<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/NCT04469842</url>
  </required_header>
  <id_info>
    <org_study_id>VEL-IIS-2020-085</org_study_id>
    <nct_id>NCT04469842</nct_id>
  </id_info>
  <brief_title>Early Use of Long-acting Tacrolimus in Lung Transplant Recipients</brief_title>
  <official_title>A Prospective, Randomized, Controlled Pilot Study of Early-Use Long Acting Tacrolimus (Envarsus XR) in Lung Transplant Recipients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Veloxis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</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>
      Lung transplantation is a life-saving therapy for patients with advanced lung disease,&#xD;
      however, necessitates the use of life-long immunosuppressive therapy for the prevention of&#xD;
      acute and chronic rejection. The backbone of immunosuppression is the calcineurin-inhibitor&#xD;
      class, with tacrolimus being the preferred drug due to its potency and improved side-effect&#xD;
      profile. Nevertheless, tacrolimus is associated with several side effects including increased&#xD;
      risk for infection and malignancy, tremors, headaches, seizures, hypertension, leukopenia and&#xD;
      renal dysfunction. In fact, by 6 months post-transplant, 50% of patients will have a 50%&#xD;
      decline in eGFR and by 5 years post-transplant ~10% of patients will have advanced renal&#xD;
      disease that may require renal replacement therapy and/or kidney transplantation. Tacrolimus&#xD;
      induces a nephropathy in two ways- acute calcineurin inhibitor nephrotoxicity (CIN) is&#xD;
      mediated by afferent arteriolar vasoconstriction, whereas chronic CIN is due to interstitial&#xD;
      nephritis and fibrosis. Immunosuppressive regimens that spare or dose-reduce calcineurin&#xD;
      inhibitors have been shown to have a modest impact on preserving renal function, but are&#xD;
      limited by timing. Although most studies support implementing renal preserving protocols&#xD;
      early on, this is balanced by the potential for acute cellular rejection, antibody mediated&#xD;
      rejection and anastomotic dehiscence.&#xD;
&#xD;
      Long-acting Tacrolimus (LCP-tacrolimus) may have the potential to bridge the balance of&#xD;
      providing potent immunosuppression, while sparing renal function, due to the better systemic&#xD;
      dose levels and improved concentration/dose ration achieved with it compared to&#xD;
      IR-tacrolimus, evidenced in the renal transplant population. There is limited experience with&#xD;
      LCP-tacrolimus in lung transplantation. Several case reports chronicling the late conversion&#xD;
      from IR-tacrolimus to LCP-tacrolimus due to absorption issues or side-effect intolerance,&#xD;
      have demonstrated safety and tolerability. The investigators seek to determine whether early&#xD;
      use of LCP-tacrolimus in lung transplant recipients following the index hospitalization is&#xD;
      acceptable, and propose a single-center prospective, randomized, controlled pilot study of&#xD;
      early-use LCP-tacrolimus in lung transplant recipients to assess safety, tolerability and&#xD;
      side-effects of LCP-tacrolimus.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Lung transplantation is a life-saving therapy for patients with end-stage lung disease&#xD;
      refractory to medical treatment, providing an improvement in both survival and quality of&#xD;
      life.[1,2] Despite the benefits, patients are at risk for myriad side effects including&#xD;
      infection, malignancy, neurologic complications (headache, tremor, seizures),&#xD;
      gastrointestinal distress and renal failure, to name a few.[3] Many of these are related to&#xD;
      the requisite need for life-long immunosuppression. Current standard immunosuppressive&#xD;
      regimens for lung transplant recipients include calcineurin inhibitors (tacrolimus preferred&#xD;
      over cyclosporine), antiproliferative agents (mycophenolate mofetil vs. azathioprine) and&#xD;
      corticosteroids; calcineurin inhibitors serve as the backbone of immunosuppression.[4] Renal&#xD;
      dysfunction is perhaps the most prevalent complication after lung transplantation, affecting&#xD;
      up to 90% of post-transplant recipients.[5] By 5-year post-transplant, ~8% of patients may&#xD;
      require renal replacement therapy and/or renal transplantation.[6] Renal dysfunction tends to&#xD;
      occur early on in the post-transplant period. Monnier and colleagues showed in a&#xD;
      single-center analysis that the incidence of acute kidney injury within the index&#xD;
      hospitalization was ~75%; the median loss of glomerular function within the first year was&#xD;
      ~45%.[7] Moreover, Canales and colleagues showed that &gt;55% of patients in a cohort of 219&#xD;
      lung transplant recipients had a doubling of their pre-transplant serum creatinine, the&#xD;
      majority occurring within the first year post-transplant.[8] Early renal dysfunction in lung&#xD;
      transplant recipients is associated with a poor overall prognosis. Broelkroleof and&#xD;
      colleagues demonstrated that loss of renal function within he first month post-transplant is&#xD;
      predictive of chronic kidney disease.[9] Moreover, chronic kidney disease is associated with&#xD;
      a five times increased risk of mortality.[5] Perhaps the greatest contributor to the&#xD;
      development of CKD in solid-organ transplant recipients are the calcineurin inhibitors&#xD;
      (CNIs).[10] CNIs cause renal compromise (calcineurin inhibitor nephropathy, CIN) via acute&#xD;
