Liver Transplant Recipient, Living Donor (of the Respective Liver Transplant Recipient)
Conditions
Keywords
Regulatory T Cells ( Treg), Donor Alloantigen Reactive Tregs (darTregs), Liver Transplant, Alloantigen Reactive Tregs, Calcineurin Inhibitors (CNI), immunosuppressants (IS)
Brief 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.
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.
Interventions
BIOLOGICALdarTregs
A single intravenous infusion as described administered over a 20-30 minute interval with close monitoring prior to, during, and after the infusion.
DRUGAcetaminophen
Pre-medication for darTregs infusion. A dose of 15 mg/kg will be administered 30 to 60 minutes prior to the darTregs infusion.
DRUGDiphenhydramine
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.
DRUGImmunosuppression (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.
PROCEDUREStudy 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).
Sponsors
Clinical Trials in Organ Transplantation in Children
Rho Federal Systems Division, Inc.
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion 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) 4. Eighteen to 70 years of age at the time of study entry/consent 5. Liver function test (LFT) results: have Alanine Aminotransferase (ALT)consistently \<60 U/L and either alkaline phosphatase consistently \<150 U/L or Gamma-glutamyl transferase (GGT) consistently \<60 U/L 6. Currently receiving a Calcineurin Inhibitor (CNI) with 12 hour trough levels consistently \<6.0 ng/mL for tacrolimus; \<150 ng/mL for cyclosporine 7. 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. 8. Female and male participants with reproductive potential must agree to use effective methods of birth control for the duration of the study. 9. If history of Hepatocellular carcinoma (HCC), liver transplantation (LT) recipients who have: 1. α-fetoprotein (AFP) less than 100 μg/L at the time of transplant AND 2. Explanted liver: * with tumor burden within the Milan criteria and * without macro- or micro-vascular invasion and * without any lesions with poorly differentiated HCC and * without cholangiocarcinoma morphology 3. Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score less than or equal to 3 10. If history of HCC, at the time of enrollment, subjects must also: 1. Be 36 months or more post-transplant AND 2. Without evidence of recurrent HCC defined as: * AFP within normal limits for performing laboratory; * Confirmatory chest CT and * Confirmatory CT or MRI of the abdomen and pelvis. 11. If history of hepatitis C virus (HCV) , recipients must be: 1. Cured of HCV as defined by achieving Sustained virologic response (SVR) and be greater than or equal to six months after the end of treatment 2. HCV RNA negative at time of study enrollment Study Enrollment
Exclusion criteria
* Participants who meet any of these criteria are not eligible for study enrollment: 1. Transplant for liver disease secondary to autoimmune disease (e.g. autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis) 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. Participation in any other studies that involved investigational drugs or regimens in the preceding year 15. Any other condition, in the investigator's judgment, that increases the risk of darTregs infusion or prevents safe trial participation 16. Unwilling or unable to adhere to study requirements and procedures 17. 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 prior to Treg infusion, assessed at the time of PBMC collection for manufacture 3. For subjects with hepatitis B virus (HBV), no detectible circulating HBV DNA, assessed at the time of PBMC collection for manufacture 4. Able to understand and provide informed consent. darTregs Infusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Liver Transplant Recipients Who Are Able to Reduce Calcineurin Inhibitor Dosing by 75 Percent and Discontinue a Second Immunosuppression Drug (if Applicable) With Stable Liver Function Tests (LFTs) for ≥ 12 Weeks | From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion | The ability to reduce baseline, standard of care calcineurin inhibitor dosing following transplantation was measured by determining the number of subjects who were able to tolerate a 75 percent reduction in their calcineurin inhibitors along with discontinuation of either prednisone or mycophenolate mofetil following initiation of immunosuppression withdrawal. |
