Study Stopped
The trial could not be completed within the grant timeline.
Donor-Alloantigen-Reactive Regulatory T Cell (darTregs) in Liver Transplantation
deLTa
4 other identifiers
interventional
15
1 country
3
Brief Summary
The purpose of this study is look at the safety of:
- Taking a specific combination of immunosuppressant drugs after liver transplantation
- Receiving one of three different doses of donor-alloantigen-reactive regulatory T cells (darTregs) while taking this specific combination of drugs
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Dec 2014
Longer than P75 for phase_1
3 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
July 10, 2014
CompletedFirst Posted
Study publicly available on registry
July 14, 2014
CompletedStudy Start
First participant enrolled
December 17, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 18, 2019
CompletedStudy Completion
Last participant's last visit for all outcomes
June 18, 2019
CompletedResults Posted
Study results publicly available
July 20, 2020
CompletedSeptember 22, 2020
September 1, 2020
4.5 years
July 10, 2014
June 16, 2020
September 2, 2020
Conditions
Keywords
Outcome Measures
Primary Outcomes (5)
Percent of Participants With Biopsy-Proven Acute and/or Chronic Rejection
Biopsy-proven acute rejection graded as Mild, Moderate or Severe, per 1997 Banff classification. Chronic Rejection graded using Banff 2000 classification. References: 1.) Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document developed by an international panel of experts in liver transplantation pathology, hepatology, and surgery (Hepatology 1997; 25(3): 658-663). 2.) Update of the International Banff Schema for Liver Allograft Rejection: Working Recommendations for the Histopathologic Staging and Reporting of Chronic Rejection (Hepatology 2000; 31(3): 792-799).
Transplantation to 40 Weeks Post Transplantation
Percent of Participants With Grade 3 or Higher Infectious Adverse Event(s)
The severity of infectious adverse events (AEs) was classified into grades as follows: * 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
Transplantation to 40 Weeks Post Transplantation
Percent of Participants With Grade 3 or Higher Wound Complication(s) Adverse Event(s)
The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009): * Grade 3 wound complications are defined as "Hernia without evidence of strangulation; fascial disruption/dehiscence; primary wound closure or revision by operative intervention indicated" * Grade 4 complications are defined as "Hernia with evidence of strangulation; major reconstruction flap, grafting, resection, or amputation indicated"
Transplantation to 40 Weeks Post Transplantation
Percent of Participants With Grade 2 or Higher Hematologic Adverse Events (AEs) of Anemia, Neutropenia, and/or Thrombocytopenia
The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009): * Grade 1 = mild AE * Grade 2 = moderate AE * Grade 3 = severe and undesirable AE * Grade 4 = life-threatening or disabling AE * Grade 5 = death
Transplantation to 40 Weeks Post Transplantation
Percent of Participants With Adverse Events (AEs) Attributable to the Donor Alloantigen Reactive Tregs (darTregs) Infusion
AEs classified by the site investigator/clinician as possibly or definitely related to the study treatment, the Donor Alloantigen Reactive Tregs (darTregs) infusion. These AEs include: * infusion reaction * Grade 3 or higher cytokine release syndrome (Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009) grading criteria * malignant cellular transformation.
Transplantation to 40 Weeks Post Transplantation
Study Arms (4)
Cohort 1 - Treg-supportive IS only
EXPERIMENTAL3 subjects (Cohort 1a) at site 1 (UCSF) and 3 subjects (Cohort 1b) from site 2 (Mayo Rochester) will receive Treg-Supportive immunosuppression (IS) regimen and will not receive Donor-Alloantigen-Reactive T Regulatory Cells (darTregs). Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.
Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
EXPERIMENTALAt least 3 subjects will receive a single infusion of 50 million darTregs. Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.
Cohort 3 - darTreg infusion,200 million(range100-240 million)
EXPERIMENTALAt least 3 subjects will receive a single infusion dose of 200 million darTregs. Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.
Cohort 4 - darTreg infusion,800 million(range 400-960 million)
EXPERIMENTALSix subjects will receive a single infusion of 800 million darTregs.
Interventions
Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects will be given a dose range of 3.0-4.5 mg/kg total, in divided doses of 1.5 mg/kg/day. Subjects who meet eligibility criteria for Thymoglobulin® administration will be given 1.5 mg/kg intravenously (IV) on post-operative day 3, within 72 hours of transplantation. Additional doses of 1.5 mg/kg IV will be administered until CD3 count is \<50/mm\^3 or when the maximal dose of 4.5/mg/kg has been given.
A single dose darTreg infusion (Cohorts 2 - 4) will be received as per protocol.
Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects meeting eligibility criteria for Treg-supportive IS regimen will begin EVR no sooner than 30 days after liver transplantation and no later than 44 days after transplantation; with target trough levels of 6-8 μg/L.EVR target trough levels will be further reduced to 4-6 μg/L 24 - 26 weeks after transplantation.
Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Between 30 and 44 days following transplant: Subjects who are not eliminated by Exclusion Criteria C1 (Protocol Section 14.3.1) will proceed in the study and receive either TAC-based or EVR- based IS, based on eligibility Criteria C2 (Section 4.3.4 ) * TAC-based IS: reduce TAC trough level to 3-8 μg/dL; continue MMF * EVR-based IS: reduce TAC trough level to 3-8 μg/dL; EVR target trough level of 6-8 μg/dL; decrease then discontinue MMF
Liver transplantation/Treg-supportive immunosuppression (IS) treatment. 1000 mg total daily dose. MMF will be initiated within 24 hours of transplantation. MMF must be discontinued as soon as target EVR trough levels have been achieved.
Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Solumedrol 500 mg will be given IV on the day of transplantation. Additional Solumedrol will be prescribed according to site-specific standard of care. Oral prednisone should be initiated once oral medication is tolerated.
Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 650mg of acetaminophen will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.
Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 25-50mg of diphenhydramine will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.
Intravenous ganciclovir and/or oral Valcyte will be administered for the prophylaxis of cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) for at least six months after liver transplantation.
Leukapheresis is necessary to ensure collection of adequate numbers of autologous Tregs to support ex vivo expansion of darTregs for infusion after liver transplantation. Participants enrolled in Cohorts 3 and 4 will undergo leukapheresis. Participants enrolled in Cohort 2 will have either whole blood collection or leukapheresis for the purpose of isolating autologous Tregs for later manufacture. If a cohort 2 subject has a hemoglobin level \>/=10.5 gm/dL, he or she will undergo phlebotomy. If the patient has a hemoglobin level \</=10.5 gm/dL and remains eligible for the study, the patient will undergo leukapheresis.
Blood draws are necessary to carefully and frequently evaluate allograft function after liver transplantation and treatment with Treg-supportive IS as well as after darTreg infusion. Peripheral blood samples will be collected and analyzed per protocol throughout subject participation in this study.
Subjects will have a liver biopsy for this study 12-14 weeks after transplantation. For subjects receiving darTregs, a second biopsy will be performed 7-10 days after darTregs infusion.
Inclusion in this trial is in the setting of subjects defined as having end-stage liver disease and listed for primary solitary liver transplant.
Eligibility Criteria
You may qualify if:
- Subjects who meet all of the following criteria are eligible for enrollment as study participants:
- Able to understand and provide informed consent
- End-stage liver disease and listed for primary solitary liver transplant
- Have a calculated Model for End Stage Liver Disease (MELD) score ≤ 25 at the time of study entry/consent
- Female and male subjects with reproductive potential must agree to use effective methods of birth control for the duration of the study.
- If history of Hepatitis C Virus (HCV), have completed or are in current treatment for HCV AND have no detectable HCV RNA.
- Subjects with HCC meeting Milan criteria.
You may not qualify if:
- End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis)
- History of less than 5 years remission of malignancy, except for 1) HCC or 2) history of adequately treated in-situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of the skin.
- History of previous organ, tissue or cell transplant
- Serologic evidence of human immunodeficiency (HIV) 1 or -2 infection
- Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) sero-negativity (EBV or CMV naïve candidates)
- Chronic use of systemic glucocorticoids or other Immunosuppression (IS), or biologic immunomodulators
- Chronic condition requiring anti-coagulation after liver transplantation
- Any chronic illness or prior treatment which, in the opinion of the investigator, precludes study participation
- Participation in any other studies that involved investigational drugs or regimens in the preceding year
- Received any vaccination within 28 days prior to leukapheresis or blood collection for Treg manufacture
- Hemoglobin \<9.0 g/dL within 10 days prior to screening
- Neutrophils \<1,500/μL within 10 days prior to screening
- Platelets \<40,000/μL within 10 days prior to screening
- Calculated Model for End Stage Liver Disease (MELD) score \>25 at the time of deceased donor liver transplant
- Last alpha-fetoprotein (AFP) obtained prior to liver transplantation \>400 μg/L for candidates with Hepatocellular Carcinoma (HCC)
- +42 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (3)
University of California, San Francisco
San Francisco, California, 94143, United States
Northwestern University
Chicago, Illinois, 55905, United States
Mayo Clinic
Rochester, Minnesota, 55905, United States
Related Links
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Limitations and Caveats
Enrollment was terminated due to several factors:high number of ineligible subjects, slow enrollment, and manufacturing difficulties within the constraints of the funding period.
Results Point of Contact
- Title
- Director, Clinical Research Operations Program
- Organization
- DAIT/NIAID
Study Officials
- PRINCIPAL INVESTIGATOR
Sandy Feng, MD, PhD
University of California, San Francisco
- PRINCIPAL INVESTIGATOR
Jeffrey Bluestone, PhD
University of California, San Francisco
- PRINCIPAL INVESTIGATOR
Sang-Mo Kang, MD, FACS
University of California, San Francisco
- PRINCIPAL INVESTIGATOR
Qizhi Tang, PhD
University of California, San Francisco
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
July 10, 2014
First Posted
July 14, 2014
Study Start
December 17, 2014
Primary Completion
June 18, 2019
Study Completion
June 18, 2019
Last Updated
September 22, 2020
Results First Posted
July 20, 2020
Record last verified: 2020-09