<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03304626</url>
  </required_header>
  <id_info>
    <org_study_id>2016-1488</org_study_id>
    <nct_id>NCT03304626</nct_id>
  </id_info>
  <brief_title>Budesonide for Liver Transplant Immune Suppression</brief_title>
  <official_title>A Pilot Study to Evaluate the Efficacy and Safety of Budesonide as an Alternative to Prednisone for Liver Transplant Immune Suppression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>American College of Gastroenterology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Cincinnati</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a pilot study that investigates the efficacy and safety of budesonide as an immune&#xD;
      suppressing agent for liver transplant recipients in the early post-transplant period.&#xD;
&#xD;
      The primary end-point is rates of acute cellular rejection within first 24 weeks post-liver&#xD;
      transplant. Secondary end points include rates of new onset diabetes after transplant and&#xD;
      safety of budesonide.&#xD;
&#xD;
      The study is structured as a prospective clinical trial. After receiving 4 days of&#xD;
      intravenous corticosteroids on liver transplant post-operative days 0 through 3, subjects&#xD;
      will be started on standard immunosuppression plus enteric coated budesonide (study drug) in&#xD;
      place of standard immune suppression plus prednisone (standard of care). Study drug will be&#xD;
      tapered over 12 weeks in accordance with the existing standard of care immune suppression&#xD;
      protocol. Subjects will be followed in outpatient transplant clinic for 24 weeks. The purpose&#xD;
      of the study is to conduct a pilot study to generate rates and effect size that can be used&#xD;
      in a subsequent equivalent trial. A total of 20 subjects will be enrolled to receive the&#xD;
      standard immunosuppression plus budesonide and their outcomes will be compared to 20 controls&#xD;
      receiving standard immunosuppression plus prednisone (standard of care). The use of controls&#xD;
      is to generate rate and variability that can be compared with the rate obtained from patients&#xD;
      that receive study drug by examining the 95% confidence band.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Enrollment of Subjects: All consecutive patients undergoing liver transplant (LT) at the&#xD;
      University Of Cincinnati Transplant Center will be screened for enrollment upon admission for&#xD;
      transplant surgery. Subjects will be approached after permission from attending on record by&#xD;
      one of the members of research team. Study rationale, procedures, different interventions,&#xD;
      potential benefits and risks as well as alternatives to study participation will be explained&#xD;
      to the subjects in their native language in non-medical terms, as much possible. For&#xD;
      non-English speakers, certified interpreter services will be used. Subjects meeting all of&#xD;
      the inclusion and none of the exclusion criteria will be educated about the study and written&#xD;
      informed consent will be obtained either 12 hours prior to undergoing LT or within 72 hours&#xD;
      of completion of a successful transplant surgery. This time frame is proposed so that&#xD;
      subjects have sufficient time to go over the study and are not pressured to sign the consent&#xD;
      within a short time frame prior to LT surgery. In addition, all patients being placed on&#xD;
      liver transplant list at our center will be provided with a copy of the consent form in the&#xD;
      LT clinic at the time of listing for review only so that this study proposal is not&#xD;
      completely novel to them at the time of LT surgery. A pregnancy test will be performed on all&#xD;
      the females of childbearing potential.&#xD;
&#xD;
      Enrollment of Controls:&#xD;
&#xD;
      Each study subject will be matched with a control subject. Patients undergoing LT at&#xD;
      University of Cincinnati that are not part of the study will serve as controls. Confounding&#xD;
      and effect modifiers will be accounted for by matching the controls on multiple variables&#xD;
      which may affect the primary outcome of ACR. These variables include: age less than 55 years,&#xD;
      serum creatinine greater than 1.5 ng/mL, the use of antibody therapy at the time of&#xD;
      transplant and a history of autoimmune hepatitis. To minimize the selection bias, the matched&#xD;
      control will be selected in a manner that he/she would have undergone liver transplantation&#xD;
      within a 24 week period (8 weeks prior or 16 weeks after) of the liver transplantation of the&#xD;
      matched study subject. This means that data from controls will also be collected&#xD;
      prospectively. Since outcomes are being measured at week 24 of liver transplantation, this&#xD;
      will ensure that the investigators have no influence on selecting the controls with a known&#xD;
      outcome. Controls will be identified through LT clinic. They will not undergo any study&#xD;
      specific procedures, interventions, testing or evaluations. A written and informed consent&#xD;
      will be obtained from all controls prior to their enrollment in the study. University of&#xD;
      Cincinnati transplant program has performed 90-100 LTs each year over last 2 calendar years.&#xD;
