SRL (Sirolimus) Withdrawal
Condition: Acute Rejection of Liver Transplant; Effects of Immunosuppressant Therapy
Study type: Interventional

Summary: 
      The significance of this clinical trial lies in its potential to increase the success of
      immunosuppression (IS) therapy withdrawal in liver transplant (LT) recipients, thus
      decreasing the negative impact of IS on their long-term outcomes. Lifetime immunosuppression
      (IS) with standard agents, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus
      (TAC), is currently required at clinically recommended doses and trough levels to prevent
      allograft rejection. However, this occurs at the significant expense of long-term CNI
      toxicity, i.e. chronic kidney disease (CKD), hypertension, hyperlipidemia, diabetes,
      infections and malignancy. With improvements in early graft and patient survival, long term
      adverse IS effects have become increasingly important in this rapidly expanding patient
      population. The strategies to reduce long term CNI toxicity include dose minimization that
      still leaves patients on CNI therapy, conversion to non-CNI therapy, or even complete IS
      withdrawal. The second approach, conversion to non-CNI IS therapy, is attractive in the
      potential to stabilize or improve renal function and other CNI toxicities. One such
      non-nephrotoxic IS agent, the mammalian target of rapamycin inhibitor (mTOR-I) SRL, has a
      different mechanism of IS action and studies have shown that CNI to SRL conversion can
      stabilize renal dysfunction with a low risk of rejection. Yet even with these possible
      benefits, patients on SRL are still subject to lifetime IS therapy with side effects and
      costs, highlighting the need to investigate the strategies that promote full IS withdrawal
      without rejection (3rd approach), also known as 'operational tolerance'.
    

Detailed description: 
      Study Overview The study proposed is a prospective trial of controlled SRL monotherapy
      minimization and withdrawal in up to 25 stable non-immune non-viremic LT recipients. Given
      the sample size calculations (see Statistical section), we plan to enroll up to 25 SRL
      monotherapy patients for this study (Figure 1). All patients will be consented to undergo
      laboratory evaluation as well as an enrollment liver biopsy and blood tests. If the patient
      meets inclusion/exclusion (I/E) criteria (see below), SRL will be minimized over 6 months
      until once a week dosing is achieved. Repeat clinical and immunological blood tests as above
      will be performed, and if no biochemical signs of rejection, SRL will be discontinued with
      blood tests and liver biopsy 12 months later for similar biochemical, histological and
      immunological measures. At any concern for rejection, liver biopsy and assays for equivalent
      biochemical, histological and immunological measures will be performed and if rejection is
      diagnosed on biopsy, a second attempt at withdrawal will not be performed. Patients will be
      monitored as standard of care with clinic visits every 6 months and laboratory tests every 2
      weeks. The total study length will be 18 months: 6 month minimization phase and 1 year
      follow-up after withdrawal success/failure. The primary outcome will be the proportion of
      tolerant patients off SRL therapy with normal liver biochemistry and graft histology at 18
      months. Secondary outcomes will include the incidence, severity and reversibility of
      rejection, patient/graft survival, resolution of SRL and other non-specific IS effects, and
      the assessment of clinical/immunological biomarkers of tolerance. All continuous/categorical
      clinical variables will be compared with the appropriate statistical analyses.The goal is
      that the primary and secondary aims will provide valuable preliminary data to further
      elucidate the mechanisms of mTOR-I immunoregulation and for determining the initial clinical
      success/feasibility of the mTOR-I approach (vs. historical 20% CNI withdrawal success seen in
      studies from the Immune Tolerance Network [ITN] and other groups). This is all so as to guide
      a submission to the Immune Tolerance Network for larger, more adequately powered prospective
      trials comparing SRL vs. CNI withdrawal and accompanying biomarker predictors of tolerance.
      If this pilot study fails to show a correlation between our biomarkers and the
      success/failure of SRL withdrawal, or is associated with an unacceptable low (e.g. <20%) rate
      of operational tolerance, then this would avoid the necessity for such large, expensive
      trials and support the continued development of alternative approaches to tolerance.

      Consent and Initial Phase of Enrollment (see Study Protocol Figure- Appendix A) These liver
      transplant candidates (up to 25 SRL) will be approached for consideration and informed
      consent into the study. The consent form will include discussion of the risks/benefits of
      their current therapy (SRL) and the planned minimization/withdrawal. Specifically, the risks
      of minimization/withdrawal (i.e. developing acute or chronic rejection, alloimmune hepatitis
      during any portion of the study), although unlikely, will be a major emphasis of the consent
      process. The consent form will also include the strict requirement for patients to follow all
      instructions from the PI in regard to the close laboratory follow-up occurring throughout the
      trial, to diagnose any episode of rejection or concern as early as possible to be able to
      respond appropriately. All of the study procedures will be discussed with the patient during
      clinic visits. They will be informed that neither participation nor refusal will influence
      their clinical care. All laboratory tests or costs related to their care in the study, with
      the exception of non-standard of care items (i.e. liver biopsies, blood assays), will be the
      responsibility of the patient and/or his/her insurance company. They will be asked questions
      afterwards to verify comprehension and then sign the consent form documenting their agreement
      to participate. A signed copy of the consent form will be given to them. Participation is
      completely voluntary and they may discontinue participation the study at any time without
      affecting their care or participation in any other study. No financial compensation will be
      given.

