<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/NCT01702207</url>
  </required_header>
  <id_info>
    <org_study_id>ESTTEROD</org_study_id>
    <nct_id>NCT01702207</nct_id>
  </id_info>
  <brief_title>Evaluation Of Switching From Twice Daily Tacrolimus To Once Daily Formulation On Cardiovascular Risk</brief_title>
  <acronym>ESTTEROD</acronym>
  <official_title>A One-Year, Prospective, Randomized, Controlled Study Evaluating The Efficacy Of Switching From The Twice Daily Tacrolimus Formulation To The Extended Release, Once Daily Formulation To Reduce The Framingham Cardiovascular Risk Scores.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Saskatchewan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Astellas Pharma Canada, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Saskatchewan</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Current standard prophylactic immunosuppression in renal transplantation includes tacrolimus,&#xD;
      a calcineurin inhibitor, dosed twice daily. In Canada, oral tacrolimus has been available as&#xD;
      a twice daily formulation marketed as Prograf® since 1997. It has recently become available&#xD;
      in an extended release formulation called Advagraf®, which is dosed once daily. Advagraf® has&#xD;
      been demonstrated to be therapeutically equivalent to Prograf® in the renal transplant&#xD;
      maintenance population, and as a result it has been is approved as an alternative to the&#xD;
      twice daily formulation in these patients. There is an evolving and expanding positive&#xD;
      clinical experience with Advagraf® in kidney transplantation and it has shown to be preferred&#xD;
      by many patients, due to the diminished dosing frequency. In clinical trials, Advagraf® has&#xD;
      been shown to have other potential benefits over Prograf® such as less inter and&#xD;
      intra-patient variability, improved cardiovascular profiles, and improved kidney function.&#xD;
      Compared to Prograf®, Advagraf® also has a lower Cmin or 'trough' concentration as well as a&#xD;
      lower Cmax or 'peak' concentration. The purpose of this study is to convert stabilized renal&#xD;
      transplant patients currently receiving Prograf® to Advagraf®, to investigate these potential&#xD;
      therapeutic benefits.&#xD;
&#xD;
      The Framingham Risk Score and the Reynold's Risk Score are currently recommended by the&#xD;
      Canadian Cardiovascular Society (CCS) to predict 10-year cardiovascular risk in the general&#xD;
      population. Surrogate markers are widely used in clinical trials to shorten follow-up&#xD;
      durations. In this study, the investigators will use the Framingham Risk Score and Reynold's&#xD;
      Risk Score to quantify changes in estimated cardiovascular risk. The investigators also&#xD;
      intend to examine novel inflammatory markers to investigate cardiovascular risk.&#xD;
&#xD;
      The investigators hypothesize that the more consistent drug exposure and lower Cmax noted&#xD;
      with Advagraf® will decrease Framingham Risk Score, Reynolds Risk score as well as markers of&#xD;
      inflammation in kidney transplant recipients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2012</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the Framingham risk scores and change in the Reynolds Risk Score.</measure>
    <time_frame>Visit 1, Visit 3 (12 months)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Comparison in GFR between the two groups.</measure>
    <time_frame>Visit 1, Visit 3 (12 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of therapy on CV biomarkers, insulin resistance and lipid profile.</measure>
    <time_frame>Visit 1, Visit 3 (12 months)</time_frame>
    <description>CV biomarkers will be assessed by luminex and insulin resistance and lipid profile will be assessed by the Metabolic Syndrome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To look at change in the glomerular filtration rate (GFR) over the duration of the study.</measure>
    <time_frame>Vist 1, Visit 3 (12 months)</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Immunosuppression</condition>
  <condition>Cardiovascular Diseases</condition>
  <condition>Kidney Transplantation</condition>
  <arm_group>
    <arm_group_label>Once Daily Tacrolimus</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Treatment Arm - Subjects are switched from the tacrolimus twice daily (Prograf®) to the once daily formulation (Advagraf®) to maintain a trough tacrolimus level of 5-8.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Twice Daily Tacrolimus</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control Arm - Subjects are kept on Prograf® which is the Twice Daily Tacrolimus</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Once Daily Tacrolimus</intervention_name>
    <description>Subjects switched from the tacrolimus twice daily (Prograf®) to the once daily formulation (Advagraf®) to maintain a trough tacrolimus level of 5-8.</description>
    <arm_group_label>Once Daily Tacrolimus</arm_group_label>
    <other_name>Advagraf®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Twice Daily Tacrolimus</intervention_name>
    <description>Subjects are kept on Prograf® which is the Twice Daily Tacrolimus</description>
    <arm_group_label>Twice Daily Tacrolimus</arm_group_label>
    <other_name>Prograf®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Kidney transplant patients currently stable on the twice-daily formulation and who are&#xD;
             followed as outpatients.&#xD;
&#xD;
          -  Stability is defined as change in serum creatinine of less than 10% over the last two&#xD;
             months&#xD;
&#xD;
          -  Age 18-74 years old&#xD;
&#xD;
          -  At least six months after transplantation&#xD;
&#xD;
          -  Lack of rejection within the last 12 weeks&#xD;
&#xD;
          -  Serum creatinine less than 300 umol/L at enrolment&#xD;
&#xD;
          -  Negative urine pregnancy test for female patients of childbearing potential&#xD;
&#xD;
          -  Consent to the study&#xD;
&#xD;
          -  Not included in a clinical trial within the last 90 days&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with other types of solid organ transplants&#xD;
&#xD;
          -  Patients with any form of substance abuse or psychiatric disorder.&#xD;
&#xD;
          -  Patients with acute or chronic diarrhea&#xD;
&#xD;
