<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/NCT04415476</url>
  </required_header>
  <id_info>
    <org_study_id>HP-00091412</org_study_id>
    <nct_id>NCT04415476</nct_id>
  </id_info>
  <brief_title>Standard Therapy Using Tacrolimus, Mycophenolate Mofetil and Prednisone For Chronic Lung Transplant Rejection (BOS)</brief_title>
  <official_title>A Randomized, Open-label,Controlled Phase II b Study to Demonstrate Efficacy and Safety of Sirolimus Chronic Rejection After Lung Transplant</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Maryland, Baltimore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Maryland, Baltimore</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective single-center, open-label, randomized, controlled pilot&#xD;
&#xD;
      study in the treatment of chronic rejection (CR), defined as grade 1 and 2&#xD;
&#xD;
      BOS, in adult recipients of a pulmonary allograft (single or double lungs).To assess the&#xD;
      efficacy and safety of sirolimus plus tacrolimus and prednisone&#xD;
&#xD;
      (S) compared to standard therapy (tacrolimus, mycophenolate mofetil&#xD;
&#xD;
      (MMF) and prednisone) (ST) for chronic rejection, defined as grades 1 and 2&#xD;
&#xD;
      bronchiolitis obliterans syndrome (BOS); BOS defined as ≥ 20% decline&#xD;
&#xD;
      from maximal post-transplant FEV1.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a prospective single-center, open-label, randomized, controlled pilot&#xD;
&#xD;
      study in the treatment of chronic rejection (CR), defined as grade 1 and 2&#xD;
&#xD;
      BOS, in adult recipients of a pulmonary allograft (single or double lungs).&#xD;
&#xD;
      Patients meeting entry criteria shall demonstrate a sustained decline in FEV1&#xD;
&#xD;
      having met stage 1 or 2 BOS. Patients randomized to the study arm, will be&#xD;
&#xD;
      treated with Sirolimus (S) orally in place of MMF in addition to tacrolimus&#xD;
&#xD;
      and prednisone compared to those patients randomized to defined ST alone&#xD;
&#xD;
      (tacrolimus, MMF and prednisone). The trial duration will be approximately&#xD;
&#xD;
      Primary endpoints will include:&#xD;
&#xD;
      Efficacy failure between ST and S randomized group investigational treatment regimens will be&#xD;
      determined at 96 weeks after the last patient is randomization and enrolled at approximately&#xD;
      study year 2. The control arm will receive standard of care treatment (ST) and&#xD;
      immunosuppression according to the University of Maryland lung transplant protocol. Efficacy&#xD;
      failure will be defined as the combined end point of progression of BOS (defined as at least&#xD;
      a 20 % decline from the initial randomization FEV1 value confirmed by two separate&#xD;
      measurements three weeks apart or more) or re-transplantation or death. The co-primary end&#xD;
      point of FEV1 and FVC changes to define functional stabilization in the S arm compared to ST&#xD;
      is to be completed when the last patient randomized (patient #30) has been enrolled for 2&#xD;
      years as well.&#xD;
&#xD;
      Efficacy of S is to be assessed using following parameters to determine its effect on lung&#xD;
      function:&#xD;
&#xD;
        1. Forced expiratory volume in one second (FEV1)&#xD;
&#xD;
        2. Forced vital capacity (FVC)&#xD;
&#xD;
        3. FEF 25-75&#xD;
&#xD;
      Secondary endpoints will include:&#xD;
&#xD;
        -  General S tolerability&#xD;
&#xD;
        -  Incidence and severity of adverse events (AE)&#xD;
&#xD;
        -  Changes in clinical laboratory parameters from baseline after randomization&#xD;
&#xD;
        -  Changes in vital signs&#xD;
&#xD;
        -  Changes in physical examinations&#xD;
&#xD;
        -  Incidence of infections&#xD;
&#xD;
        -  Average maintenance doses of calcineurin inhibitors, antimetabolite agents, and&#xD;
           corticosteroids&#xD;
&#xD;
        -  Number of courses of augmented immunosuppressants&#xD;
&#xD;
        -  Number and days of hospitalization&#xD;
&#xD;
        -  Incidence of malignancies&#xD;
&#xD;
        -  Overall mortality (including transplant-related mortality)&#xD;
&#xD;