      and chronic mechanisms. Acute CIN is due to potent vasoconstriction of afferent arterioles in&#xD;
      the kidney, resulting in ischemia.[11,12] Chronic CIN is thought to be largely mediated by&#xD;
      interstitial fibrosis as the end-result of arteriolar sclerosis, oxygen free-radical injury,&#xD;
      and upregulation of pro-fibrotic pathways including PDGF, renin-angiotensin-aldosterone&#xD;
      signaling, TGFB and matrix metalloproteinase-9.[11,13] Attempts at utilizing CNI-free or&#xD;
      CNI-reduced regimens in the lung transplantation population has been understudied and/or&#xD;
      unsuccessful to date. Belatacept, a CTLA4-fusion molecule that prevents CD28-mediated&#xD;
      co-stimulation to activate T-lymphocytes, has been well-studied in renal transplantation as&#xD;
      an alternative to CNIs. The BENEFIT Trial, a phase III clinical study of Belatacept vs.&#xD;
      Cyclosporine in renal transplant recipients, demonstrated improvement in patient and&#xD;
      allograft survival, and mean eGFR (~70 cc/min vs ~45cc/min) at seven years. However, rates of&#xD;
      biopsy proven acute cellular rejection were twice as much with Belatacept.[14] Case reports&#xD;
      of Belatacept as rescue therapy in lung transplant recipients intolerant of CNIs are mixed;&#xD;
      there are reports of increased ACR and fulminant acute respiratory distress syndrome.[15,16]&#xD;
      The mTOR inhibitor class of immunosuppression has also been incorporated into regimens in an&#xD;
      effort to ameliorate CNI-toxicity. Villanueva and colleagues assessed outcomes of conversion&#xD;
      to Sirolimus and reduced Tacrolimus in 49 patients with bronchiolitis obliterans syndrome&#xD;
      (chronic rejection) or CNI-intolerance; there was no difference in renal function one year&#xD;
      following sirolimus initiation.[17] Conversely, Shitrit and colleagues demonstrated that&#xD;
      sirolimus plus low-dose tacrolimus led to an improvement in GFR of 10 mL/min, compared to&#xD;
      control maintenance immunosuppression in a pilot study of sixteen lung allograft&#xD;
      recipients.[18] More recently, Gottlieb and colleagues demonstrated that conversion to&#xD;
      quadruple immunosuppression therapy with low-dose CNI (target tacrolimus trough 3-5) led to&#xD;
      improvements in eGFR of 10cc/mL compared to standard immunosuppression (tacrolimus trough&#xD;
      &gt;5). There was no considerable difference in biopsy-proven acute rejection, chronic rejection&#xD;
      and death.[20] The conversion for those in the 4-drug experimental group occurred on average&#xD;
      11 months following transplant, which may account for the muted benefit; perhaps an earlier&#xD;
      change in immunosuppression management would have led to more clinically significant results.&#xD;
      Notably, discontinuation rates of sirolimus in case reports are variable, with most studies&#xD;
      reporting a 20-80% discontinuation rate due to gastrointestinal distress, pneumonitis,&#xD;
      thrombocytopenia, etc., making the mTOR inhibitor class less appealing.[19] It is apparent&#xD;
      that changes to immunosuppression management earlier in the post-transplant period are ideal&#xD;
      to see a maximum benefit in preserved renal function.9 However, this is complicated by the&#xD;
      concerns for acute cellular rejection, which has a peak incidence at 6 months post-lung&#xD;
      transplantation.[21,22] Acute cellular rejection is a leading risk factor for the development&#xD;
      of chronic lung allograft dysfunction (CLAD, chronic rejection).[23] Hence any dose reduction&#xD;
      in CNI or the use of an agent associated with ACR (Belatacept) is less desirable within the&#xD;
      first few months post-transplant.&#xD;
&#xD;
      Given the preference to utilize a CNI-based regimen early-post transplant but still minimize&#xD;
      nephrotoxic effects, the investigators seek to determine whether the early use of long acting&#xD;
      tacrolimus, LCP-Tacrolimus (LCP-tacro, Envarsus XR, Veloxis Pharmaceuticals), results in&#xD;
      improved renal function compared to intermediate release tacrolimus (IR-tacrolimus,&#xD;
      IR-tacro). Anecdotally, LCP-tacro has been used in lung transplant recipients as an&#xD;
      alternative agent for those with debilitating headache or tremor. Early use of LCP-tacro has&#xD;
      not been widely adopted due to perceptions associated with ability to closely titrate trough&#xD;
      levels and cost. However, early use of LCP-tacro may provide several benefits. As a&#xD;
      long-acting formulation, LCP-tacro allows for daily dosing. Moreover, LCP-tacro has greater&#xD;
      absorption and bioavailability, leading to decreased swings in peak and trough&#xD;
      concentrations; frequent fluctuations in serum tacrolimus levels potentiates afferent&#xD;
      arteriolar vasoconstriction.[24] A steady state of systemic tacrolimus trough levels is&#xD;
      desirable, since tacrolimus metabolism is directly related to nephrotoxicity.[25] The use of&#xD;
      LCP-Tacro has been studied in renal transplant recipients. Langone and colleagues identified&#xD;
      that LCP-tacrolimus compared to IR-tacrolimus was associated with improved tremor incidence&#xD;
      and quality of life.[1] Rostaing and colleagues demonstrated that the use of LCP-tacro&#xD;
      compared to intermediate tacrolimus was non-inferior in terms of combined death, allograft&#xD;
      failure, biopsy-proven acute rejection and loss to follow-up. However, the use of LCP-tacro&#xD;