      Application of inclusion and exclusion criteria of our study to this database estimates that&#xD;
      65% of all LTs will be potential candidates for participation either as study subject or&#xD;
      control. Based on this estimate the investigators are confident that this enrollment goal of&#xD;
      20 subjects and 20 controls can be achieved in 9-12 month period.&#xD;
&#xD;
      Study Drug:&#xD;
&#xD;
      After LT surgery, subjects will be started on SIS including intravenous corticosteroids,&#xD;
      calcineurin inhibitor (CNI), mycophenolate mofetil (MMF) +/- thymoglobulin as per University&#xD;
      of Cincinnati LT immune suppression protocol (UC-ISP).&#xD;
&#xD;
      On post-operative day 4, intravenous corticosteroids will be discontinued and replaced by the&#xD;
      study drug; budesonide. Based on pharmacokinetic and bioavailability studies, 3 mg of&#xD;
      budesonide is equivalent to 10 mg of prednisone. Starting dose of budesonide will be 9 mg by&#xD;
      mouth daily which will be equivalent to 30-40 mg of prednisone used as standard of care.&#xD;
      Study drug will be tapered over the next 3 months as detailed in Table 1 and in line with&#xD;
      UC-ISP. At 3 months post LT, study drug will be discontinued. Subjects with autoimmune&#xD;
      hepatitis as an etiology for LT will be initiated on prednisone 5 mg daily in addition to SIS&#xD;
      as per UC-ISP.&#xD;
&#xD;
      Table 1: Study Drug Taper Time post Liver Transplantation Immunosuppressive therapy Days 0-3&#xD;
      Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Budesonide 9&#xD;
      mg Days 31-45 SIS + Budesonide 6 mg Days 46-90 SIS + Budesonide 3 mg Days 90 onwards SIS&#xD;
&#xD;
      Study Assessments (Visits 3-7):&#xD;
&#xD;
      Subjects will undergo study visits in the LT clinic or inpatient transplant unit at post-LT&#xD;
      weeks 2,4,6,8 and 12 (Figure 1). At each visit, data regarding history and physical, vital&#xD;
      signs, concomitant medications, use of hypoglycemic agents or insulin, adverse event&#xD;
      assessment, laboratory blood work including blood counts, chemistries, blood glucose, liver&#xD;
      function test, and tacrolimus trough level will be recorded. Blood samples for early morning&#xD;
      cortisol level (between 6 AM and 9 AM) will be collected at week 4 and week 8 visits only.&#xD;
      These samples will be centrifuged at 3600 rpm for 15 minutes, appropriately labelled and&#xD;
      stored in - 80 C freezer at Schubert Research Clinic. All the samples from the study will be&#xD;
      analyzed for serum cortisol in 1-2 batches to ensure uniform and standardized testing&#xD;
      conditions and reagents. No other testing will be performed on these samples. Hemoglobin A1c&#xD;
      will be checked at week 12 (visit 7). Additionally, at each visit, the study team will&#xD;
      perform a pill count for the study drug. Study drugs will be dispensed every 4 weeks at study&#xD;
      visits 2, 4 and 6. Decisions regarding obtaining a liver biopsy for evaluation of abnormal&#xD;
      liver tests will be at the discretion of treating physician. Biopsy proven ACR will be&#xD;
      treated according to UC-Rejection protocol.&#xD;
&#xD;
      Study drug will be discontinued at week 12 (visit 7) and subjects will continue routine&#xD;
      post-LT follow up as per the current standard of care.&#xD;
&#xD;
      A low dose ACTH stimulation test will be performed at Schubert Research Clinic at week 12&#xD;
      visit. This test comprises of intravenous injection of cosyntropin at a dose of 1 micrograms&#xD;
      per 1.73 m2 of body surface area and checking the serum cortisol levels at baseline and 30&#xD;
      minutes after cosyntropin injection. This test is used to assess adrenal insufficiency with a&#xD;
      high sensitivity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 27, 2017</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">December 31, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <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</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Acute Cellular Rejection Between Study and Control Groups</measure>
    <time_frame>Post-Transplant day 4 to week 24</time_frame>
    <description>Acute Cellular Rejection of liver graft was determined by liver biopsy using Banff criteria. The decision to perform liver biopsy was as per treating physician based on patient's clinical course and blood chemisteries. Protocol bioopsies were not performed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of New Onset Diabetes After Transplant</measure>
    <time_frame>Post-Transplant day 4 to week 24</time_frame>
    <description>Rates of new onset diabetes in patients who did not have diabetes prior to liver transplant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adrenal Suppression</measure>
    <time_frame>Post-Transplant week 12</time_frame>
    <description>This outcomes was measured in Budesonide group only. Serum cortisol levels after 12 weeks of Budesonide use were checked to see if they fall below the adrenal suppression threshold of 3microgram/dl. If these were below 3 microgram/dl then patient is considered to have developed adrenal suppression.&#xD;
