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

Information source: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Liver Transplant Recipient; Living Donor (of the Respective Liver Transplant Recipient)

Intervention: darTregs (Biological); Acetaminophen (Drug); Diphenhydramine (Drug); Immunosuppression (IS) Withdrawal (Drug); Study Mandated Procedures (Procedure)

Phase: Phase 1/Phase 2

Status: Not yet recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Sandy Feng, Principal Investigator, Affiliation: University of California at San Francisco
Jeffrey Bluestone, PhD, Study Chair, Affiliation: University of California at San Francisco
Qizhi Tang, PhD, Study Chair, Affiliation: University of California at San Francisco


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.

Clinical Details

Official title: Safety of Donor Alloantigen Reactive Tregs to Facilitate Minimization and/or Discontinuation of Immunosuppression in Adult Liver Transplant Recipients (CTOTC-12)

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Incidence of >/=Grade 3 Adverse Events (AEs)

Incidence of Study Defined Grade 3 or Higher Infections infections

Incidence of Any Malignancy

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

Secondary outcome:

Rate of Composite Outcome Measure

Incidence of Biopsy Proven or Clinical Acute Rejection (AR) and/or Chronic Rejection

Severity of Biopsy Proven Acute Rejection (AR) and/or Chronic Rejection

Efficacy of a Single Intravenous (IV) dose of Donor Alloantigen Reactive Regulatory T cells (darTregs)

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.


Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.


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) and buccal (cheek) swab for HLA typing 4. Liver function test (LFT) results: have an ALT consistently <60 U/L and either alkaline phosphatase consistently <150 U/L or Gamma-glutamyl transferase (GGT) consistently <60 U/L during the preceding 12 months 5. Currently receiving a calcineurin inhibitor (CNI) with 12 hour trough levels consistently <6. 0 ng/mL for tacrolimus; <150 ng/mL for cyclosporine during the preceding 6 months 6. 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. 7. Female and male participants with reproductive potential must agree to use effective methods of birth control for the duration of the study. Study Enrollment Exclusion Criteria:

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

1. Transplant for liver disease secondary to hepatitis C or autoimmune disease (e. g. autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis), or Hepatocellular Carcinoma (HCC) 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. Peripheral blood Tregs <30/μL at screening 15. Participation in any other studies that involved investigational drugs or regimens in the preceding year 16. Any other condition, in the investigator's judgment, that increases the risk of darTregs infusion or prevents safe trial participation 17. Unwilling or unable to adhere to study requirements and procedures 18. 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 4 weeks prior to Treg infusion 3. For subjects with hepatitis B virus (HBV), no detectible circulating HBV DNA. 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.

Locations and Contacts

University of California at San Francisco, San Francisco, California 94143, United States; Not yet recruiting
Sharon Blaschka, Phone: 415-476-3229, Email: Sharon.Blaschka@ucsfmedctr.org
Sandy Feng, MD, PhD, Principal Investigator

Mayo Clinic in Rochester, Rochester, Minnesota 55905, United States; Not yet recruiting
Kristin Cornwell, Phone: 507-284-6814, Email: Cornwell.kristin@mayo.edu
Tamucin Taner, MD, Principal Investigator

Additional Information

National Institute of Allergy and Infectious Diseases (NIAID)

Clinical Trials in Organ Transplantation in Children (CTOT-C)

Starting date: July 2015
Last updated: June 15, 2015

Page last updated: August 23, 2015

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