      was associated with a significant reduction in total daily dose, and a 30% reduction in peak&#xD;
      dose, without an increase in biopsy proven acute rejection episodes. Although not a&#xD;
      prospective end-point, there was no significant impact on renal function.[26] In other&#xD;
      studies, though, higher concentration/ drug (C/D) ratios for tacrolimus are associated with&#xD;
      an improved renal safety profile.[27] It is conceivable that a clinical benefit of LCP-tacro&#xD;
      over IR-tacro may be better manifested in clinical arenas that require higher target&#xD;
      tacrolimus trough levels, such as lung allograft recipients, where initial post-transplant&#xD;
      targets can be as high as 12-15 ng/mL, compared to renal transplantation where target trough&#xD;
      levels are a relatively conservative 4-8 ng/mL.[2, 3] The experience of LCP-tacrolimus in the&#xD;
      realm of lung transplantation is limited. Murakoezy and colleagues studied 53 patients that&#xD;
      were converted from short-acting Tacrolimus to long-acting Envarsus. Conversion was performed&#xD;
      at an average 3.6 years post-transplant. Ten patients were switched back due to side-effects&#xD;
      (unknown), though the remainder tolerated conversion without complication. Ahmed and&#xD;
      colleagues demonstrated feasibility in using long-acting Tacrolimus in 8 patients that were&#xD;
      unable to achieve sufficient therapeutic levels with a short-acting formulation due to&#xD;
      suspected polymorphisms of CYP3A4/3A5.[28] McCurry and colleagues assessed safety and&#xD;
      feasibility of LCP-tacrolimus in a retrospective analysis of 18 lung transplant recipients.&#xD;
      They found that patients on LCP-tacro had a 27% reduction in total dose. No patients&#xD;
      experienced any adverse effects. Moreover, 2/18 patients had an improvement in tremors and&#xD;
      headache.[29] Given the limited experience with of LCP-tacrolimus in lung transplant&#xD;
      populations, the investigators propose a prospective, randomized, controlled pilot study to&#xD;
      assess the safety, tolerability, and side-effect profile of early use LCP-tacro within the&#xD;
      first 9 months post-transplantation. It is hypothesized that the early use of LCP-tacro in&#xD;
      lung transplant recipients is safe and tolerable, and associated with an improved side-effect&#xD;
      profile compared to patients treated with standard IR-tacro.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">August 2023</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">August 2025</primary_completion_date>
  <phase>Early Phase 1</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>
    <intervention_model_description>Prospective, randomized, controlled pilot study.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and Tolerability</measure>
    <time_frame>6 months</time_frame>
    <description>Composite of mortality, allograft failure, potential drug induced liver injury, supra-therapeutic trough levels (&gt;20 ng/mL), sub-therapeutic trough levels (&lt;5 ng/mL), seizures, encephalopathy, thrombotic microangiopathy and serious hyperkalemia associated with use of LCP-tacrolimus, compared to matched historical controls administered IR-tacrolimus.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Median change in eGFR at 9 months post-transplant.</measure>
    <time_frame>9 months</time_frame>
    <description>Median change in eGFR from study start to 9 months post-transplantation with patients administered LCP-tacrolimus compared to IR-tacrolimus.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Headache frequency and severity</measure>
    <time_frame>9 months</time_frame>
    <description>Quality of life related to headache frequency and severity using the Headache Impact Tool (HIT-6).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life related to tremor</measure>
    <time_frame>9 months</time_frame>
    <description>Quality of life related to tremor as measured by the QUEST tool.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute cellular rejection</measure>
    <time_frame>9 months</time_frame>
    <description>Incidence of acute cellular rejection (&gt;= A1) or lymphocytic bronchiolitis (&gt;= B1R)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of de novo donor-specific anti-HLA antibodies</measure>
    <time_frame>9 months</time_frame>
    <description>Incidence of de novo donor-specific anti-HLA antibodies (MFI &gt; 1500) within the first 9 months post-transplant.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">48</enrollment>
  <condition>Lung Transplant; Complications</condition>
  <arm_group>
    <arm_group_label>Immunosuppression with Extended-Release Tacrolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LCP-tacrolimus administered daily to target a goal trough level of 10-14 ng/mL x 7 months (with Mycophenolate mofetil and prednisone).&#xD;
Additional standard immunosuppression with either mycophenolate mofetil (500-1500mg twice daily) OR Azathioprine (up to 2mg/kg daily) AND Prednisone (5-10mg daily) will be administered.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Immunosuppression with Intermediate Release Tacrolimus</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>IR-tacrolimus administered twice daily to target a goal trough level of 10-14 ng/mL x 7 months (with Mycophenolate mofetil and prednisone). This is currently the standard of care at Vanderbilt University Medical Center and most other lung transplant centers (ISHLT Registry 2019).&#xD;