Second measure used to check for adrenal suppression was Cosyntorpin stimulation test. One-time, low-dose, cosyntropin stimulation test at week 12 was performed by administering cosyntropin at a dose of 0.5 µg/1.73 m2 of the body surface area and checking the serum cortisol levels at baseline and at 30 minutes after cosyntropin injection. A serum cortisol value of &lt;11 µg/dL after cosyntropin stimulation was used to define adrenal suppression. Participant meeting any of these criteria was said to have developed adrenal suppression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events</measure>
    <time_frame>Post-Transplant day 4 to week 24</time_frame>
    <description>Rates of adverse events&#xD;
All cause mortality&#xD;
Graft failure&#xD;
Acute cellular rejection&#xD;
New Onset Diabetes after Transplant&#xD;
Rates of bacterial, fungal or viral infections&#xD;
Other adverse events including ascites, pleural effusion, kidney injury, biliary stricture</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Acute Cellular Graft Rejection</condition>
  <condition>New Onset Diabetes After Transplant</condition>
  <arm_group>
    <arm_group_label>Study Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard of Care&#xD;
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Budesonide 3Mg Capsule</intervention_name>
    <description>Budesonide capsule in place of prednisone (standard of care)</description>
    <arm_group_label>Study Group</arm_group_label>
    <other_name>Entocort EC</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard of Care Prednisone</intervention_name>
    <description>Prednisone taper (Standard of Care)</description>
    <arm_group_label>Control Group</arm_group_label>
    <other_name>Prednisone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female or male subjects aged 21-75 years old&#xD;
&#xD;
          -  Received a primary liver transplant within 4 days of enrollment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Received previous organ transplants&#xD;
&#xD;
          -  Undergoing multiple organ transplants&#xD;
&#xD;
          -  Recipients with advanced fibrosis in graft&#xD;
&#xD;
          -  Treatment plan for subject includes receiving immunosuppressant therapy other than&#xD;
             standard immune suppression (SIS) as per University of Cincinnati LT immune&#xD;
             suppression protocol (UC-ISP).&#xD;
&#xD;
          -  Inability to take enteral (orally or by tube feed) medications by day 4&#xD;
             post-transplant&#xD;
&#xD;
          -  Subjects with diabetes mellitus prior to transplant (diabetes mellitus defined as use&#xD;
             of hypoglycemic agents or HbA1c &gt; 6.4 prior to transplant)&#xD;
&#xD;
          -  Subjects who have any severe medical condition requiring acute or chronic treatment&#xD;
             that in the investigator's opinion would interfere with study participation.&#xD;
&#xD;
          -  Subjects who have been exposed to an investigational therapy within 30 days prior to&#xD;
             enrollment or 5 half-lives on the investigational product, whichever is greater.&#xD;
&#xD;
          -  Subjects in which concomitant use of medications which are inhibitors of CYP3A4 (such&#xD;
             as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) cannot&#xD;
             be avoided during the study period.&#xD;
&#xD;
          -  Pregnant females&#xD;
&#xD;
          -  Diminished mental capacity to consent for the study as determined by attending on the&#xD;
             record.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of Cincinnati Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>October 3, 2017</study_first_submitted>
  <study_first_submitted_qc>October 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 9, 2017</study_first_posted>
  <results_first_submitted>May 4, 2021</results_first_submitted>
  <results_first_submitted_qc>June 29, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">July 20, 2021</results_first_posted>
  <last_update_submitted>June 29, 2021</last_update_submitted>
  <last_update_submitted_qc>June 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Cincinnati</investigator_affiliation>
    <investigator_full_name>Khurram Bari</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Budesonide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 25, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/26/NCT03304626/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Study Group</title>
          <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1&#xD;
Budesonide 3Mg Capsule: Budesonide capsule in place of prednisone (standard of care)</description>
        </group>
        <group group_id="P2">
          <title>Control Group</title>
          <description>Standard of Care Controls that received&#xD;
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Study Group</title>
          <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1&#xD;
Budesonide 3Mg Capsule: Budesonide capsule in place of prednisone (standard of care)</description>
        </group>
        <group group_id="B2">
          <title>Control Group</title>
          <description>Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57" lower_limit="42" upper_limit="64"/>
                    <measurement group_id="B2" value="56" lower_limit="44" upper_limit="63"/>