| Number of Participants Who Experienced Grade 3 or Higher Adverse Events (AEs) Deemed Attributable to darTreg Infusion | From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion | The National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to grade the severity of all AEs. A participant was considered to have met this endpoint if they experienced at least one CTCAE Grade 3 or higher AE deemed attributable (i.e., considered at least possibly related) to darTreg infusion (infusion reaction, cytokine release syndrome). |
| Number of Participants With Study Defined Grade 3 or Higher Infections | From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion | The following grading system was applied 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 A participant was considered to have met this endpoint if they experienced at least one Grade 3 or higher infection. |
| Number of Participants With Any Malignancy | From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion | Number of participants with any malignancy, including Post -Transplant Lymphoproliferative Disorder (PTLD). PTLD is a specific type of malignancy that can occur following transplantation of a solid organ and is characterized by a proliferation of B cells, which may result in lymphoma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Liver Transplant Recipients Who Experience the Composite Outcome | From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion | This measure includes refractory acute rejection, chronic rejection, re-transplantation, and death. Rejection was diagnosed based on local pathology. Participants are considered to have met this endpoint if they experience any one of these events at least once. |
| Number of Participants Who Experience at Least One Episode of Biopsy Proven Acute Rejection, Clinical Acute Rejection, or Chronic Rejection | From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion | A participant was considered to have met this endpoint if they experienced at least one episode of biopsy proven acute rejection, clinical acute rejection, or chronic rejection based on local pathology. Biopsy proven acute rejection was assessed as Grade I or higher based on the Banff (1997) global criteria featuring the following grades: * Indeterminate * Grade I Mild Acute Rejection * Grade II Moderate Acute Rejection * Grade III Severe Acute Rejection. Clinical AR was determined based on the participant receiving treatment for rejection with or without biopsy confirmation of rejection. Chronic rejection was determined by the presence of abnormal total and direct bilirubin in the conjunction with liver pathology fulfilling the Banff (2000) criteria as outlined: * Early Stage Chronic Rejection * Late Stage Chronic Rejection. |
| Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection | From initiation of immunosuppression withdrawal to 52 weeks after darTregs infusion | Participants are counted in each grade of rejection they experienced; however, a participant is only counted once within a specific grade. Biopsy proven acute rejection and Chronic rejection were graded based on local pathology according to the Banff (1997 for Acute Rejection; 2000 for Chronic Rejection) global assessment criteria as outlined below. Biopsy proven acute rejection was assessed as Grade I or higher using the following grades: * Indeterminate * Grade I Mild Acute Rejection * Grade II Moderate Acute Rejection * Grade III Severe Acute Rejection. Chronic rejection was determined by the presence of abnormal total and direct bilirubin in the conjunction with liver pathology fulfilling the Banff criteria as outlined: * Early Stage Chronic Rejection * Late Stage Chronic Rejection. |
| Number of Participants Achieving Efficacy Status Post Receipt of a Single Intravenous (IV) Dose of Donor Alloantigen Reactive Regulatory T Cells (darTregs) | From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion | Efficacy was assessed by determining the number (and percentage) of participants who have received darTreg 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred between June 2016 and October 2018 at 3 clinical centers across the United States. A total of 15 participants were enrolled.
Pre-assignment details
Five participants who signed informed consents did not proceed to immunosuppression withdrawal: 4 did not meet inclusion/exclusion criteria, 1 chose not to continue in the study.