Additional standard immunosuppression with either mycophenolate mofetil (500-1500mg twice daily) OR Azathioprine (up to 2mg/kg daily) AND Prednisone (5-10mg daily) will be administered.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus Extended Release Oral Tablet [Envarsus]</intervention_name>
    <description>Immunosuppression regimen with Tacrolimus Extended Release as the backbone.</description>
    <arm_group_label>Immunosuppression with Extended-Release Tacrolimus</arm_group_label>
    <other_name>Envarsus XR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>Standard Immunosuppression regimen with Intermediate-Release Tacrolimus.</description>
    <arm_group_label>Immunosuppression with Intermediate Release Tacrolimus</arm_group_label>
    <other_name>Intermediate Release Tacrolimus</other_name>
    <other_name>Prograf</other_name>
    <other_name>FK506</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mycophenolate Mofetil Hydrochloride</intervention_name>
    <description>Standard immunosuppression of the anti-proliferative class.</description>
    <arm_group_label>Immunosuppression with Extended-Release Tacrolimus</arm_group_label>
    <arm_group_label>Immunosuppression with Intermediate Release Tacrolimus</arm_group_label>
    <other_name>MMF</other_name>
    <other_name>CellCept</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Standard immunosuppression (corticosteroid class).</description>
    <arm_group_label>Immunosuppression with Extended-Release Tacrolimus</arm_group_label>
    <arm_group_label>Immunosuppression with Intermediate Release Tacrolimus</arm_group_label>
    <other_name>Deltasone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azathioprine</intervention_name>
    <description>Standard immunosuppression of the anti-proliferative class.</description>
    <arm_group_label>Immunosuppression with Extended-Release Tacrolimus</arm_group_label>
    <arm_group_label>Immunosuppression with Intermediate Release Tacrolimus</arm_group_label>
    <other_name>Imuran</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Status-post single or bilateral lung transplantation&#xD;
&#xD;
          -  Participant is able to give informed consent for participation in the study.&#xD;
&#xD;
          -  Male or female age 18 years or above.&#xD;
&#xD;
          -  Actively receives care at VUMC and is adherent with medical therapies.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of prior organ transplantation&#xD;
&#xD;
          -  History of tacrolimus use prior to transplantation&#xD;
&#xD;
          -  Intolerance of tacrolimus (that precludes use)&#xD;
&#xD;
          -  Having DSA pre-transplant (Positive virtual crossmatch)&#xD;
&#xD;
          -  Active infection with Hepatitis B or C&#xD;
&#xD;
          -  Active infection with Human Immunodeficiency Virus (HIV)&#xD;
&#xD;
          -  Baseline AST / ALT &gt; three times upper limit normal&#xD;
&#xD;
          -  Primary graft dysfunction grade 3 at 72 hours&#xD;
&#xD;
          -  Acute kidney injury during index hospitalization that does not resolve to two times&#xD;
             the pre-transplant baseline value.&#xD;
&#xD;
          -  Contraindication to PO (per os) intake of medications&#xD;
&#xD;
          -  Impaired GI absorption (defined as sublingual administration of IR-tacro)&#xD;
&#xD;
          -  History of frequent headaches&#xD;
&#xD;
          -  Seizure history&#xD;
&#xD;
          -  Cannot provide consent (at least verbally)&#xD;
&#xD;
          -  Pregnancy or breast-feeding&#xD;
&#xD;
          -  Participation in another interventional clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anil J Trindade, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Anil J Trindade, MD</last_name>
    <phone>615-875-1380</phone>
    <email>anil.trindade@vumc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Haley Hoy, PhD, NP</last_name>
    <phone>615-202-8576</phone>
    <email>haley.hoy@vumc.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
    <contact>
      <last_name>Anil J. Trindade, MD</last_name>
      <phone>615-875-1380</phone>
      <email>anil.trindade@vumc.org</email>
    </contact>
    <investigator>
      <last_name>Anil J Trindade, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Haley Hoy, PhD, NP</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Amit Parulekar, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ivan Robbins, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ciara Shaver, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Stephanie Norfolk, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Katie McPherson, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Rana A, Gruessner A, Agopian VG, Khalpey Z, Riaz IB, Kaplan B, Halazun KJ, Busuttil RW, Gruessner RW. Survival benefit of solid-organ transplant in the United States. JAMA Surg. 2015 Mar 1;150(3):252-9. doi: 10.1001/jamasurg.2014.2038.</citation>
    <PMID>25629390</PMID>
  </reference>
  <reference>
    <citation>Singer JP, Katz PP, Soong A, Shrestha P, Huang D, Ho J, Mindo M, Greenland JR, Hays SR, Golden J, Kukreja J, Kleinhenz ME, Shah RJ, Blanc PD. Effect of Lung Transplantation on Health-Related Quality of Life in the Era of the Lung Allocation Score: A U.S. Prospective Cohort Study. Am J Transplant. 2017 May;17(5):1334-1345. doi: 10.1111/ajt.14081. Epub 2017 Jan 3.</citation>
    <PMID>27743488</PMID>
  </reference>
  <reference>
    <citation>Lyu DM, Zamora MR. Medical complications of lung transplantation. Proc Am Thorac Soc. 2009 Jan 15;6(1):101-7. doi: 10.1513/pats.200808-077GO.</citation>
    <PMID>19131535</PMID>
  </reference>
  <reference>