                    <measurement group_id="B3" value="56" lower_limit="43" upper_limit="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="37"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Acute Cellular Rejection Between Study and Control Groups</title>
        <description>Acute Cellular Rejection of liver graft was determined by liver biopsy using Banff criteria. The decision to perform liver biopsy was as per treating physician based on patient's clinical course and blood chemisteries. Protocol bioopsies were not performed.</description>
        <time_frame>Post-Transplant day 4 to week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Group</title>
            <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1&#xD;
Budesonide 3Mg Capsule: Budesonide capsule in place of prednisone (standard of care)</description>
          </group>
          <group group_id="O2">
            <title>Control Group</title>
            <description>Standard of Care&#xD;
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS&#xD;
Standard of Care Prednisone: Prednisone taper (Standard of Care)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Acute Cellular Rejection Between Study and Control Groups</title>
          <description>Acute Cellular Rejection of liver graft was determined by liver biopsy using Banff criteria. The decision to perform liver biopsy was as per treating physician based on patient's clinical course and blood chemisteries. Protocol bioopsies were not performed.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of New Onset Diabetes After Transplant</title>
        <description>Rates of new onset diabetes in patients who did not have diabetes prior to liver transplant</description>
        <time_frame>Post-Transplant day 4 to week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Group</title>
            <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1&#xD;
Budesonide 3Mg Capsule: Budesonide capsule in place of prednisone (standard of care)</description>
          </group>
          <group group_id="O2">
            <title>Control Group</title>
            <description>Standard of Care Controls that received&#xD;
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of New Onset Diabetes After Transplant</title>
          <description>Rates of new onset diabetes in patients who did not have diabetes prior to liver transplant</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adrenal Suppression</title>
        <description>This outcomes was measured in Budesonide group only. Serum cortisol levels after 12 weeks of Budesonide use were checked to see if they fall below the adrenal suppression threshold of 3microgram/dl. If these were below 3 microgram/dl then patient is considered to have developed adrenal suppression.&#xD;
Second measure used to check for adrenal suppression was Cosyntorpin stimulation test. One-time, low-dose, cosyntropin stimulation test at week 12 was performed by administering cosyntropin at a dose of 0.5 µg/1.73 m2 of the body surface area and checking the serum cortisol levels at baseline and at 30 minutes after cosyntropin injection. A serum cortisol value of &lt;11 µg/dL after cosyntropin stimulation was used to define adrenal suppression. Participant meeting any of these criteria was said to have developed adrenal suppression</description>
        <time_frame>Post-Transplant week 12</time_frame>
        <population>This outcome was measured in study group only due to limited size and budget of the study</population>
        <group_list>
          <group group_id="O1">
            <title>Study Group</title>
            <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1&#xD;
Budesonide 3Mg Capsule: Budesonide capsule in place of prednisone (standard of care)</description>
          </group>
          <group group_id="O2">
            <title>Control Group</title>
            <description>Standard of Care Controls that received&#xD;
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adrenal Suppression</title>
          <description>This outcomes was measured in Budesonide group only. Serum cortisol levels after 12 weeks of Budesonide use were checked to see if they fall below the adrenal suppression threshold of 3microgram/dl. If these were below 3 microgram/dl then patient is considered to have developed adrenal suppression.&#xD;
Second measure used to check for adrenal suppression was Cosyntorpin stimulation test. One-time, low-dose, cosyntropin stimulation test at week 12 was performed by administering cosyntropin at a dose of 0.5 µg/1.73 m2 of the body surface area and checking the serum cortisol levels at baseline and at 30 minutes after cosyntropin injection. A serum cortisol value of &lt;11 µg/dL after cosyntropin stimulation was used to define adrenal suppression. Participant meeting any of these criteria was said to have developed adrenal suppression</description>
          <population>This outcome was measured in study group only due to limited size and budget of the study</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events</title>
        <description>Rates of adverse events&#xD;
All cause mortality&#xD;
Graft failure&#xD;
Acute cellular rejection&#xD;
New Onset Diabetes after Transplant&#xD;
Rates of bacterial, fungal or viral infections&#xD;
Other adverse events including ascites, pleural effusion, kidney injury, biliary stricture</description>
