Immunosuppression, Liver Transplantation, Liver Transplant Recipients
Conditions
Keywords
liver transplant, allograft function, anti-rejection, immunosuppression withdrawal, tolerance
Brief summary
The primary objective of this study is to assess the efficacy of immunosuppression withdrawal (ISW) in pediatric liver transplant (tx) recipients.
Detailed description
Anti-rejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent rejection of the new organ. Long-term use of these medicines places transplant recipients at higher risk of serious infections and certain types of cancer. This study seeks to: * Find out if it is safe to slowly reduce and then completely stop the immunosuppression taken by children who have received liver transplants. This process is called 'immunosuppression withdrawal'or ISW. * Find blood or liver biopsy tests that can help transplant doctors in the future to predict if it is safe to decrease or stop immunosuppression drugs in children who have had a liver transplant.
Interventions
Participants will undergo gradual ISW in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants will be followed for 48 months ensuring a minimum of 36 months of follow-up after successful ISW.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Immune Tolerance Network (ITN)
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
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
* Subject and/or parent guardian must be able to understand and provide informed consent; * Is the recipient of a living or deceased donor liver tx when subject was less than or equal to 6 years of age; * Is at least 4 years post-tx at the time of study enrollment; * Has normal allograft function defined as Alanine aminotransferase (ALT) \< 50 IU/l and gamma-glutamyl transferase (GGT) \< 50 IU/l; * Has no evidence of acute rejection (AR) or chronic rejection (CR) within the past 2 years, based on medical history; * Is stable on IS monotherapy with a calcineurin inhibitor (CNI); * For female subjects of childbearing potential, subject must have a negative pregnancy test upon study entry; * For female and male subjects with reproductive potential, subject must agree to use FDA approved methods of birth control for the duration of the study; * Must be negative for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection within one year of enrollment; * Must have screening biopsy that fulfills, based on central pathology reading, the following criteria: * Portal inflammation and interface activity: Preferably absent, but minimal to focal mild portal mononuclear inflammation may be present. Interface necro-inflammatory activity is absent or equivocal/minimal and, if present, involves a minority of portal tracts. * Centrizonal/peri-venular inflammation: Preferably absent, but minimal to focal mild perivenular mononuclear inflammation may be present. Perivenular necro-inflammatory activity is absent or equivocal/minimal and, if present, involves a minority of terminal hepatic venules. * Bile duct changes: No lymphocytic bile duct damage, ductopenia and biliary epithelial senescence changes, unless there is an alternative, non-immunologic explanation (e.g. biliary strictures). * Fibrosis: \< Ishak Stage 3 (i.e. not more than occasional portal-to-portal bridging). Perivenular fibrosis should be less than moderate, according to Banff Criteria. * Arteries: Negative for obliterative or foam cell arteriopathy.
Exclusion criteria
* Have received a liver tx for autoimmune liver disease, including autoimmune hepatitis or primary sclerosing cholangitis; * Have received a liver tx for hepatitis B or hepatitis C; * Have received a second organ transplant before, simultaneously, or after liver tx; * Have a calculated glomerular filtration rate (modified Schwartz formula) of less than 60 mL/min/1.73 m\^2; * Have had a 50 percent (%) dose increase in CNI within 6 months of screening; * Have discontinued a second IS agent within 12 months of screening; * Have any systemic illness requiring or likely to require chronic or recurrent use of IS; * Is pregnant or breastfeeding; * Is unwilling or unable to adhere with study requirements and procedures; * Have mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements; * Is unwilling or unable to provide consent or comply with the study protocol; * Has used investigational drugs within 4 weeks of enrollment; * Is receiving treatment for HIV infection; * Has received any licensed or investigational live attenuated vaccine(s) within two months of enrollment; * Has any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Operationally Tolerant Participants | 12 Months after complete immunosuppression withdrawal | Number of participants that are operationally tolerant, defined as those who successfully withdraw from immunosuppression and maintain normal allograft status as assessed by liver biopsy and liver tests 12 months after complete immunosuppression withdrawal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Increased Immunosuppression or Re-Initiation of Immunosuppression | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | The median time (in days) from start of withdrawal from immunosuppression drugs to increasing or re-starting immunosuppression. |
| Time to Resolution of Rejection | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | The median time (in weeks) from biopsy proven rejection to resolution of rejection defined as both liver function tests Alanine Aminotransferase (ALT) and Gamma-Glutamyl Transferase (GGT) returning to ≤ 1.5 the baseline values. |
