Donor-Alloantigen-Reactive Regulatory T Cell (darTregs) in Liver Transplantation

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

• Ages 21 to 70 years
• All sexes
• No healthy volunteers
• Adult, Older adult

Trial locations and contacts

3 sites in 1 country.

About this study

Official title: Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Liver Transplantation (RTB-002)

Conditions

Liver Transplantation

Being tested

Anti-Thymocyte Globulin - Rabbit, darTreg Infusion, Everolimus, Tacrolimus, Mycophenolate mofetil

Keywords

Donor-Alloantigen-Reactive Regulatory T Cell Therapy, Tregs, Cell- and Tissue-Based Therapy, Immunotherapy, Adoptive, Liver Transplantation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

• Anti-Thymocyte Globulin - RabbitBiological

  Also called ATG (Anti-Thymocyte Globulin), Thymoglobulin®

  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.

• darTreg InfusionBiological

  Also called Donor-Alloantigen-Reactive Regulatory T Cell Infusion

  A single dose darTreg infusion (Cohorts 2 - 4) will be received as per protocol.

• EverolimusDrug

  Also called EVR, Zortress®

  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.

• TacrolimusDrug

  Also called Prograf®

  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

• Mycophenolate mofetilDrug

  Also called MMF, Cellcept, Myfortic

  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.

• PrednisoneDrug

  Also called Solumedrol

  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.

• AcetaminophenDrug

  Also called Tylenol®

  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.

• DiphenhydramineDrug

  Also called Diphenhydramine Hydrochloride

  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.

• Anti-Infective ProphylaxisDrug

  Also called Antiviral Prophylaxis, ganciclovir, Cytovene, Valganciclovir

  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.

• LeukapheresisProcedure or surgery

  Also called Leukocytapheresis

  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 drawsProcedure or surgery

  Also called Venipuncture, Phlebotomy

  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.

• Liver biopsiesProcedure or surgery

  Also called Liver biopsy samples

  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.

• Liver transplantationProcedure or surgery

  Also called Liver transplant

  Inclusion in this trial is in the setting of subjects defined as having end-stage liver disease and listed for primary solitary liver transplant.

What is being measured

The primary outcome is the main question the study is designed to answer.

1. 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).

   Measured: Transplantation to 40 Weeks Post Transplantation

2. 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

   Measured: Transplantation to 40 Weeks Post Transplantation

3. 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"

   Measured: Transplantation to 40 Weeks Post Transplantation

4. 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

   Measured: Transplantation to 40 Weeks Post Transplantation

5. 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.

   Measured: Transplantation to 40 Weeks Post Transplantation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1. First posted14 Jul 2014 (estimated)
2. Study start17 Dec 2014
3. Primary completion18 Jun 2019
4. Study completion18 Jun 2019

Why it stopped: The trial could not be completed within the grant timeline.

Resources

• Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
• Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
• Other trials for Liver TransplantationStudies of the same condition, open and under way.
• More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
• What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.