        -  Retransplantation&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study did not proceed to IRB approval.&#xD;
  </why_stopped>
  <start_date type="Anticipated">June 30, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2028</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Paralled Assignment</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Death</measure>
    <time_frame>2 years</time_frame>
    <description>Increase in motility</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Re-Transplantation</measure>
    <time_frame>2 years</time_frame>
    <description>Increase in re-transplantation from baseline</description>
  </primary_outcome>
  <primary_outcome>
    <measure>FEV1 (Forced Respiratory Volume in 1 second)</measure>
    <time_frame>2 years</time_frame>
    <description>Greater or equal to 20% decline in FEV1 from randomization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>FVC (Forced Vital Capacity)</measure>
    <time_frame>2 years</time_frame>
    <description>Caparison between the two treatment groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FEF (forced expiratory flow)</measure>
    <time_frame>2 years</time_frame>
    <description>The rate of airflow recorded in measurements of forced vital capacity, usually calculated as an average flow over a given portion of the expiratory curve; the portion between 25 and 75 per cent of forced vital capacity.&#xD;
Comparison on FEF(25-75) between the two treatment groups.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Disorder Related to Lung Transplantation</condition>
  <condition>Chronic Rejection of Lung Transplant</condition>
  <condition>Decreased Immunologic Activity</condition>
  <arm_group>
    <arm_group_label>Sirolimus and Tacrolimus and prednisone</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Assigned Interventions Sirolimus (Rapamune) Tacrolimus (Prograft) Prednisone (Deltasone, Prednicot, Rayos, Sterapred)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arm1:) sirolimus and tacrolimus and prednisone group:&#xD;
Tacrolimus, The patient will receive 0.1-0.15 mg/kg/day PO in 2 divided doses Adjust trough blood 5-12 ng/ml.&#xD;
Mycophenolate mofetil (NA )Stopped upon sirolimus initiation Sirolimus:1-5 mg/day PO if &gt;40 kg / 1 mg/m²/day if &lt;40 kg trough blood levels 5-12 ng/ml Prednisone:20 mg/day PO if &gt;40 kg and 10 mg/day if &lt;40 kg, adjust based on adverse effects.&#xD;
Arm 2) Standard Therapy Tacrolimus:0.1 to 0.15 mg/kg/day PO in 2 divided doses Adjust trough blood 8-12 ng/ml Mycophenolate mofetil:750-1250 mg bid PO and adjust to tolerance (WBCs and GI side effects Sirolimus: NA Prednisone: Prednisone dose 20 mg/day PO if &gt;40 kg and 10 mg/day if &lt;40 kg, adjust based on adverse effect</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Assigned Interventions</intervention_name>
    <description>This is a prospective single-center, open-label, randomized, controlled pilot study in the treatment of chronic rejection (CR), defined as grade 1 and 2 BOS, in adult recipients of a pulmonary allograft (single or double lungs). Patients meeting entry criteria shall demonstrate a sustained decline in FEV1 having met stage 1 or 2 BOS. Patients randomized to the study arm, will be treated with Sirolimus (S) orally in place of MMF in addition to tacrolimus and prednisone compared to those patients randomized to defined ST alone (tacrolimus, MMF and prednisone). The trial duration will be approximately 2 years for each subject randomized. Treatment compliance and safety will be monitored by clinic visits at 4-6 week intervals for the 2 year subject duration and will include standard physical examinations and monitoring of routine clinical and laboratory parameters including cause of hospitalizations and rate of adverse events including death in each group. T</description>
    <arm_group_label>Sirolimus and Tacrolimus and prednisone</arm_group_label>
    <arm_group_label>Standard of Care</arm_group_label>
    <other_name>Tacrolimus</other_name>
    <other_name>Mycophenolate mofetil</other_name>
    <other_name>Prednisone</other_name>
    <other_name>Sirolimus</other_name>
    <other_name>Prograft</other_name>
    <other_name>Cellcept</other_name>
    <other_name>Deltasone</other_name>