| Number and Severity of Biopsies Read as Histologic Acute Rejection | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | Number of biopsies that were diagnosed as histologic acute rejection in participants who initiated immunosuppression withdrawal by severity of rejection episode. Rejection severity (mild, moderate, severe) is based on the Banff global assessment grade according to the central pathology reading of the liver biopsy. Mild severity criteria: rejection infiltrate in a minority of triads that is generally mild and confined within the portal spaces. Moderate rejection criteria: rejection infiltrate expanding most or all of the triads. Severe rejection criteria: rejection infiltrate expanding most or all of the triads with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis. BPAR: biopsy-proven acute rejection. |
| Clinical Severity of Acute Rejection | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | The clinical severity of acute rejection was descriptively analyzed using hierarchical categories, as follows: * Dose increase: Increase in IS dose and/or frequency but to a level less than the regimen at study entry, prior to initiating ISW * Reinstitution: Returning to the regimen at study entry, prior to ISW * Intensification: Increased IS dose compared with the dose at study entry, prior to ISW * Conversion: Change to different IS drug * Addition: Initiation of a second IS drug; * Corticosteroids: Administration of any intravenous or oral corticosteroids * Antibody (Ab) treatment: Administration of any rabbit thymoglobulin; usually with corticosteroids |
| Reason for Discontinuation of Withdrawal | Time from start of immunosuppression withdrawal through discontinuation of withdrawal, a maximum of 52 weeks | Reasons participants discontinued immunosuppression withdrawal, such as Biopsy Proven Acute Rejection, Chronic Rejection, Clinical Rejection, Death, Pregnancy, etc.). Only the root cause for discontinuation for each subject is presented in these results if multiple events led to discontinuation of immunosuppression withdrawal. |
| Number of Participants With Clinical Complications Usually Attributed to Immunosuppression | Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up | This composite endpoint is comprised of clinical complications related to immunosuppression withdrawal and is defined as the occurrence of any of the following: death or graft loss, histologic evidence of refractory acute rejection or biopsy confirmed chronic rejection (CR). |
| Duration of Operational Tolerance | Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up | Median participant duration of operational tolerance. Duration of operational tolerance is defined as the number of days that participants are not taking immunosuppression medications. |
| Change in Immunosuppression Medication (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure | Time from starting immunosuppression withdrawal until immunosuppression withdrawal failure, maximum 52 weeks | The mean percent of immunosuppression (IS) dose reduction from baseline to the time of immunosuppression withdrawal failure. Immunosuppression withdrawal failure is defined as any incidence of increasing immunosuppression medications instead of completing withdrawal. |
| Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | Change of immunosuppression (IS) dose from baseline to end of study for all participants not deemed tolerant by the trial definition either due to discontinuing IS withdrawal or completing withdrawal but not meeting the criteria for tolerance on the primary endpoint biopsy assessment. |
| Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up | Health related quality of life was measured by the PedsQL 4.0 Generic Core scale, the Multidimensional Fatigue scale, and the PedsQL 3.0 Transplant module. Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and at month 36 for the total generic score, the total fatigue score, and total transplant score. This change was calculated separately for tolerant and non-tolerant subjects. Each score ranges from 0-100, with a higher score indicating a better quality of life. |
| Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology | Time from screening biopsy to end of study (month 48) biopsy | The impact of ISW on allograft fibrosis using the Ishak scoring system to measure the change in fibrosis from the screening liver biopsy to the end-of-study (month-48) liver biopsy. In the Ishak histologic scoring system, the higher the score/stage, the more fibrosis: Scores range from 0 to 6, with 6 representing the most fibrosis: 0=No fibrosis; 1=Fibrous expansion of some portal areas, with or without short fibrous septa; 2=Fibrous expansion of most portal areas, with or without short fibrous septa; 3=Fibrous expansion of most portal areas, with occasional portal to portal bridging; 4=Fibrous expansion of portal areas with marked bridging (portal to portal) as well as portal to central; 5=Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis); and 6=Cirrhosis, probable or definite. Decrease in score from screening (baseline) indicates improvement |
Countries
Canada, United States
Participant flow
Recruitment details
161 participants were enrolled (11 sites in the US,1 site in Canada) between August 2012 and April 2014. N=88 of the enrolled participants were eligible to initiate immunosuppression withdrawal (ISW) and the remaining N=73 participants were terminated (e.g., ineligible to proceed with ISW) based on biopsy findings or other pre-specified criteria.
