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