    <citation>Scheffert JL, Raza K. Immunosuppression in lung transplantation. J Thorac Dis. 2014 Aug;6(8):1039-53. doi: 10.3978/j.issn.2072-1439.2014.04.23.</citation>
    <PMID>25132971</PMID>
  </reference>
  <reference>
    <citation>Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 Sep 4;349(10):931-40. doi: 10.1056/NEJMoa021744.</citation>
    <PMID>12954741</PMID>
  </reference>
  <reference>
    <citation>Chambers DC, Cherikh WS, Harhay MO, Hayes D Jr, Hsich E, Khush KK, Meiser B, Potena L, Rossano JW, Toll AE, Singh TP, Sadavarte A, Zuckermann A, Stehlik J; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant. 2019 Oct;38(10):1042-1055. doi: 10.1016/j.healun.2019.08.001. Epub 2019 Aug 8. No abstract available.</citation>
    <PMID>31548030</PMID>
  </reference>
  <reference>
    <citation>Canales M, Youssef P, Spong R, Ishani A, Savik K, Hertz M, Ibrahim HN. Predictors of chronic kidney disease in long-term survivors of lung and heart-lung transplantation. Am J Transplant. 2006 Sep;6(9):2157-63. doi: 10.1111/j.1600-6143.2006.01458.x. Epub 2006 Jul 6.</citation>
    <PMID>16827787</PMID>
  </reference>
  <reference>
    <citation>Broekroelofs J, Navis GJ, Stegeman CA, van der Bij W, de Boer WJ, de Zeeuw D, de Jong PE. Long-term renal outcome after lung transplantation is predicted by the 1-month postoperative renal function loss. Transplantation. 2000 Apr 27;69(8):1624-8. doi: 10.1097/00007890-200004270-00017.</citation>
    <PMID>10836372</PMID>
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    <citation>Baker RJ, Mark PB, Patel RK, Stevens KK, Palmer N. Renal association clinical practice guideline in post-operative care in the kidney transplant recipient. BMC Nephrol. 2017 Jun 2;18(1):174. doi: 10.1186/s12882-017-0553-2.</citation>
    <PMID>28571571</PMID>
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    <citation>Troster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 2005 Sep;11(6):367-73. doi: 10.1016/j.parkreldis.2005.05.009.</citation>
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    <PMID>20819842</PMID>
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    <citation>Bunnapradist S, Ciechanowski K, West-Thielke P, Mulgaonkar S, Rostaing L, Vasudev B, Budde K; MELT investigators. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013 Mar;13(3):760-9. doi: 10.1111/ajt.12035. Epub 2012 Dec 21.</citation>
    <PMID>23279614</PMID>
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    <citation>Kotloff RM, Ahya VN. Medical complications of lung transplantation. Eur Respir J. 2004 Feb;23(2):334-42. doi: 10.1183/09031936.03.00043403.</citation>
    <PMID>14979513</PMID>
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    <citation>Ferrari U, Empl M, Kim KS, Sostak P, Forderreuther S, Straube A. Calcineurin inhibitor-induced headache: clinical characteristics and possible mechanisms. Headache. 2005 Mar;45(3):211-4. doi: 10.1111/j.1526-4610.2005.05046.x.</citation>
    <PMID>15836594</PMID>
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    <citation>Maggioni F, Mantovan MC, Rigotti P, Cadrobbi R, Mainardi F, Mampreso E, Ermani M, Cortelazzo S, Zanchin G. Headache in kidney transplantation. J Headache Pain. 2009 Dec;10(6):455-60. doi: 10.1007/s10194-009-0148-9. Epub 2009 Aug 27.</citation>
    <PMID>19711000</PMID>
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    <citation>Waikar SS, Rebholz CM, Zheng Z, Hurwitz S, Hsu CY, Feldman HI, Xie D, Liu KD, Mifflin TE, Eckfeldt JH, Kimmel PL, Vasan RS, Bonventre JV, Inker LA, Coresh J; Chronic Kidney Disease Biomarkers Consortium Investigators. Biological Variability of Estimated GFR and Albuminuria in CKD. Am J Kidney Dis. 2018 Oct;72(4):538-546. doi: 10.1053/j.ajkd.2018.04.023. Epub 2018 Jul 18.</citation>
    <PMID>30031564</PMID>
  </reference>
  <reference>
    <citation>Levine DJ, Glanville AR, Aboyoun C, Belperio J, Benden C, Berry GJ, Hachem R, Hayes D Jr, Neil D, Reinsmoen NL, Snyder LD, Sweet S, Tyan D, Verleden G, Westall G, Yusen RD, Zamora M, Zeevi A. Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2016 Apr;35(4):397-406. doi: 10.1016/j.healun.2016.01.1223. Epub 2016 Feb 10.</citation>
    <PMID>27044531</PMID>
  </reference>
  <reference>
    <citation>Ahmed SK, Seethamraju H. CYP3A5 Polymorphisms and Conversion to Once-Daily, Extended-Release Tacrolimus in Lung Transplant (LTx). J Heart Lung Transplant. 2020; 39(4): S505.</citation>
  </reference>
  <results_reference>
    <citation>Monnier A, Kummel T, Collage O, et al. Prevalence of Acute and Chronic Renal Failure After Lung Transplantation. In. Vol 34. Journal Heart Lung Transplantation 2015:S261.</citation>
  </results_reference>
  <results_reference>
    <citation>McCurry KA,Fitzgerald LJ, Chan JM, Jia S. Conversion from Tacrolimus IR (Twice Daily) or Cyclosporine to Tacrolimus XR (Envarsus®, Once Daily) in Lung Transplant Recipients. J Heart Lung Transplant. 2020; 39(4): S505</citation>
  </results_reference>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 9, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>July 6, 2023</last_update_submitted>
  <last_update_submitted_qc>July 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Anil Trindade</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Lung Transplantation</keyword>
  <keyword>Calcineurin inhibitor</keyword>
  <keyword>LCP-tacrolimus (Envarsus XR)</keyword>
  <keyword>Calcineurin-inhibitor nephrotoxicity (CIN)</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mycophenolic Acid</mesh_term>
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Azathioprine</mesh_term>
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04469842
org study id: VEL-IIS-2020-085
nct id: NCT04469842