Pre-assignment details
Informed consent was obtained from eligible individuals who then underwent a study-mandated biopsy to determine if they were eligible to initiate immunosuppression withdrawal, based on pre-specified histologic and other criteria.
Participants by arm
| Arm | Count |
|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) Pediatric liver transplant recipients with stable liver tests (ALT and GGT), no evidence of rejection in the preceding 2 years, and at least 4 years post-transplant, and a qualifying liver biopsy at screening underwent gradual Immunosuppression withdrawal in no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants were followed for 48 months ensuring a minimum of 36 months of follow-up after successful Immunosuppression withdrawal. | 88 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Subject declined to travel for biopsy | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Participants That Initiated Immunosuppression Withdrawal (ISW) |
|---|---|
| Age, Categorical <=18 years | 88 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 10.4 years STANDARD_DEVIATION 3.4 |
| Entry Calcineurin Inhibitor (CNI) Daily Dose Cyclosporine | 65.7 mg STANDARD_DEVIATION 22.99 |
| Entry Calcineurin Inhibitor (CNI) Daily Dose Tacrolimus | 2.1 mg STANDARD_DEVIATION 1.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 76 Participants |
| Region of Enrollment Canada | 6 participants |
| Region of Enrollment United States | 82 participants |
| Screening Biopsy Ishak Stage 0 | 19 Participants |
| Screening Biopsy Ishak Stage 1 | 57 Participants |
| Screening Biopsy Ishak Stage 2 | 12 Participants |
| Screening Child Health Related Quality of Life Scores on a Scale All Participants - Total Fatigue Score | 74.9 Quality of Life Scores on a Scale STANDARD_DEVIATION 17.75 |
| Screening Child Health Related Quality of Life Scores on a Scale All Participants - Total Generic Score | 80.7 Quality of Life Scores on a Scale STANDARD_DEVIATION 13.69 |
| Screening Child Health Related Quality of Life Scores on a Scale All Participants - Total Transplant Score | 85.6 Quality of Life Scores on a Scale STANDARD_DEVIATION 9.54 |
| Screening Child Health Related Quality of Life Scores on a Scale Non-Tolerant Participants - Total Fatigue Score | 74.5 Quality of Life Scores on a Scale STANDARD_DEVIATION 18.94 |
| Screening Child Health Related Quality of Life Scores on a Scale Non-Tolerant Participants - Total Generic Score | 80.6 Quality of Life Scores on a Scale STANDARD_DEVIATION 13.26 |
| Screening Child Health Related Quality of Life Scores on a Scale Non-Tolerant Participants - Total Transplant Score | 85.4 Quality of Life Scores on a Scale STANDARD_DEVIATION 9.27 |
| Screening Child Health Related Quality of Life Scores on a Scale Tolerant Participants - Total Fatigue Score | 75.6 Quality of Life Scores on a Scale STANDARD_DEVIATION 15.82 |
| Screening Child Health Related Quality of Life Scores on a Scale Tolerant Participants - Total Generic Score | 80.7 Quality of Life Scores on a Scale STANDARD_DEVIATION 14.59 |
| Screening Child Health Related Quality of Life Scores on a Scale Tolerant Participants - Total Transplant Score | 86.0 Quality of Life Scores on a Scale STANDARD_DEVIATION 10.16 |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 161 |
| other Total, other adverse events | 87 / 161 |
| serious Total, serious adverse events | 23 / 161 |
Outcome results
Primary
Number of Operationally Tolerant Participants
Number of participants that are operationally tolerant, defined as those who successfully withdraw from immunosuppression and maintain normal allograft status as assessed by liver biopsy and liver tests 12 months after complete immunosuppression withdrawal.