Participants by arm
| Arm | Count |
|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs Initiated Immunosuppression Withdrawal, Received darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and received the darTreg infusion. Adverse events were collected for these participants. | 5 |
| Initiated Immunosuppression Withdrawal, Did Not Receive darTregs Initiated Immunosuppression Withdrawal, Did Not Receive darTregs: Adult liver transplant recipients who signed informed consent, began immunosuppression withdrawal, and did not receive the darTreg infusion. Adverse events were collected for these participants. | 5 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Did not meet eligibility criteria | 0 | 0 | 2 | 2 |
| Overall Study | Did not receive Tregs due to insufficient manufacture | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | Initiated Immunosuppression Withdrawal, Received darTregs | Total | Initiated Immunosuppression Withdrawal, Did Not Receive darTregs |
|---|---|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 15.42 | 53.2 years STANDARD_DEVIATION 16.98 | 57.6 years STANDARD_DEVIATION 19.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 8 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 7 Participants | 4 Participants |
| Region of Enrollment United States | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 2 Participants |
| Time Post-Transplant | 3.3 years STANDARD_DEVIATION 1.59 | 3.4 years STANDARD_DEVIATION 1.43 | 3.4 years STANDARD_DEVIATION 1.43 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 2 |
| other Total, other adverse events | 0 / 5 | 2 / 5 | 0 / 2 |
| serious Total, serious adverse events | 4 / 5 | 1 / 5 | 0 / 2 |
Outcome results
Primary
Number of Participants Who Experienced Grade 3 or Higher Adverse Events (AEs) Deemed Attributable to darTreg Infusion
The National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to grade the severity of all AEs. A participant was considered to have met this endpoint if they experienced at least one CTCAE Grade 3 or higher AE deemed attributable (i.e., considered at least possibly related) to darTreg infusion (infusion reaction, cytokine release syndrome).
Time frame: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion
Population: Participants who initiated immunosuppression withdrawal and received darTregs
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Number of Participants Who Experienced Grade 3 or Higher Adverse Events (AEs) Deemed Attributable to darTreg Infusion | 0 Participants |
Primary
Number of Participants With Any Malignancy
Number of participants with any malignancy, including Post -Transplant Lymphoproliferative Disorder (PTLD). PTLD is a specific type of malignancy that can occur following transplantation of a solid organ and is characterized by a proliferation of B cells, which may result in lymphoma.
Time frame: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion
Population: All participants who initiated immunosuppression withdrawal. Since both groups initiated immunosuppression withdrawal, the participants who received darTregs were combined with the participants who did not receive the darTreg infusion to form the pre-defined group for assessment of this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Number of Participants With Any Malignancy | 0 Participants |
Primary
Number of Participants With Study Defined Grade 3 or Higher Infections
The following grading system was applied 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 A participant was considered to have met this endpoint if they experienced at least one Grade 3 or higher infection.
Time frame: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion
Population: All participants who initiated immunosuppression withdrawal. Since both groups initiated immunosuppression withdrawal, the participants who received darTregs were combined with the participants who did not receive the darTreg infusion to form the pre-defined group for assessment of this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Number of Participants With Study Defined Grade 3 or Higher Infections | 0 Participants |
Primary
Proportion of Liver Transplant Recipients Who Are Able to Reduce Calcineurin Inhibitor Dosing by 75 Percent and Discontinue a Second Immunosuppression Drug (if Applicable) With Stable Liver Function Tests (LFTs) for ≥ 12 Weeks
The ability to reduce baseline, standard of care calcineurin inhibitor dosing following transplantation was measured by determining the number of subjects who were able to tolerate a 75 percent reduction in their calcineurin inhibitors along with discontinuation of either prednisone or mycophenolate mofetil following initiation of immunosuppression withdrawal.
Time frame: From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion
Population: All participants who initiated immunosuppression withdrawal. Since both groups initiated immunosuppression withdrawal, the participants who received darTregs were combined with the participants who did not receive the darTreg infusion to form the pre-defined group for assessment of this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Proportion of Liver Transplant Recipients Who Are Able to Reduce Calcineurin Inhibitor Dosing by 75 Percent and Discontinue a Second Immunosuppression Drug (if Applicable) With Stable Liver Function Tests (LFTs) for ≥ 12 Weeks | 0.20 Proportion of Participants |
Secondary
Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection
Participants are counted in each grade of rejection they experienced; however, a participant is only counted once within a specific grade. Biopsy proven acute rejection and Chronic rejection were graded based on local pathology according to the Banff (1997 for Acute Rejection; 2000 for Chronic Rejection) global assessment criteria as outlined below. Biopsy proven acute rejection was assessed as Grade I or higher using the following grades: * Indeterminate * Grade I Mild Acute Rejection * Grade II Moderate Acute Rejection * Grade III Severe Acute Rejection. Chronic rejection was determined by the presence of abnormal total and direct bilirubin in the conjunction with liver pathology fulfilling the Banff criteria as outlined: * Early Stage Chronic Rejection * Late Stage Chronic Rejection.
