Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (ARTEMIS)
This research study is for liver transplant recipients and their respective living donors.
The purpose of this study is:
- To see if it is safe for liver recipients to receive one dose of donor reactive T regulatory cells (Tregs)
- To see if the Tregs allows a liver recipient to take less, or completely stop medications normally taken after receiving an organ transplant.
|Liver Transplant Recipient Living Donor (of the Respective Liver Transplant Recipient)||Biological: darTregs Drug: Acetaminophen Drug: Diphenhydramine Drug: Immunosuppression (IS) Withdrawal Procedure: Study Mandated Procedures||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Safety of Donor Alloantigen Reactive Tregs to Facilitate Minimization and/or Discontinuation of Immunosuppression in Adult Liver Transplant Recipients (CTOTC-12)|
- 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 ]
- 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.
|Study Start Date:||September 2015|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||April 2018 (Final data collection date for primary outcome measure)|
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
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 TregsDrug: 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 HydrochlorideDrug: 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: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).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02474199
|United States, California|
|University of California at San Francisco||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Sharon Blaschka 415-476-3229 Sharon.Blaschka@ucsfmedctr.org|
|Principal Investigator: Sandy Feng, MD, PhD|
|United States, Illinois|
|Northwestern University Comprehensive Transplant Ctr||Not yet recruiting|
|Chicago, Illinois, United States, 60611|
|Contact: Patrice Al-Saden 312-503-1058 email@example.com|
|Principal Investigator: Josh Levitsky, MD|
|United States, Minnesota|
|Mayo Clinic in Rochester||Recruiting|
|Rochester, Minnesota, United States, 55905|
|Contact: Kristin Cornwell 507-284-6814 Cornwell.firstname.lastname@example.org|
|Principal Investigator: Tamucin Taner, MD|
|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|