Time frame: 12 Months after complete immunosuppression withdrawal
Population: Intent-to-Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Number of Operationally Tolerant Participants | 33 Participants |
Secondary
Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects
Health related quality of life was measured by the PedsQL 4.0 Generic Core scale, the Multidimensional Fatigue scale, and the PedsQL 3.0 Transplant module. Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and at month 36 for the total generic score, the total fatigue score, and total transplant score. This change was calculated separately for tolerant and non-tolerant subjects. Each score ranges from 0-100, with a higher score indicating a better quality of life.
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
Population: Intent-to-Treat
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | Total Generic Score | 3.4 Quality of Life Scores on a Scale |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | Total Fatigue Score | 5.0 Quality of Life Scores on a Scale |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | Total Transplant Score | 5.7 Quality of Life Scores on a Scale |
| Participants Who Were Not Operationally Tolerant | Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | Total Generic Score | 1.2 Quality of Life Scores on a Scale |
| Participants Who Were Not Operationally Tolerant | Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | Total Fatigue Score | 2.0 Quality of Life Scores on a Scale |
| Participants Who Were Not Operationally Tolerant | Change in Child Health Related Quality of Life Scores Between Tolerant and Non-tolerant Subjects | Total Transplant Score | 0.9 Quality of Life Scores on a Scale |
Secondary
Change in Immunosuppression Medication (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure
The mean percent of immunosuppression (IS) dose reduction from baseline to the time of immunosuppression withdrawal failure. Immunosuppression withdrawal failure is defined as any incidence of increasing immunosuppression medications instead of completing withdrawal.
Time frame: Time from starting immunosuppression withdrawal until immunosuppression withdrawal failure, maximum 52 weeks
Population: Intent-to-Treat who failed immunosuppression withdrawal
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Change in Immunosuppression Medication (Calcineurin Inhibitor) Dose From Start of Immunosuppression Withdrawal to the Time of Immunosuppression Withdrawal Failure | -76.1 percentage of dose |
Secondary
Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study
Change of immunosuppression (IS) dose from baseline to end of study for all participants not deemed tolerant by the trial definition either due to discontinuing IS withdrawal or completing withdrawal but not meeting the criteria for tolerance on the primary endpoint biopsy assessment.
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
Population: Intent-to-Treat participants who were not operationally tolerant and who remained on the same medication throughout the study. Three subjects that were not operationally tolerant converted to alternate immunosuppression medications.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Change in Immunosuppression Medication Dose From Study Initiation of Withdrawal to the End of the Study | 0.4 percentage of dose |
Secondary
Clinical Severity of Acute Rejection
The clinical severity of acute rejection was descriptively analyzed using hierarchical categories, as follows: * Dose increase: Increase in IS dose and/or frequency but to a level less than the regimen at study entry, prior to initiating ISW * Reinstitution: Returning to the regimen at study entry, prior to ISW * Intensification: Increased IS dose compared with the dose at study entry, prior to ISW * Conversion: Change to different IS drug * Addition: Initiation of a second IS drug; * Corticosteroids: Administration of any intravenous or oral corticosteroids * Antibody (Ab) treatment: Administration of any rabbit thymoglobulin; usually with corticosteroids
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
Population: Participants who experienced rejection (biopsy-proven or clinical)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Clinical Severity of Acute Rejection | Dose increase | 0.068 Proportion |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Clinical Severity of Acute Rejection | Reinstitution | 0.261 Proportion |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Clinical Severity of Acute Rejection | Intensification | 0.227 Proportion |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Clinical Severity of Acute Rejection | Conversion | 0.011 Proportion |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Clinical Severity of Acute Rejection | Addition | 0.023 Proportion |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Clinical Severity of Acute Rejection | Corticosteroids | 0.364 Proportion |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Clinical Severity of Acute Rejection | Ab treatment | 0 Proportion |
Secondary
Duration of Operational Tolerance
Median participant duration of operational tolerance. Duration of operational tolerance is defined as the number of days that participants are not taking immunosuppression medications.