      Screening Evaluation at Enrollment (see Study Protocol Figure) After long term (> 3 years
      post-LT, > 3 months on SRL monotherapy) on SRL monotherapy, inclusion/exclusion criteria will
      be reviewed and if appropriate, consent as above will be obtained. If the patient agrees and
      signs consent, baseline standard of care screening laboratories complete blood count,
      comprehensive metabolic panel, sirolimus (CBC, CMP, SRL trough level, fasting lipid profile,
      hemoglobin A1C [HbA1C], urine protein/creatinine ratio) and non-standard of care biomarker
      assays (blood immunophenotyping, proteogenomics) and liver biopsy (histology and graft
      immunohistochemistry) will be performed as dictated by the protocol. In addition, the liver
      biopsy will be used to determine stability in graft function (i.e. no evidence of rejection
      or immune-mediated hepatitis) before considering minimization/withdrawal. SRL
      minimization/withdrawal will only be performed if clinically, biochemically and
      histologically [by biopsy; liver transplant pathology read (Yang, Rao)] stable. Throughout
      the entire study, liver function tests will be monitored every 2 weeks (monthly is standard
      of care, so the interim non-standard of care 2 week blood tests will be covered by the study
      funds). Patients entering the minimization/withdrawal phases will be reduced by a total dose
      of 50% of their baseline dose every month until patients are on 0.5 mg SRL daily. At this
      point, every other day dosing will begin x 1 month. If no LFT abnormalities, twice weekly
      dosing x 1 month, then once a week dosing x 1 month. Prior to complete discontinuation,
      repeat clinical (screening labs above) and blood biomarker assays (blood immunophenotyping,
      proteogenomics) will be performed. Liver biopsy will not be performed at this juncture unless
      there are biochemical signs of liver injury. If complete withdrawal is deemed safe (no
      evidence of biochemical abnormalities) patients will be withdrawn completely (i.e. the
      once/week SRL dose discontinued) and followed off IS therapy for one year. In this time
      period, liver function tests will be monitored every 2 weeks, as usual, and repeat clinical
      (screening labs above), liver biopsy and blood (blood immunophenotyping, proteogenomics)
      assays performed at the end of this year or at any concern for rejection.

      Blood and Tissue Samples Standard of care laboratories (CBC, CMP) will be performed every
      month on all patients, and only LFTs performed in the interim 2 weeks between each month
      (non-standard of care; covered by the study funds) until complete withdrawal. 3 green top 5
      mL and 3 red top 5 mL tubes of blood for biomarker assays will be taken on all patients prior
      to study enrollment, prior to complete withdrawal, and one year after withdrawal or at the
      time of suspected rejection. Liver biopsy (one 3 cm biopsy- 2 cm for histology and 1 cm for
      genomic assays) will be performed at baseline (pre-minimization) and 1 year post withdrawal.
      A separate clinical informed consent will be obtained each time a liver biopsy is performed.
      If the patient develops elevation in liver transaminases requiring a liver biopsy at any
      stage of the study protocol, blood (all for immune monitoring (IM) assays) will be requested
      from the patient at the time of the biopsy. If rejection occurs, the patient will be followed
      in the study until completion but not be further withdrawn from SRL or have a liver biopsy at
      the end of the study

      Follow-up Laboratory follow-up is described above- every 2 weeks throughout the trial until
      complete withdrawal. Any biochemical (or clinical) signs or significant liver function test
      abnormalities will be acted on immediately either by liver biopsy or a pause in IS withdrawal
      per investigator discretion. All patients will be seen in the clinic every 3 months to assess
      for any new signs or symptoms or resolution of drug side effects in the minimization or
      withdrawal arm. Quality of life questionnaires; Post Liver Transplant Quality of Life
      Instrument (pLTQ) and the Promis-29 profile v1.0 will be administered at the study onset and
      after successful vs. unsuccessful withdrawal (end of study)

      Outcome Measures 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.
      This rate will be a composite of the cumulative number of biopsy-proven graft dysfunctions
      requiring conversion back to SRL or additional IS therapy or discontinuation of
      minimization/withdrawal that occur during the course of the study. 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. Clinical secondary outcomes will be compared: the number of
      infectious complications, liver biopsy complications, cardiovascular outcomes (i.e. blood
      pressure, diabetes control, lipid levels), renal function, hematopoietic parameters,
      gastrointestinal effects, or other side effects of SRL that may or may not improve or develop
      with minimization/withdrawal. These will all be documented by a study database during patient
      visits, electronic charts and/or by phone communication. Finally, quality of life (Post Liver
      Transplant Quality of Life Instrument (pLTQ) and the Promis-29 profile v1.0) will be analyzed
      at the end of the study to determine the effect of IS minimization/withdrawal on other health
      benefits.
    

Intervention name(s): Sirolimus
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): Withdrawal from Immunosuppressant Therapy; Minimization of Immunosuppressant Therapy
Intervention MeSH terms: Sirolimus; Immunosuppressive Agents
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Liver Transplant; Sirolimus; Rapamune; Immunosuppressant Therapy; Withdrawal