    <other_name>Prednicot</other_name>
    <other_name>Rayos</other_name>
    <other_name>Sterapred</other_name>
    <other_name>Rapamune</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age: 18 or older.&#xD;
&#xD;
          2. Recipient of a single or double pulmonary allograft at least twelve months before&#xD;
             study entry.&#xD;
&#xD;
          3. Clinically diagnosed BOS grade 1 or 2&#xD;
&#xD;
          4. Receiving oral TAC-based immunosuppression according to institutional standards.&#xD;
&#xD;
          5. Capable of understanding the purposes and risks of the study, has given written&#xD;
             informed consent and agrees to comply with the study requirements and capable of&#xD;
             protocol adherence.&#xD;
&#xD;
          6. Women of childbearing potential must have a negative serum pregnancy test within 7&#xD;
             days prior to study entry.&#xD;
&#xD;
          7. Stable to enable routine pre and post-transplant bronchoscopy with BAL and biopsy.&#xD;
&#xD;
          8. Fasting cholesterol &lt; 250 mg/dL, fasting triglycerides &lt; 250 mg/dL -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Active bacterial, viral or fungal infection not successfully resolved at least 4 weeks&#xD;
             prior to study entry.&#xD;
&#xD;
          2. Mechanical ventilation.&#xD;
&#xD;
          3. At screening FEV1 &lt; 1 liter and/or &lt; FEV1 of 25 % predicted.&#xD;
&#xD;
          4. Pregnant women or women who are unwilling to use appropriate birth control to avoid&#xD;
             pregnancy.&#xD;
&#xD;
          5. Women who breastfeed.&#xD;
&#xD;
          6. Known hypersensitivity to sirolimus.&#xD;
&#xD;
          7. Serum creatinine value of &gt; 2.5 mg/dL or chronic dialysis use or liver disease with a&#xD;
             bilirubin &gt; 2 mg/dL.&#xD;
&#xD;
          8. Subjects with severe underlying disease other than BOS that is thought to become fatal&#xD;
             within four months of clinical assessment.&#xD;
&#xD;
          9. Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to&#xD;
             study entry. This is defined as any treatment that is implemented under an&#xD;
             Investigational New Drug.&#xD;
&#xD;
         10. Psychiatric disorders or altered mental status precluding understanding of the&#xD;
             informed consent process and/or completion of the necessary procedures.&#xD;
&#xD;
         11. Any co-existing medical condition that in the Investigator's judgment will&#xD;
             substantially increase the risk associated with the patient's participation in the&#xD;
             clinical trial.&#xD;
&#xD;
         12. Clinically significant bronchial strictures unresponsive to dilatation procedures.&#xD;
&#xD;
         13. Subjects with malignancy diagnosed within one year prior to screen (with the exception&#xD;
             of skin cancers).&#xD;
&#xD;
         14. Lipid panel fasting cholesterol &gt; 250 mg/dL, fasting triglycerides &gt;250 mg/dL&#xD;
&#xD;
             -&#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>Aldo T Iacono, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Maryland, Baltimore</affiliation>
  </overall_official>
  <results_reference>
    <citation>Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, Fung JJ, Burckart GJ, McCurry KR, Griffith BP. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med. 2006 Jan 12;354(2):141-50. doi: 10.1056/NEJMoa043204.</citation>
    <PMID>16407509</PMID>
  </results_reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>May 13, 2020</study_first_submitted>
  <study_first_submitted_qc>June 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>lung function</keyword>
  <keyword>Lung Transplantation</keyword>
  <keyword>case-control study</keyword>
  <keyword>bronchiolitis obliterans syndrome (BOS)</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mycophenolic Acid</mesh_term>
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Prednisone</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/NCT04415476
org study id: HP-00091412
nct id: NCT04415476
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a prospective single-center, open-label, randomized, controlled pilot

