<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/NCT03005236</url>
  </required_header>
  <id_info>
    <org_study_id>AGEING</org_study_id>
    <nct_id>NCT03005236</nct_id>
  </id_info>
  <brief_title>AGe-adapted Benefits of Envarsus Versus Twice-daily Tacrolimus ImmunosuppressioN druGs After Kidney Transplantation</brief_title>
  <acronym>AGEING</acronym>
  <official_title>AGe-adapted Benefits of Envarsus Versus Twice-daily Tacrolimus ImmunosuppressioN druGs After Kidney Transplantation (AGEING) - a Feasibility Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Birmingham NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital Birmingham NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The proportion of elderly patients with end-stage kidney disease undergoing renal replacement&#xD;
      therapy (RRT) is steadily increasing. Although kidney transplantation remains the optimal RRT&#xD;
      of choice, it is clear that older adults have a differential risk versus benefit profile&#xD;
      after kidney transplantation compared to younger adults. No age-adapted immunosuppression for&#xD;
      older adults has been shown to improve kidney allograft outcomes but recent sub-analyses of&#xD;
      clinical trial data has hinted at improved outcomes for older kidney transplant patients&#xD;
      receiving Envarsus versus standard twice-daily tacrolimus formulations. This feasibility&#xD;
      study will investigate this effect to see whether a full scale randomised controlled trial is&#xD;
      warranted and to provide information regarding study feasibility.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The proportion of elderly patients with end-stage kidney disease undergoing renal replacement&#xD;
      therapy (RRT) is steadily increasing. National registry data consistently shows a trend&#xD;
      towards increasing median ages for patients both starting dialysis and awaiting kidney&#xD;
      transplantation on deceased-donor waiting lists (www.renalreg.org). For example, in the&#xD;
      United Kingdom, national audit data from the UK Renal Registry demonstrates that the median&#xD;
      age for all incident patients commencing RRT was 64.5 years (www.renalreg.org). Among the&#xD;
      prevalent RRT population, the percentage of patients aged greater than 70 years has increased&#xD;
      from 19.2% (in 2000) to 25.0% (in 2013) in the last registry report (www.renalreg.org).&#xD;
      Focusing on data from the UK Transplant Registry, 28% of transplant recipients receiving a&#xD;
      deceased-donor kidney allograft in the last year were aged 60 and over (7% were aged 70 and&#xD;
      over), while 32% of the active kidney transplant waiting list is aged 60 and over (9% aged 70&#xD;
      and over) (http://www.odt.nhs.uk/uk-transplant-registry/). With chronic kidney disease&#xD;
      increasingly recognized as a public health epidemic, the long-term prospects are of an&#xD;
      increasingly elderly component to our end-stage kidney disease population.&#xD;
&#xD;
      Kidney transplantation is the gold standard method of RRT due to superior mortality, quality&#xD;
      of life and cost effectiveness versus dialysis. It is therefore concerning that&#xD;
      transplantation is an infrequent RRT choice for older adults and the number of older adults&#xD;
      aged 70 and over who are listed for a kidney transplant is &lt;10%. The Renal Association&#xD;
      states; &quot;age is not a contra-indication for transplantation but age related co-morbidity is&#xD;
      an important limiting factor&quot;, but clearly the risk versus benefit ratio remains unclear for&#xD;
      clinicians because mortality risk is higher for older versus younger kidney transplant&#xD;
      recipients. However, improved mortality is observed with kidney transplantation versus&#xD;
      wait-listed dialysis patients across all age groups, and specifically among older adults aged&#xD;
      70 and above in US studies, and therefore Investigators should consider kidney&#xD;
      transplantation for this increasing large cohort. The risk of immunosuppression-related&#xD;
      complications increases with age and therefore age-adapted immunosuppression should be&#xD;
      considered to balance efficacy versus complications. However, no targeted age-adapted&#xD;
      immunosuppression clinical trials have been conducted in kidney transplantation and this&#xD;
      remains a major gap in the literature.&#xD;
&#xD;
      Sub-analyses of recently published work showed clinically relevant advantages of Envarsus&#xD;
      versus twice-daily tacrolimus for prevention of treatment failure after 2-years among&#xD;
      patients aged 65 and over (age ≥65 yrs; -25.89% (-45.11%, 0.36%), p=0.067) (Rostaing et al,&#xD;
      AJKD 2016; Budde et al, AJT 2014). However, small numbers render the effect of borderline&#xD;
      statistical significance&#xD;
&#xD;
      As one of the largest growing demographics, it is imperative to design a targeted clinical&#xD;
      trial to ascertain if Envarsus has clinical benefits above and beyond twice-daily tacrolimus&#xD;
      in older kidney transplant recipients. Before that is possible, investigators must&#xD;
      investigate two things in preparation for a definitive study; 1) investigators must confirm&#xD;
      reproducibility of this trend among older kidney transplant recipients in a separate cohort&#xD;
      to determine effect size and power calculations, and 2) identify possible mechanistic,&#xD;