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Lung transplantation is a life-saving therapy for patients with advanced lung disease,
      however, necessitates the use of life-long immunosuppressive therapy for the prevention of
      acute and chronic rejection. The backbone of immunosuppression is the calcineurin-inhibitor
      class, with tacrolimus being the preferred drug due to its potency and improved side-effect
      profile. Nevertheless, tacrolimus is associated with several side effects including increased
      risk for infection and malignancy, tremors, headaches, seizures, hypertension, leukopenia and
      renal dysfunction. In fact, by 6 months post-transplant, 50% of patients will have a 50%
      decline in eGFR and by 5 years post-transplant ~10% of patients will have advanced renal
      disease that may require renal replacement therapy and/or kidney transplantation. Tacrolimus
      induces a nephropathy in two ways- acute calcineurin inhibitor nephrotoxicity (CIN) is
      mediated by afferent arteriolar vasoconstriction, whereas chronic CIN is due to interstitial
      nephritis and fibrosis. Immunosuppressive regimens that spare or dose-reduce calcineurin
      inhibitors have been shown to have a modest impact on preserving renal function, but are
      limited by timing. Although most studies support implementing renal preserving protocols
      early on, this is balanced by the potential for acute cellular rejection, antibody mediated
      rejection and anastomotic dehiscence.

      Long-acting Tacrolimus (LCP-tacrolimus) may have the potential to bridge the balance of
      providing potent immunosuppression, while sparing renal function, due to the better systemic
      dose levels and improved concentration/dose ration achieved with it compared to
      IR-tacrolimus, evidenced in the renal transplant population. There is limited experience with
      LCP-tacrolimus in lung transplantation. Several case reports chronicling the late conversion
      from IR-tacrolimus to LCP-tacrolimus due to absorption issues or side-effect intolerance,
      have demonstrated safety and tolerability. The investigators seek to determine whether early
      use of LCP-tacrolimus in lung transplant recipients following the index hospitalization is
      acceptable, and propose a single-center prospective, randomized, controlled pilot study of
      early-use LCP-tacrolimus in lung transplant recipients to assess safety, tolerability and
      side-effects of LCP-tacrolimus.
Lung transplantation is a life-saving therapy for patients with end-stage lung disease
      refractory to medical treatment, providing an improvement in both survival and quality of
      life.[1,2] Despite the benefits, patients are at risk for myriad side effects including
      infection, malignancy, neurologic complications (headache, tremor, seizures),
      gastrointestinal distress and renal failure, to name a few.[3] Many of these are related to
      the requisite need for life-long immunosuppression. Current standard immunosuppressive
      regimens for lung transplant recipients include calcineurin inhibitors (tacrolimus preferred
      over cyclosporine), antiproliferative agents (mycophenolate mofetil vs. azathioprine) and
      corticosteroids; calcineurin inhibitors serve as the backbone of immunosuppression.[4] Renal
      dysfunction is perhaps the most prevalent complication after lung transplantation, affecting
      up to 90% of post-transplant recipients.[5] By 5-year post-transplant, ~8% of patients may
      require renal replacement therapy and/or renal transplantation.[6] Renal dysfunction tends to
      occur early on in the post-transplant period. Monnier and colleagues showed in a
      single-center analysis that the incidence of acute kidney injury within the index
      hospitalization was ~75%; the median loss of glomerular function within the first year was
      ~45%.[7] Moreover, Canales and colleagues showed that >55% of patients in a cohort of 219
      lung transplant recipients had a doubling of their pre-transplant serum creatinine, the
      majority occurring within the first year post-transplant.[8] Early renal dysfunction in lung
      transplant recipients is associated with a poor overall prognosis. Broelkroleof and
      colleagues demonstrated that loss of renal function within he first month post-transplant is
      predictive of chronic kidney disease.[9] Moreover, chronic kidney disease is associated with
      a five times increased risk of mortality.[5] Perhaps the greatest contributor to the
      development of CKD in solid-organ transplant recipients are the calcineurin inhibitors
      (CNIs).[10] CNIs cause renal compromise (calcineurin inhibitor nephropathy, CIN) via acute
      and chronic mechanisms. Acute CIN is due to potent vasoconstriction of afferent arterioles in
      the kidney, resulting in ischemia.[11,12] Chronic CIN is thought to be largely mediated by
      interstitial fibrosis as the end-result of arteriolar sclerosis, oxygen free-radical injury,
      and upregulation of pro-fibrotic pathways including PDGF, renin-angiotensin-aldosterone
      signaling, TGFB and matrix metalloproteinase-9.[11,13] Attempts at utilizing CNI-free or
      CNI-reduced regimens in the lung transplantation population has been understudied and/or
      unsuccessful to date. Belatacept, a CTLA4-fusion molecule that prevents CD28-mediated
      co-stimulation to activate T-lymphocytes, has been well-studied in renal transplantation as
      an alternative to CNIs. The BENEFIT Trial, a phase III clinical study of Belatacept vs.
