Budesonide for Liver Transplant Immune Suppression
Condition: Acute Cellular Graft Rejection; New Onset Diabetes After Transplant
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a pilot study that investigates the efficacy and safety of budesonide as an immune
      suppressing agent for liver transplant recipients in the early post-transplant period.

      The primary end-point is rates of acute cellular rejection within first 24 weeks post-liver
      transplant. Secondary end points include rates of new onset diabetes after transplant and
      safety of budesonide.

      The study is structured as a prospective clinical trial. After receiving 4 days of
      intravenous corticosteroids on liver transplant post-operative days 0 through 3, subjects
      will be started on standard immunosuppression plus enteric coated budesonide (study drug) in
      place of standard immune suppression plus prednisone (standard of care). Study drug will be
      tapered over 12 weeks in accordance with the existing standard of care immune suppression
      protocol. Subjects will be followed in outpatient transplant clinic for 24 weeks. The purpose
      of the study is to conduct a pilot study to generate rates and effect size that can be used
      in a subsequent equivalent trial. A total of 20 subjects will be enrolled to receive the
      standard immunosuppression plus budesonide and their outcomes will be compared to 20 controls
      receiving standard immunosuppression plus prednisone (standard of care). The use of controls
      is to generate rate and variability that can be compared with the rate obtained from patients
      that receive study drug by examining the 95% confidence band.
    

Detailed description: 
      Enrollment of Subjects: All consecutive patients undergoing liver transplant (LT) at the
      University Of Cincinnati Transplant Center will be screened for enrollment upon admission for
      transplant surgery. Subjects will be approached after permission from attending on record by
      one of the members of research team. Study rationale, procedures, different interventions,
      potential benefits and risks as well as alternatives to study participation will be explained
      to the subjects in their native language in non-medical terms, as much possible. For
      non-English speakers, certified interpreter services will be used. Subjects meeting all of
      the inclusion and none of the exclusion criteria will be educated about the study and written
      informed consent will be obtained either 12 hours prior to undergoing LT or within 72 hours
      of completion of a successful transplant surgery. This time frame is proposed so that
      subjects have sufficient time to go over the study and are not pressured to sign the consent
      within a short time frame prior to LT surgery. In addition, all patients being placed on
      liver transplant list at our center will be provided with a copy of the consent form in the
      LT clinic at the time of listing for review only so that this study proposal is not
      completely novel to them at the time of LT surgery. A pregnancy test will be performed on all
      the females of childbearing potential.

      Enrollment of Controls:

      Each study subject will be matched with a control subject. Patients undergoing LT at
      University of Cincinnati that are not part of the study will serve as controls. Confounding
      and effect modifiers will be accounted for by matching the controls on multiple variables
      which may affect the primary outcome of ACR. These variables include: age less than 55 years,
      serum creatinine greater than 1.5 ng/mL, the use of antibody therapy at the time of
      transplant and a history of autoimmune hepatitis. To minimize the selection bias, the matched
      control will be selected in a manner that he/she would have undergone liver transplantation
      within a 24 week period (8 weeks prior or 16 weeks after) of the liver transplantation of the
      matched study subject. This means that data from controls will also be collected
      prospectively. Since outcomes are being measured at week 24 of liver transplantation, this
      will ensure that the investigators have no influence on selecting the controls with a known
      outcome. Controls will be identified through LT clinic. They will not undergo any study
      specific procedures, interventions, testing or evaluations. A written and informed consent
      will be obtained from all controls prior to their enrollment in the study. University of
      Cincinnati transplant program has performed 90-100 LTs each year over last 2 calendar years.
      Application of inclusion and exclusion criteria of our study to this database estimates that
      65% of all LTs will be potential candidates for participation either as study subject or
      control. Based on this estimate the investigators are confident that this enrollment goal of
      20 subjects and 20 controls can be achieved in 9-12 month period.

      Study Drug:

      After LT surgery, subjects will be started on SIS including intravenous corticosteroids,
      calcineurin inhibitor (CNI), mycophenolate mofetil (MMF) +/- thymoglobulin as per University
      of Cincinnati LT immune suppression protocol (UC-ISP).

      On post-operative day 4, intravenous corticosteroids will be discontinued and replaced by the
      study drug; budesonide. Based on pharmacokinetic and bioavailability studies, 3 mg of
      budesonide is equivalent to 10 mg of prednisone. Starting dose of budesonide will be 9 mg by
      mouth daily which will be equivalent to 30-40 mg of prednisone used as standard of care.
      Study drug will be tapered over the next 3 months as detailed in Table 1 and in line with
      UC-ISP. At 3 months post LT, study drug will be discontinued. Subjects with autoimmune
      hepatitis as an etiology for LT will be initiated on prednisone 5 mg daily in addition to SIS
      as per UC-ISP.

      Table 1: Study Drug Taper Time post Liver Transplantation Immunosuppressive therapy Days 0-3
      Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Budesonide 9
      mg Days 31-45 SIS + Budesonide 6 mg Days 46-90 SIS + Budesonide 3 mg Days 90 onwards SIS

      Study Assessments (Visits 3-7):

      Subjects will undergo study visits in the LT clinic or inpatient transplant unit at post-LT
      weeks 2,4,6,8 and 12 (Figure 1). At each visit, data regarding history and physical, vital
      signs, concomitant medications, use of hypoglycemic agents or insulin, adverse event
      assessment, laboratory blood work including blood counts, chemistries, blood glucose, liver
      function test, and tacrolimus trough level will be recorded. Blood samples for early morning
      cortisol level (between 6 AM and 9 AM) will be collected at week 4 and week 8 visits only.
      These samples will be centrifuged at 3600 rpm for 15 minutes, appropriately labelled and
      stored in - 80 C freezer at Schubert Research Clinic. All the samples from the study will be
      analyzed for serum cortisol in 1-2 batches to ensure uniform and standardized testing
      conditions and reagents. No other testing will be performed on these samples. Hemoglobin A1c
      will be checked at week 12 (visit 7). Additionally, at each visit, the study team will
      perform a pill count for the study drug. Study drugs will be dispensed every 4 weeks at study
      visits 2, 4 and 6. Decisions regarding obtaining a liver biopsy for evaluation of abnormal
      liver tests will be at the discretion of treating physician. Biopsy proven ACR will be
      treated according to UC-Rejection protocol.

      Study drug will be discontinued at week 12 (visit 7) and subjects will continue routine
      post-LT follow up as per the current standard of care.

      A low dose ACTH stimulation test will be performed at Schubert Research Clinic at week 12
      visit. This test comprises of intravenous injection of cosyntropin at a dose of 1 micrograms
      per 1.73 m2 of body surface area and checking the serum cortisol levels at baseline and 30
      minutes after cosyntropin injection. This test is used to assess adrenal insufficiency with a
      high sensitivity.
    

Intervention name(s): Budesonide 3Mg Capsule; Standard of Care Prednisone
Intervention type(s): Drug; Drug
Intervention description(s): Budesonide capsule in place of prednisone (standard of care); Prednisone taper (Standard of Care)
Other intervention name(s): Entocort EC; Prednisone
Intervention MeSH terms: Prednisone; Budesonide
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: 20 subjects will receive open label Budesonide along with standard immune suppression and their outcomes will be compared to 20 matched controls receiving standard of care treatment including prednisone plus standard immune suppression
Masking: None (Open Label)
Primary purpose: Treatment