Trial Outcomes & Findings for SRL (Sirolimus) Withdrawal (NCT NCT02062944)

Results Overview

The primary outcome will be the proportion of patients off SRL therapy with normal liver biochemistry and graft histology at 12 months (i.e. tolerant). Thus, the incidence of graft dysfunction (acute rejection, immune mediated or autoimmune hepatitis, chronic rejection) or non-tolerance will be assessed in this SRL withdrawal group and compared to the historical CNI group (20% tolerant; 80% failure) as the primary endpoint.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

21 participants

Primary outcome timeframe

12 months

Results posted on

2022-07-14

Participant Flow

To identify our cohort, we screened our database for all living LTRs transplanted at Northwestern (1995-2012) who met the following inclusion criteria: (1) adult LTR ≥18 years of age, (2) ≥3 months of SRL monotherapy with trough levels of 3-8 ng/mL, and (3) ≥3 years post-LT (primary living or deceased donor).

Baseline physical examination and laboratory tests were performed, and if acceptable per the criteria above, a baseline liver biopsy was performed within 1 month. Patients were excluded from IS withdrawal if any of the following were present on local biopsy read: (1) ≥grade 2 inflammation or stage 2 fibrosis, (2) acute or chronic rejection, (3) de novo autoimmune hepatitis, (4) inflammation of \> 50% of portal tracts, and (5) other pathology not specified but deemed high risk per the pathologist.

Participant milestones

Participant milestones
Measure	Single-arm Study Sirolimus Withdrawal Sirolimus: SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Overall Study STARTED	21
Overall Study COMPLETED	15
Overall Study NOT COMPLETED	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Single-arm Study Sirolimus Withdrawal Sirolimus: SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Overall Study Lost to Follow-up	1
Overall Study New hemotological disorder identified	1
Overall Study Uncontrolled Hypertension	1
Overall Study underwent pre-weaning biospsy and excluded for mild subclinical ACR	3

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Single-arm Study Sirolimus Withdrawal n=15 Participants Sirolimus: SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Age, Categorical <=18 years	0 Participants n=15 Participants
Age, Categorical Between 18 and 65 years	11 Participants n=15 Participants
Age, Categorical >=65 years	4 Participants n=15 Participants
Sex: Female, Male Female	4 Participants n=15 Participants
Sex: Female, Male Male	11 Participants n=15 Participants

PRIMARY outcome

Timeframe: 12 months

The primary outcome will be the proportion of patients off SRL therapy with normal liver biochemistry and graft histology at 12 months (i.e. tolerant). Thus, the incidence of graft dysfunction (acute rejection, immune mediated or autoimmune hepatitis, chronic rejection) or non-tolerance will be assessed in this SRL withdrawal group and compared to the historical CNI group (20% tolerant; 80% failure) as the primary endpoint.

Outcome measures

Outcome measures
Measure	Single-arm Study Sirolimus Withdrawal n=15 Participants SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months. Sirolimus: SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Proportion of Tolerant Patients Off SRL Therapy With Normal Liver Biochemistry and Graft Histology at 12 Months	8 Participants

SECONDARY outcome

Timeframe: 12 months

Major secondary measures compared will be the predictive capacity of the blood and graft biomarker assays (immunophenotyping, genomic/proteomics) before and after minimization/withdrawal in the success vs. failure groups.

Outcome measures

Outcome measures
Measure	Single-arm Study Sirolimus Withdrawal n=15 Participants SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months. Sirolimus: SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Number of Subjects With TCMR Rejection	6 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months

patient did not have rejection during withdrawal but was withdrawn from the trial due to an unexpected adrenal metastasis of hepatocellular carcinoma.

Outcome measures

Outcome measures
Measure	Single-arm Study Sirolimus Withdrawal n=15 Participants SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months. Sirolimus: SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Number of Participants Resumed SRL After Minimization	1 Participants

Adverse Events

Single-arm Study Sirolimus Withdrawal

Serious events: 2 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Single-arm Study Sirolimus Withdrawal n=15 participants at risk SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months. Sirolimus: SRL minimization will be performed if clinically, biochemically and histologically stable. Patients entering the minimization phases will be reduced every month by 50% of total dose of Sirolimus until they reach .5mg daily for one month. Then .5 mg every other day, then twice weekly, the once weekly dosing. This should take approximately 6 month to complete minimization. Liver function tests will be monitored every 2 weeks. For any patient developing liver dysfunction, liver biopsy will be performed. Patients will then be completely withdrawn and followed post-withdrawal for 12 months.
Hepatobiliary disorders biopsy-proven mild rejection	6.7% 1/15 • Number of events 1 • 12 months
Hepatobiliary disorders Stool in blood after biopsy	6.7% 1/15 • Number of events 1 • 12 months

Other adverse events

Adverse event data not reported

Additional Information

Josh Levitsky

Northwestern University

Phone: 312 695 4413

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place