      Cyclosporine in renal transplant recipients, demonstrated improvement in patient and
      allograft survival, and mean eGFR (~70 cc/min vs ~45cc/min) at seven years. However, rates of
      biopsy proven acute cellular rejection were twice as much with Belatacept.[14] Case reports
      of Belatacept as rescue therapy in lung transplant recipients intolerant of CNIs are mixed;
      there are reports of increased ACR and fulminant acute respiratory distress syndrome.[15,16]
      The mTOR inhibitor class of immunosuppression has also been incorporated into regimens in an
      effort to ameliorate CNI-toxicity. Villanueva and colleagues assessed outcomes of conversion
      to Sirolimus and reduced Tacrolimus in 49 patients with bronchiolitis obliterans syndrome
      (chronic rejection) or CNI-intolerance; there was no difference in renal function one year
      following sirolimus initiation.[17] Conversely, Shitrit and colleagues demonstrated that
      sirolimus plus low-dose tacrolimus led to an improvement in GFR of 10 mL/min, compared to
      control maintenance immunosuppression in a pilot study of sixteen lung allograft
      recipients.[18] More recently, Gottlieb and colleagues demonstrated that conversion to
      quadruple immunosuppression therapy with low-dose CNI (target tacrolimus trough 3-5) led to
      improvements in eGFR of 10cc/mL compared to standard immunosuppression (tacrolimus trough
      >5). There was no considerable difference in biopsy-proven acute rejection, chronic rejection
      and death.[20] The conversion for those in the 4-drug experimental group occurred on average
      11 months following transplant, which may account for the muted benefit; perhaps an earlier
      change in immunosuppression management would have led to more clinically significant results.
      Notably, discontinuation rates of sirolimus in case reports are variable, with most studies
      reporting a 20-80% discontinuation rate due to gastrointestinal distress, pneumonitis,
      thrombocytopenia, etc., making the mTOR inhibitor class less appealing.[19] It is apparent
      that changes to immunosuppression management earlier in the post-transplant period are ideal
      to see a maximum benefit in preserved renal function.9 However, this is complicated by the
      concerns for acute cellular rejection, which has a peak incidence at 6 months post-lung
      transplantation.[21,22] Acute cellular rejection is a leading risk factor for the development
      of chronic lung allograft dysfunction (CLAD, chronic rejection).[23] Hence any dose reduction
      in CNI or the use of an agent associated with ACR (Belatacept) is less desirable within the
      first few months post-transplant.

      Given the preference to utilize a CNI-based regimen early-post transplant but still minimize
      nephrotoxic effects, the investigators seek to determine whether the early use of long acting
      tacrolimus, LCP-Tacrolimus (LCP-tacro, Envarsus XR, Veloxis Pharmaceuticals), results in
      improved renal function compared to intermediate release tacrolimus (IR-tacrolimus,
      IR-tacro). Anecdotally, LCP-tacro has been used in lung transplant recipients as an
      alternative agent for those with debilitating headache or tremor. Early use of LCP-tacro has
      not been widely adopted due to perceptions associated with ability to closely titrate trough
      levels and cost. However, early use of LCP-tacro may provide several benefits. As a
      long-acting formulation, LCP-tacro allows for daily dosing. Moreover, LCP-tacro has greater
      absorption and bioavailability, leading to decreased swings in peak and trough
      concentrations; frequent fluctuations in serum tacrolimus levels potentiates afferent
      arteriolar vasoconstriction.[24] A steady state of systemic tacrolimus trough levels is
      desirable, since tacrolimus metabolism is directly related to nephrotoxicity.[25] The use of
      LCP-Tacro has been studied in renal transplant recipients. Langone and colleagues identified
      that LCP-tacrolimus compared to IR-tacrolimus was associated with improved tremor incidence
      and quality of life.[1] Rostaing and colleagues demonstrated that the use of LCP-tacro
      compared to intermediate tacrolimus was non-inferior in terms of combined death, allograft
      failure, biopsy-proven acute rejection and loss to follow-up. However, the use of LCP-tacro
      was associated with a significant reduction in total daily dose, and a 30% reduction in peak
      dose, without an increase in biopsy proven acute rejection episodes. Although not a
      prospective end-point, there was no significant impact on renal function.[26] In other
      studies, though, higher concentration/ drug (C/D) ratios for tacrolimus are associated with
      an improved renal safety profile.[27] It is conceivable that a clinical benefit of LCP-tacro
      over IR-tacro may be better manifested in clinical arenas that require higher target
      tacrolimus trough levels, such as lung allograft recipients, where initial post-transplant
      targets can be as high as 12-15 ng/mL, compared to renal transplantation where target trough
      levels are a relatively conservative 4-8 ng/mL.[2, 3] The experience of LCP-tacrolimus in the
      realm of lung transplantation is limited. Murakoezy and colleagues studied 53 patients that
      were converted from short-acting Tacrolimus to long-acting Envarsus. Conversion was performed
      at an average 3.6 years post-transplant. Ten patients were switched back due to side-effects
      (unknown), though the remainder tolerated conversion without complication. Ahmed and
      colleagues demonstrated feasibility in using long-acting Tacrolimus in 8 patients that were
      unable to achieve sufficient therapeutic levels with a short-acting formulation due to
      suspected polymorphisms of CYP3A4/3A5.[28] McCurry and colleagues assessed safety and
      feasibility of LCP-tacrolimus in a retrospective analysis of 18 lung transplant recipients.