      biological and/or pharmacogenomic rationale to understand any effect. This feasibility study&#xD;
      will be the first contemporary randomised controlled trial in kidney transplantation looking&#xD;
      at a modified age-adapted immunosuppression protocol specifically for older adults,&#xD;
      attempting to determine whether the above results can be recreated and probed in greater&#xD;
      detail. As one of the most topical questions in the field of transplantation, the results of&#xD;
      this feasibility study would advise on the merits of undertaking a more definitive study&#xD;
      which would almost certainly be one of the most eagerly awaited studies by global transplant&#xD;
      clinicians.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>April 2017</start_date>
  <completion_date type="Anticipated">October 2019</completion_date>
  <primary_completion_date type="Anticipated">April 2019</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recruitment rates</measure>
    <time_frame>6-months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment failure (composite endpoint of mortality, graft survival, rejection, loss to follow up)</measure>
    <time_frame>6-months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Kidney Transplant Failure and Rejection</condition>
  <arm_group>
    <arm_group_label>Envarsus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Basiliximab induction with maintenance therapy of Envarsus, mycophenolate mofetil and corticosteroids. Envarsus constitutes the experimental component of immunosuppression in older kidney transplant recipients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard twice daily tacrolimus</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Basiliximab induction with maintenance therapy of standard tacrolimus, mycophenolate mofetil and corticosteroids. Standard tacrolimus constitutes the control component of immunosuppression in older kidney transplant recipients.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ENVARSUS</intervention_name>
    <description>Envarsus is a once-a-day oral formulation of tacrolimus.</description>
    <arm_group_label>Envarsus</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard twice daily tacrolimus</intervention_name>
    <description>Standard tacrolimus will include twice-daily formulations that are currently available.</description>
    <arm_group_label>Standard twice daily tacrolimus</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  kidney alone transplant, age ≥60, known sensitivity to tacrolimus&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  contra-indication to transplantation, multi-organ transplant, aged &lt;60&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adnan Sharif, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Consultant Nephrologist</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Adnan Sharif, MD</last_name>
    <phone>0121 371 5861</phone>
    <email>adnan.sharif@uhb.nhs.uk</email>
  </overall_contact>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>November 30, 2016</study_first_submitted>
  <study_first_submitted_qc>December 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 29, 2016</study_first_posted>
  <last_update_submitted>December 28, 2016</last_update_submitted>
  <last_update_submitted_qc>December 28, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 29, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Birmingham NHS Foundation Trust</investigator_affiliation>
    <investigator_full_name>Adnan Sharif</investigator_full_name>
    <investigator_title>Consultant Nephrologist</investigator_title>
  </responsible_party>
  <keyword>Kidney transplant</keyword>
  <keyword>Tacrolimus</keyword>
  <keyword>Envarsus</keyword>
  <keyword>Older adult</keyword>
  <keyword>Elderly</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03005236
org study id: AGEING
nct id: NCT03005236
lead sponsor: 
has dmc: Yes
The proportion of elderly patients with end-stage kidney disease undergoing renal replacement
      therapy (RRT) is steadily increasing. Although kidney transplantation remains the optimal RRT
      of choice, it is clear that older adults have a differential risk versus benefit profile
      after kidney transplantation compared to younger adults. No age-adapted immunosuppression for
      older adults has been shown to improve kidney allograft outcomes but recent sub-analyses of
      clinical trial data has hinted at improved outcomes for older kidney transplant patients
      receiving Envarsus versus standard twice-daily tacrolimus formulations. This feasibility
      study will investigate this effect to see whether a full scale randomised controlled trial is
      warranted and to provide information regarding study feasibility.
The proportion of elderly patients with end-stage kidney disease undergoing renal replacement
      therapy (RRT) is steadily increasing. National registry data consistently shows a trend
      towards increasing median ages for patients both starting dialysis and awaiting kidney
      transplantation on deceased-donor waiting lists (www.renalreg.org). For example, in the
      United Kingdom, national audit data from the UK Renal Registry demonstrates that the median
      age for all incident patients commencing RRT was 64.5 years (www.renalreg.org). Among the
      prevalent RRT population, the percentage of patients aged greater than 70 years has increased
      from 19.2% (in 2000) to 25.0% (in 2013) in the last registry report (www.renalreg.org).