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up
Population: Participants that Completed Withdrawal and were Operationally Tolerant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Duration of Operational Tolerance | 1209.5 days |
Secondary
Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology
The impact of ISW on allograft fibrosis using the Ishak scoring system to measure the change in fibrosis from the screening liver biopsy to the end-of-study (month-48) liver biopsy. In the Ishak histologic scoring system, the higher the score/stage, the more fibrosis: Scores range from 0 to 6, with 6 representing the most fibrosis: 0=No fibrosis; 1=Fibrous expansion of some portal areas, with or without short fibrous septa; 2=Fibrous expansion of most portal areas, with or without short fibrous septa; 3=Fibrous expansion of most portal areas, with occasional portal to portal bridging; 4=Fibrous expansion of portal areas with marked bridging (portal to portal) as well as portal to central; 5=Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis); and 6=Cirrhosis, probable or definite. Decrease in score from screening (baseline) indicates improvement
Time frame: Time from screening biopsy to end of study (month 48) biopsy
Population: Intent-to-Treat~-Of the original 88 participants, 3 participants did not finish the study and 1 participant did not complete the final liver biopsy.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology | Ishak Score Change of -1 | 18 Participants |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology | Ishak Score Change of 0 | 43 Participants |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology | Ishak Score Change of 1 | 19 Participants |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology | Ishak Score Change of 2 | 3 Participants |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Impact of Immunosuppression Withdrawal (ISW) on Allograft Histology | Ishak Score Change of 3 | 1 Participants |
Secondary
Number and Severity of Biopsies Read as Histologic Acute Rejection
Number of biopsies that were diagnosed as histologic acute rejection in participants who initiated immunosuppression withdrawal by severity of rejection episode. Rejection severity (mild, moderate, severe) is based on the Banff global assessment grade according to the central pathology reading of the liver biopsy. Mild severity criteria: rejection infiltrate in a minority of triads that is generally mild and confined within the portal spaces. Moderate rejection criteria: rejection infiltrate expanding most or all of the triads. Severe rejection criteria: rejection infiltrate expanding most or all of the triads with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis. BPAR: biopsy-proven acute rejection.
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
Population: Intent-to-Treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Number and Severity of Biopsies Read as Histologic Acute Rejection | Mild | 43 Biopsies Diagnosed as BPAR |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Number and Severity of Biopsies Read as Histologic Acute Rejection | Moderate | 7 Biopsies Diagnosed as BPAR |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Number and Severity of Biopsies Read as Histologic Acute Rejection | Severe | 0 Biopsies Diagnosed as BPAR |
Secondary
Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
This composite endpoint is comprised of clinical complications related to immunosuppression withdrawal and is defined as the occurrence of any of the following: death or graft loss, histologic evidence of refractory acute rejection or biopsy confirmed chronic rejection (CR).
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and a maximum of 48 months of follow-up
Population: Intent-to-Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Number of Participants With Clinical Complications Usually Attributed to Immunosuppression | 0 Participants |
Secondary
Reason for Discontinuation of Withdrawal
Reasons participants discontinued immunosuppression withdrawal, such as Biopsy Proven Acute Rejection, Chronic Rejection, Clinical Rejection, Death, Pregnancy, etc.). Only the root cause for discontinuation for each subject is presented in these results if multiple events led to discontinuation of immunosuppression withdrawal.
Time frame: Time from start of immunosuppression withdrawal through discontinuation of withdrawal, a maximum of 52 weeks
Population: Participants who failed immunosuppression withdrawal.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Reason for Discontinuation of Withdrawal | Biopsy Proven Acute Rejection | 30 Participants |
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Reason for Discontinuation of Withdrawal | Clinical Rejection | 3 Participants |
Secondary
Time to Increased Immunosuppression or Re-Initiation of Immunosuppression
The median time (in days) from start of withdrawal from immunosuppression drugs to increasing or re-starting immunosuppression.
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
Population: Participants that either restarted immunosuppression or increased their dose of immunosuppression
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Time to Increased Immunosuppression or Re-Initiation of Immunosuppression | 204 days |
Secondary
Time to Resolution of Rejection
The median time (in weeks) from biopsy proven rejection to resolution of rejection defined as both liver function tests Alanine Aminotransferase (ALT) and Gamma-Glutamyl Transferase (GGT) returning to ≤ 1.5 the baseline values.
Time frame: Time from immunosuppression withdrawal through a minimum of 36 months and maximum of 48 months of follow-up
Population: Intent-to-Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants That Initiated Immunosuppression Withdrawal (ISW) | Time to Resolution of Rejection | 13 Weeks |