      They found that patients on LCP-tacro had a 27% reduction in total dose. No patients
      experienced any adverse effects. Moreover, 2/18 patients had an improvement in tremors and
      headache.[29] Given the limited experience with of LCP-tacrolimus in lung transplant
      populations, the investigators propose a prospective, randomized, controlled pilot study to
      assess the safety, tolerability, and side-effect profile of early use LCP-tacro within the
      first 9 months post-transplantation. It is hypothesized that the early use of LCP-tacro in
      lung transplant recipients is safe and tolerable, and associated with an improved side-effect
      profile compared to patients treated with standard IR-tacro.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Prospective, randomized, controlled pilot study.
primary purpose: Treatment
masking: None (Open Label)
measure: Safety and Tolerability
time frame: 6 months
description: Composite of mortality, allograft failure, potential drug induced liver injury, supra-therapeutic trough levels (>20 ng/mL), sub-therapeutic trough levels (<5 ng/mL), seizures, encephalopathy, thrombotic microangiopathy and serious hyperkalemia associated with use of LCP-tacrolimus, compared to matched historical controls administered IR-tacrolimus.
measure: Median change in eGFR at 9 months post-transplant.
time frame: 9 months
description: Median change in eGFR from study start to 9 months post-transplantation with patients administered LCP-tacrolimus compared to IR-tacrolimus.
measure: Headache frequency and severity
time frame: 9 months
description: Quality of life related to headache frequency and severity using the Headache Impact Tool (HIT-6).
measure: Quality of life related to tremor
time frame: 9 months
description: Quality of life related to tremor as measured by the QUEST tool.
measure: Incidence of acute cellular rejection
time frame: 9 months
description: Incidence of acute cellular rejection (>= A1) or lymphocytic bronchiolitis (>= B1R)
measure: Incidence of de novo donor-specific anti-HLA antibodies
time frame: 9 months
description: Incidence of de novo donor-specific anti-HLA antibodies (MFI > 1500) within the first 9 months post-transplant.
arm group label: Immunosuppression with Extended-Release Tacrolimus
arm group type: Experimental
description: LCP-tacrolimus administered daily to target a goal trough level of 10-14 ng/mL x 7 months (with Mycophenolate mofetil and prednisone).
Additional standard immunosuppression with either mycophenolate mofetil (500-1500mg twice daily) OR Azathioprine (up to 2mg/kg daily) AND Prednisone (5-10mg daily) will be administered.
arm group label: Immunosuppression with Intermediate Release Tacrolimus
arm group type: Active Comparator
description: IR-tacrolimus administered twice daily to target a goal trough level of 10-14 ng/mL x 7 months (with Mycophenolate mofetil and prednisone). This is currently the standard of care at Vanderbilt University Medical Center and most other lung transplant centers (ISHLT Registry 2019).
Additional standard immunosuppression with either mycophenolate mofetil (500-1500mg twice daily) OR Azathioprine (up to 2mg/kg daily) AND Prednisone (5-10mg daily) will be administered.
intervention type: Drug
intervention name: Tacrolimus Extended Release Oral Tablet [Envarsus]
description: Immunosuppression regimen with Tacrolimus Extended Release as the backbone.
arm group label: Immunosuppression with Extended-Release Tacrolimus
other name: Envarsus XR
intervention type: Drug
intervention name: Tacrolimus
description: Standard Immunosuppression regimen with Intermediate-Release Tacrolimus.
arm group label: Immunosuppression with Intermediate Release Tacrolimus
other name: Intermediate Release Tacrolimus
other name: Prograf
other name: FK506
intervention type: Drug
intervention name: Mycophenolate Mofetil Hydrochloride
description: Standard immunosuppression of the anti-proliferative class.
arm group label: Immunosuppression with Extended-Release Tacrolimus
arm group label: Immunosuppression with Intermediate Release Tacrolimus
other name: MMF
other name: CellCept
intervention type: Drug
intervention name: Prednisone
description: Standard immunosuppression (corticosteroid class).
arm group label: Immunosuppression with Extended-Release Tacrolimus
arm group label: Immunosuppression with Intermediate Release Tacrolimus
other name: Deltasone
intervention type: Drug
intervention name: Azathioprine
description: Standard immunosuppression of the anti-proliferative class.
arm group label: Immunosuppression with Extended-Release Tacrolimus
arm group label: Immunosuppression with Intermediate Release Tacrolimus
other name: Imuran
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anil J Trindade, MD
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
last name: Anil J Trindade, MD
phone: 615-875-1380
email: anil.trindade@vumc.org
last name: Haley Hoy, PhD, NP
phone: 615-202-8576
email: haley.hoy@vumc.org
facility: 
contact: 
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country: United States
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citation: Ahmed SK, Seethamraju H. CYP3A5 Polymorphisms and Conversion to Once-Daily, Extended-Release Tacrolimus in Lung Transplant (LTx). J Heart Lung Transplant. 2020; 39(4): S505.
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responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Anil Trindade
investigator title: Associate Professor of Medicine
mesh term: Mycophenolic Acid
mesh term: Prednisone
mesh term: Azathioprine
mesh term: Tacrolimus
sharing ipd: No