        <time_frame>Post-Transplant day 4 to week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Study Group</title>
            <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1&#xD;
Budesonide 3Mg Capsule: Budesonide capsule in place of prednisone (standard of care)</description>
          </group>
          <group group_id="O2">
            <title>Control Group</title>
            <description>Standard of Care Controls that received&#xD;
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events</title>
          <description>Rates of adverse events&#xD;
All cause mortality&#xD;
Graft failure&#xD;
Acute cellular rejection&#xD;
New Onset Diabetes after Transplant&#xD;
Rates of bacterial, fungal or viral infections&#xD;
Other adverse events including ascites, pleural effusion, kidney injury, biliary stricture</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <desc>Adverse events recorded in Standard of Care Control Arm were limited to&#xD;
All cause mortality&#xD;
Graft failure&#xD;
Acute cellular rejection&#xD;
New Onset Diabetes after Transplant&#xD;
Rates of bacterial, fungal or viral infections</desc>
      <group_list>
        <group group_id="E1">
          <title>Study Group</title>
          <description>Budesonide EC 3 mg capsule. The dose will be as follows&#xD;
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 SIS1&#xD;
Budesonide 3Mg Capsule: Budesonide capsule in place of prednisone (standard of care)</description>
        </group>
        <group group_id="E2">
          <title>Control Group</title>
          <description>Standard of Care Controls that received&#xD;
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Ascites or Pleural effusion</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Bile leak</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Biliary stricture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute Kidney injury</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Khurram Bari</name_or_title>
      <organization>University of Cincinnati</organization>
      <phone>513-558-2898</phone>
      <email>khurram.bari@uc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03304626
org study id: 2016-1488
nct id: NCT03304626
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
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
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Acute Cellular Rejection Between Study and Control Groups
time frame: Post-Transplant day 4 to week 24
description: Acute Cellular Rejection of liver graft was determined by liver biopsy using Banff criteria. The decision to perform liver biopsy was as per treating physician based on patient's clinical course and blood chemisteries. Protocol bioopsies were not performed.
measure: Rate of New Onset Diabetes After Transplant
time frame: Post-Transplant day 4 to week 24
description: Rates of new onset diabetes in patients who did not have diabetes prior to liver transplant
measure: Number of Participants With Adrenal Suppression
time frame: Post-Transplant week 12
description: This outcomes was measured in Budesonide group only. Serum cortisol levels after 12 weeks of Budesonide use were checked to see if they fall below the adrenal suppression threshold of 3microgram/dl. If these were below 3 microgram/dl then patient is considered to have developed adrenal suppression.
Second measure used to check for adrenal suppression was Cosyntorpin stimulation test. One-time, low-dose, cosyntropin stimulation test at week 12 was performed by administering cosyntropin at a dose of 0.5 µg/1.73 m2 of the body surface area and checking the serum cortisol levels at baseline and at 30 minutes after cosyntropin injection. A serum cortisol value of <11 µg/dL after cosyntropin stimulation was used to define adrenal suppression. Participant meeting any of these criteria was said to have developed adrenal suppression
measure: Number of Participants With Adverse Events
time frame: Post-Transplant day 4 to week 24
description: Rates of adverse events
All cause mortality
Graft failure
Acute cellular rejection
New Onset Diabetes after Transplant
Rates of bacterial, fungal or viral infections
Other adverse events including ascites, pleural effusion, kidney injury, biliary stricture
arm group label: Study Group
arm group type: Experimental
description: Budesonide EC 3 mg capsule. The dose will be as follows
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 SIS1
arm group label: Control Group
arm group type: Active Comparator
description: Standard of Care
Time post Liver Transplantation Immunosuppressive therapy Days 0-3 Standard immune suppression (SIS) + Intravenous corticosteroids Days 4-30 SIS + Prednisone 15-60 mg Days 31-45 SIS + Prednisone 10 mg Days 46-90 SIS + Prednisone 2.5 to 7.5 mg Days 90 onwards SIS
intervention type: Drug
intervention name: Budesonide 3Mg Capsule
description: Budesonide capsule in place of prednisone (standard of care)
arm group label: Study Group
other name: Entocort EC
intervention type: Drug
intervention name: Standard of Care Prednisone
description: Prednisone taper (Standard of Care)
arm group label: Control Group
other name: Prednisone
criteria: 
gender: All
minimum age: 21 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Cincinnati
investigator full name: Khurram Bari
investigator title: Assistant Professor
mesh term: Prednisone
mesh term: Budesonide
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 