          -  Patients receiving anti-lymphocyte treatment for rejection within the last six months&#xD;
&#xD;
          -  Patients on cyclosporine and or not receiving a mycophenolate derivative.&#xD;
&#xD;
          -  Patients with significant liver disease defined as having an elevated bilirubin by at&#xD;
             least two times the upper value of the normal range&#xD;
&#xD;
          -  Patients who have any unstable medical condition that could interfere with the study&#xD;
&#xD;
          -  Patients with chronic viral infection with HIV, Hep C and HCV.&#xD;
&#xD;
          -  Presence of any acute illness requiring admission to the hospital for the last 4 weeks&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Significant cardiovascular event such as MI, stroke or TIA within the last 12 weeks or&#xD;
             uncontrolled hypertension.&#xD;
&#xD;
          -  Immunosuppressant changes within the last month.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>74 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ahmed Shoker, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Saskatchewan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>St Paul's Hospital</name>
      <address>
        <city>Saskatoon</city>
        <state>Saskatchewan</state>
        <zip>S7M0Z9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>September 27, 2012</study_first_submitted>
  <study_first_submitted_qc>October 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <last_update_submitted>January 4, 2018</last_update_submitted>
  <last_update_submitted_qc>January 4, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 8, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Saskatchewan</investigator_affiliation>
    <investigator_full_name>AShoker</investigator_full_name>
    <investigator_title>M.D.</investigator_title>
  </responsible_party>
  <keyword>Prograf®</keyword>
  <keyword>Advagraf®</keyword>
  <keyword>tacrolimus</keyword>
  <keyword>kidney transplant</keyword>
  <keyword>renal transplant</keyword>
  <keyword>cardiovascular risk</keyword>
  <keyword>Framingham Risk</keyword>
  <keyword>Reynolds Risk</keyword>
  <keyword>immunosuppression</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT01702207
org study id: ESTTEROD
nct id: NCT01702207
lead sponsor: 
collaborator: 
has dmc: No
Current standard prophylactic immunosuppression in renal transplantation includes tacrolimus,
      a calcineurin inhibitor, dosed twice daily. In Canada, oral tacrolimus has been available as
      a twice daily formulation marketed as Prograf® since 1997. It has recently become available
      in an extended release formulation called Advagraf®, which is dosed once daily. Advagraf® has
      been demonstrated to be therapeutically equivalent to Prograf® in the renal transplant
      maintenance population, and as a result it has been is approved as an alternative to the
      twice daily formulation in these patients. There is an evolving and expanding positive
      clinical experience with Advagraf® in kidney transplantation and it has shown to be preferred
      by many patients, due to the diminished dosing frequency. In clinical trials, Advagraf® has
      been shown to have other potential benefits over Prograf® such as less inter and
      intra-patient variability, improved cardiovascular profiles, and improved kidney function.
      Compared to Prograf®, Advagraf® also has a lower Cmin or 'trough' concentration as well as a
      lower Cmax or 'peak' concentration. The purpose of this study is to convert stabilized renal
      transplant patients currently receiving Prograf® to Advagraf®, to investigate these potential
      therapeutic benefits.

      The Framingham Risk Score and the Reynold's Risk Score are currently recommended by the
      Canadian Cardiovascular Society (CCS) to predict 10-year cardiovascular risk in the general
      population. Surrogate markers are widely used in clinical trials to shorten follow-up
      durations. In this study, the investigators will use the Framingham Risk Score and Reynold's
      Risk Score to quantify changes in estimated cardiovascular risk. The investigators also
      intend to examine novel inflammatory markers to investigate cardiovascular risk.

      The investigators hypothesize that the more consistent drug exposure and lower Cmax noted
      with Advagraf® will decrease Framingham Risk Score, Reynolds Risk score as well as markers of
      inflammation in kidney transplant recipients.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Supportive Care
masking: None (Open Label)
measure: Change in the Framingham risk scores and change in the Reynolds Risk Score.
time frame: Visit 1, Visit 3 (12 months)
measure: Comparison in GFR between the two groups.
time frame: Visit 1, Visit 3 (12 months)
measure: Effect of therapy on CV biomarkers, insulin resistance and lipid profile.
time frame: Visit 1, Visit 3 (12 months)
description: CV biomarkers will be assessed by luminex and insulin resistance and lipid profile will be assessed by the Metabolic Syndrome
measure: To look at change in the glomerular filtration rate (GFR) over the duration of the study.
time frame: Vist 1, Visit 3 (12 months)
arm group label: Once Daily Tacrolimus
arm group type: Active Comparator
description: Treatment Arm - Subjects are switched from the tacrolimus twice daily (Prograf®) to the once daily formulation (Advagraf®) to maintain a trough tacrolimus level of 5-8.
arm group label: Twice Daily Tacrolimus
arm group type: Active Comparator
description: Control Arm - Subjects are kept on Prograf® which is the Twice Daily Tacrolimus
intervention type: Drug
intervention name: Once Daily Tacrolimus
description: Subjects switched from the tacrolimus twice daily (Prograf®) to the once daily formulation (Advagraf®) to maintain a trough tacrolimus level of 5-8.
arm group label: Once Daily Tacrolimus
other name: Advagraf®
intervention type: Drug
intervention name: Twice Daily Tacrolimus
description: Subjects are kept on Prograf® which is the Twice Daily Tacrolimus
arm group label: Twice Daily Tacrolimus
other name: Prograf®
criteria: 
gender: All
minimum age: 18 Years
maximum age: 74 Years
healthy volunteers: No
last name: Ahmed Shoker, MD
role: Principal Investigator
affiliation: University of Saskatchewan
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University of Saskatchewan
investigator full name: AShoker
investigator title: M.D.
mesh term: Cardiovascular Diseases
mesh term: Tacrolimus