      Focusing on data from the UK Transplant Registry, 28% of transplant recipients receiving a
      deceased-donor kidney allograft in the last year were aged 60 and over (7% were aged 70 and
      over), while 32% of the active kidney transplant waiting list is aged 60 and over (9% aged 70
      and over) (http://www.odt.nhs.uk/uk-transplant-registry/). With chronic kidney disease
      increasingly recognized as a public health epidemic, the long-term prospects are of an
      increasingly elderly component to our end-stage kidney disease population.

      Kidney transplantation is the gold standard method of RRT due to superior mortality, quality
      of life and cost effectiveness versus dialysis. It is therefore concerning that
      transplantation is an infrequent RRT choice for older adults and the number of older adults
      aged 70 and over who are listed for a kidney transplant is <10%. The Renal Association
      states; "age is not a contra-indication for transplantation but age related co-morbidity is
      an important limiting factor", but clearly the risk versus benefit ratio remains unclear for
      clinicians because mortality risk is higher for older versus younger kidney transplant
      recipients. However, improved mortality is observed with kidney transplantation versus
      wait-listed dialysis patients across all age groups, and specifically among older adults aged
      70 and above in US studies, and therefore Investigators should consider kidney
      transplantation for this increasing large cohort. The risk of immunosuppression-related
      complications increases with age and therefore age-adapted immunosuppression should be
      considered to balance efficacy versus complications. However, no targeted age-adapted
      immunosuppression clinical trials have been conducted in kidney transplantation and this
      remains a major gap in the literature.

      Sub-analyses of recently published work showed clinically relevant advantages of Envarsus
      versus twice-daily tacrolimus for prevention of treatment failure after 2-years among
      patients aged 65 and over (age ≥65 yrs; -25.89% (-45.11%, 0.36%), p=0.067) (Rostaing et al,
      AJKD 2016; Budde et al, AJT 2014). However, small numbers render the effect of borderline
      statistical significance

      As one of the largest growing demographics, it is imperative to design a targeted clinical
      trial to ascertain if Envarsus has clinical benefits above and beyond twice-daily tacrolimus
      in older kidney transplant recipients. Before that is possible, investigators must
      investigate two things in preparation for a definitive study; 1) investigators must confirm
      reproducibility of this trend among older kidney transplant recipients in a separate cohort
      to determine effect size and power calculations, and 2) identify possible mechanistic,
      biological and/or pharmacogenomic rationale to understand any effect. This feasibility study
      will be the first contemporary randomised controlled trial in kidney transplantation looking
      at a modified age-adapted immunosuppression protocol specifically for older adults,
      attempting to determine whether the above results can be recreated and probed in greater
      detail. As one of the most topical questions in the field of transplantation, the results of
      this feasibility study would advise on the merits of undertaking a more definitive study
      which would almost certainly be one of the most eagerly awaited studies by global transplant
      clinicians.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recruitment rates
time frame: 6-months
measure: Treatment failure (composite endpoint of mortality, graft survival, rejection, loss to follow up)
time frame: 6-months
arm group label: Envarsus
arm group type: Experimental
description: Basiliximab induction with maintenance therapy of Envarsus, mycophenolate mofetil and corticosteroids. Envarsus constitutes the experimental component of immunosuppression in older kidney transplant recipients.
arm group label: Standard twice daily tacrolimus
arm group type: Active Comparator
description: Basiliximab induction with maintenance therapy of standard tacrolimus, mycophenolate mofetil and corticosteroids. Standard tacrolimus constitutes the control component of immunosuppression in older kidney transplant recipients.
intervention type: Drug
intervention name: ENVARSUS
description: Envarsus is a once-a-day oral formulation of tacrolimus.
arm group label: Envarsus
intervention type: Drug
intervention name: Standard twice daily tacrolimus
description: Standard tacrolimus will include twice-daily formulations that are currently available.
arm group label: Standard twice daily tacrolimus
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: No
last name: Adnan Sharif, MD
role: Principal Investigator
affiliation: Consultant Nephrologist
last name: Adnan Sharif, MD
phone: 0121 371 5861
email: adnan.sharif@uhb.nhs.uk
responsible party type: Principal Investigator
investigator affiliation: University Hospital Birmingham NHS Foundation Trust
investigator full name: Adnan Sharif
investigator title: Consultant Nephrologist
mesh term: Tacrolimus
sharing ipd: Undecided