of research looks at how blood cells work to reject or accept an organ transplant. Studies show that some of the recipient's own cells, called T regulatory cells (Tregs), may play a part in accepting the transplanted liver and preventing rejection.

A recipient's Tregs can be grown in the laboratory to increase their number. Exposing the recipient's Tregs to the liver donor's cells will stimulate the Tregs that recognize the liver donor to grow vigorously. Giving these "donor reactive" Tregs back to the transplant recipient through a vein (intravenously) might allow a liver transplant recipient to take lower doses of IS, or perhaps to stop them altogether, without rejecting the liver.

The study team will collect information about the Treg infusion, liver tests and drug doses during IS withdrawal, and any problems that may arise in the study. Blood, liver tissue, and buccal (cheek) cells will be collected for research tests.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Liver Transplant Recipient
  • Living Donor (of the Respective Liver Transplant Recipient)
Intervention  ICMJE
  • Biological: darTregs
    A single intravenous infusion as described administered over a 20-30 minute interval with close monitoring prior to, during, and after the infusion.
    Other Name: Donor Alloantigen Reactive Tregs
  • Drug: Acetaminophen
    Pre-medication for darTregs infusion. A dose of 15 mg/kg will be administered 30 to 60 minutes prior to the darTregs infusion.
  • Drug: Diphenhydramine
    Pre-medication for darTregs infusion. A dose of 1-2 mg/kg diphenhydramine will be administered 30 to 60 minutes prior to the darTregs infusion.
    Other Name: Diphenhydramine Hydrochloride
  • Drug: Immunosuppression (IS) Withdrawal
    Subjects:1.) who fulfill study eligibility criteria will withdraw IS 2.) enter the study on calcineurin inhibitor (CNI) monotherapy or a CNI‐based regimen with either Prednisone or MMF as a second IS medication 3.) will proceed with changes in CNI dosing according to the protocol's CNI withdrawal algorithm.During the last 2 weeks of IS withdrawal (e.g., Step 2 in algorithm -CNI reduced 25%-"pre darTregs"), a single dose of darTregs will be infused IV. The subject will then, if eligible, proceed with IS withdrawal within 2 weeks after the infusion. Eligible subjects meeting the primary endpoint of 75% reduction in CNI from baseline after darTregs will be offered the opportunity to continue IS withdrawal until complete discontinuation of IS.
    Other Names:
    • IS Withdrawal
    • CNI based IS regimen
  • Procedure: Study Mandated Procedures
    Blood draws (venipuncture); collection of peripheral blood mononuclear cells (PBMCs) by a procedure known as leukapheresis or venipuncture; buccal (cheek) swab for HLA typing; liver biopsies (per protocol and for cause).
Study Arms  ICMJE Experimental: darTregs
Donor Alloantigen Reactive Tregs (darTregs). Participants will receive a target dose of 400X10^6 darTregs (range 300-500 x10^6) infused intravenously (IV) over an approximate 20-30 minute interval
Interventions:
  • Biological: darTregs
  • Drug: Acetaminophen
  • Drug: Diphenhydramine
  • Drug: Immunosuppression (IS) Withdrawal
  • Procedure: Study Mandated Procedures
Publications * Not Provided

*   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: June 15, 2015)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2020
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Study Enrollment Inclusion Criteria:

  • Subjects who meet all of the following criteria are eligible for enrollment:

    1. Able to understand and provide informed consent
    2. Have received a primary, solitary, living donor liver transplant more 24 months and less than 84 months ago
    3. Have a living donor who is willing to consent to a one time blood draw of 100 mLs to enable the manufacture of Donor Alloantigen Reactive Regulatory T cells (darTregs)
    4. Eighteen to 70 years of age at the time of study entry/consent
    5. Liver function test (LFT) results: have Alanine Aminotransferase (ALT)consistently <60 U/L and either alkaline phosphatase consistently <150 U/L or Gamma-glutamyl transferase (GGT) consistently <60 U/L
    6. Currently receiving a Calcineurin Inhibitor (CNI) with 12 hour trough levels consistently <6.0 ng/mL for tacrolimus; <150 ng/mL for cyclosporine
    7. Currently receiving CNI monotherapy or CNI and one of the following:

      1. Prednisone: maximum dose of 5mg daily
      2. Mycophenolate mofetil (MMF): maximum dose of 500 mg administered twice daily for Cellcept or 360mg twice daily for Myfortic.
    8. Female and male participants with reproductive potential must agree to use effective methods of birth control for the duration of the study.
    9. If history of Hepatocellular carcinoma (HCC), liver transplantation (LT) recipients who have:

      1. α-fetoprotein (AFP) less than 100 μg/L at the time of transplant AND
      2. Explanted liver:

        • with tumor burden within the Milan criteria and
        • without macro- or micro-vascular invasion and
        • without any lesions with poorly differentiated HCC and
        • without cholangiocarcinoma morphology
      3. Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score less than or equal to 3
    10. If history of HCC, at the time of enrollment, subjects must also:

      1. Be 36 months or more post-transplant AND
      2. Without evidence of recurrent HCC defined as:

        • AFP within normal limits for performing laboratory;
        • Confirmatory chest CT and
        • Confirmatory CT or MRI of the abdomen and pelvis.
    11. If history of hepatitis C virus (HCV) , recipients must be:

      1. Cured of HCV as defined by achieving Sustained virologic response (SVR) and be greater than or equal to six months after the end of treatment
      2. HCV RNA negative at time of study enrollment

Study Enrollment Exclusion Criteria:

  • Participants who meet any of these criteria are not eligible for study enrollment:

    1. Transplant for liver disease secondary to autoimmune disease (e.g. autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis)
    2. Matched at both human leukocyte antigen (HLA)-DR loci to the donor
    3. Organ, tissue or cell transplant prior to or after the primary solitary living donor liver transplant
    4. For subjects with hepatitis B, detectible hepatitis B virus (HBV) DNA
    5. History of malignancy within 5 years of enrollment. History of adequately treated in-situ cervical carcinoma and/or skin cancer (basal or squamous cell) will be permitted.
    6. Serologic evidence of human immunodeficiency 1 or 2 infection
    7. Epstein Barr Virus (EBV) seronegativity (EBV naïve) if living donor is EBV seropositive
    8. Cytomegalovirus (CMV) seronegativity (CMV naïve) if living donor is CMV seropositive
    9. Calculated Glomerular filtration rate (GFR) less than 50 mL/min/1.73m^2 at the time of enrollment
    10. An episode of Acute Rejection (AR) within one year of enrollment
    11. Systemic illness requiring or likely to require recurrent or chronic immunosuppression (IS) drug use
    12. Any chronic condition for which anti-coagulation cannot be safely interrupted for liver biopsy
    13. Positive pregnancy test
    14. Participation in any other studies that involved investigational drugs or regimens in the preceding year
    15. Any other condition, in the investigator's judgment, that increases the risk of darTregs infusion or prevents safe trial participation
    16. Unwilling or unable to adhere to study requirements and procedures
    17. Screening liver biopsy with any of the following histological criteria, as determined by the reading of a central pathologist.

darTregs Infusion Inclusion Criteria:

  • Subjects must meet all criteria below to receive darTregs infusion:

    1. Stable liver tests, defined as ALT and either alkaline phosphatase or GGT either within normal limits OR <\=1.5 X baseline
    2. No detectible circulating EBV or CMV DNA prior to Treg infusion, assessed at the time of PBMC collection for manufacture
    3. For subjects with hepatitis B virus (HBV), no detectible circulating HBV DNA, assessed at the time of PBMC collection for manufacture
    4. Able to understand and provide informed consent.

darTregs Infusion Exclusion Criteria:

Subjects who meet any of these criteria are not eligible for darTregs infusion:

  1. Diagnosis of AR after initiation of IS withdrawal
  2. Any vaccination given within 28 days prior to Treg collection for Treg production
  3. Receipt of a vaccination within 14 days prior to Treg infusion
  4. Unacceptable darTregs product
  5. Positive pregnancy test
  6. Clinical evidence of viral syndrome less than 7 days prior to darTregs infusion.

Inclusion Criteria for Resuming IS Withdrawal after darTregs Infusion:

Subjects are eligible to resume IS withdrawal after darTregs infusion if all criteria below are met:

  1. Subject received at least 100 x 10^6 darTregs
  2. ALT and either alkaline phosphatase or GGT remain within normal limits or <\= 1.5 x baseline after darTregs infusion
  3. For subjects with elevated liver tests as defined above, local pathology reading of liver biopsy 6-10 days after darTregs infusion is without AR according to Banff criteria
  4. IS withdrawal resumes no later than 14 days after darTregs infusion
  5. Site principal investigator determines it is acceptable for the study subject to resume IS withdrawal.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02474199
Other Study ID Numbers  ICMJE DAIT CTOTC-12
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Clinical Trials in Organ Transplantation in Children
Investigators  ICMJE
Principal Investigator: Sandy Feng University of California at San Francisco
Study Chair: Jeffrey Bluestone, PhD University of California at San Francisco
Study Chair: Qizhi Tang, PhD University of California at San Francisco
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date January 2019

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