Time frame: From initiation of immunosuppression withdrawal to 52 weeks after darTregs infusion
Population: All participants who initiated immunosuppression withdrawal. Since both groups initiated immunosuppression withdrawal, the participants who received darTregs were combined with the participants who did not receive the darTreg infusion to form the pre-defined group for assessment of this outcome.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection | Mild Acute Rejection | 2 Participants |
| Initiated Immunosuppression Withdrawal, Received darTregs | Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection | Moderate Acute Rejection | 0 Participants |
| Initiated Immunosuppression Withdrawal, Received darTregs | Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection | Severe Acute Rejection | 0 Participants |
| Initiated Immunosuppression Withdrawal, Received darTregs | Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection | Early Stage Chronic Rejection | 0 Participants |
| Initiated Immunosuppression Withdrawal, Received darTregs | Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection | Late Stage Chronic Rejection | 0 Participants |
Secondary
Number of Liver Transplant Recipients Who Experience the Composite Outcome
This measure includes refractory acute rejection, chronic rejection, re-transplantation, and death. Rejection was diagnosed based on local pathology. Participants are considered to have met this endpoint if they experience any one of these events at least once.
Time frame: From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion
Population: All participants who initiated immunosuppression withdrawal. Since both groups initiated immunosuppression withdrawal, the participants who received darTregs were combined with the participants who did not receive the darTreg infusion to form the pre-defined group for assessment of this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Number of Liver Transplant Recipients Who Experience the Composite Outcome | 0 Participants |
Secondary
Number of Participants Achieving Efficacy Status Post Receipt of a Single Intravenous (IV) Dose of Donor Alloantigen Reactive Regulatory T Cells (darTregs)
Efficacy was assessed by determining the number (and percentage) of participants who have received darTreg 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.
Time frame: From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion
Population: Participants who initiated immunosuppression withdrawal and received darTregs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Number of Participants Achieving Efficacy Status Post Receipt of a Single Intravenous (IV) Dose of Donor Alloantigen Reactive Regulatory T Cells (darTregs) | 0 Participants |
Secondary
Number of Participants Who Experience at Least One Episode of Biopsy Proven Acute Rejection, Clinical Acute Rejection, or Chronic Rejection
A participant was considered to have met this endpoint if they experienced at least one episode of biopsy proven acute rejection, clinical acute rejection, or chronic rejection based on local pathology. Biopsy proven acute rejection was assessed as Grade I or higher based on the Banff (1997) global criteria featuring the following grades: * Indeterminate * Grade I Mild Acute Rejection * Grade II Moderate Acute Rejection * Grade III Severe Acute Rejection. Clinical AR was determined based on the participant receiving treatment for rejection with or without biopsy confirmation of rejection. Chronic rejection was determined by the presence of abnormal total and direct bilirubin in the conjunction with liver pathology fulfilling the Banff (2000) criteria as outlined: * Early Stage Chronic Rejection * Late Stage Chronic Rejection.
Time frame: From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion
Population: All participants who initiated immunosuppression withdrawal. Since both groups initiated immunosuppression withdrawal, the participants who received darTregs were combined with the participants who did not receive the darTreg infusion to form the pre-defined group for assessment of this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Initiated Immunosuppression Withdrawal, Received darTregs | Number of Participants Who Experience at Least One Episode of Biopsy Proven Acute Rejection, Clinical Acute Rejection, or Chronic Rejection | 5 Participants |