      study in the treatment of chronic rejection (CR), defined as grade 1 and 2

      BOS, in adult recipients of a pulmonary allograft (single or double lungs).To assess the
      efficacy and safety of sirolimus plus tacrolimus and prednisone

      (S) compared to standard therapy (tacrolimus, mycophenolate mofetil

      (MMF) and prednisone) (ST) for chronic rejection, defined as grades 1 and 2

      bronchiolitis obliterans syndrome (BOS); BOS defined as ≥ 20% decline

      from maximal post-transplant FEV1.
This is a prospective single-center, open-label, randomized, controlled pilot

      study in the treatment of chronic rejection (CR), defined as grade 1 and 2

      BOS, in adult recipients of a pulmonary allograft (single or double lungs).

      Patients meeting entry criteria shall demonstrate a sustained decline in FEV1

      having met stage 1 or 2 BOS. Patients randomized to the study arm, will be

      treated with Sirolimus (S) orally in place of MMF in addition to tacrolimus

      and prednisone compared to those patients randomized to defined ST alone

      (tacrolimus, MMF and prednisone). The trial duration will be approximately

      Primary endpoints will include:

      Efficacy failure between ST and S randomized group investigational treatment regimens will be
      determined at 96 weeks after the last patient is randomization and enrolled at approximately
      study year 2. The control arm will receive standard of care treatment (ST) and
      immunosuppression according to the University of Maryland lung transplant protocol. Efficacy
      failure will be defined as the combined end point of progression of BOS (defined as at least
      a 20 % decline from the initial randomization FEV1 value confirmed by two separate
      measurements three weeks apart or more) or re-transplantation or death. The co-primary end
      point of FEV1 and FVC changes to define functional stabilization in the S arm compared to ST
      is to be completed when the last patient randomized (patient #30) has been enrolled for 2
      years as well.

      Efficacy of S is to be assessed using following parameters to determine its effect on lung
      function:

        1. Forced expiratory volume in one second (FEV1)

        2. Forced vital capacity (FVC)

        3. FEF 25-75

      Secondary endpoints will include:

        -  General S tolerability

        -  Incidence and severity of adverse events (AE)

        -  Changes in clinical laboratory parameters from baseline after randomization

        -  Changes in vital signs

        -  Changes in physical examinations

        -  Incidence of infections

        -  Average maintenance doses of calcineurin inhibitors, antimetabolite agents, and
           corticosteroids

        -  Number of courses of augmented immunosuppressants

        -  Number and days of hospitalization

        -  Incidence of malignancies

        -  Overall mortality (including transplant-related mortality)

        -  Retransplantation
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Paralled Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Death
time frame: 2 years
description: Increase in motility
measure: Re-Transplantation
time frame: 2 years
description: Increase in re-transplantation from baseline
measure: FEV1 (Forced Respiratory Volume in 1 second)
time frame: 2 years
description: Greater or equal to 20% decline in FEV1 from randomization
measure: FVC (Forced Vital Capacity)
time frame: 2 years
description: Caparison between the two treatment groups.
measure: FEF (forced expiratory flow)
time frame: 2 years
description: The rate of airflow recorded in measurements of forced vital capacity, usually calculated as an average flow over a given portion of the expiratory curve; the portion between 25 and 75 per cent of forced vital capacity.
Comparison on FEF(25-75) between the two treatment groups.
arm group label: Sirolimus and Tacrolimus and prednisone
arm group type: Other
description: Assigned Interventions Sirolimus (Rapamune) Tacrolimus (Prograft) Prednisone (Deltasone, Prednicot, Rayos, Sterapred)
arm group label: Standard of Care
arm group type: Experimental
description: Arm1:) sirolimus and tacrolimus and prednisone group:
Tacrolimus, The patient will receive 0.1-0.15 mg/kg/day PO in 2 divided doses Adjust trough blood 5-12 ng/ml.
Mycophenolate mofetil (NA )Stopped upon sirolimus initiation Sirolimus:1-5 mg/day PO if >40 kg / 1 mg/m²/day if <40 kg trough blood levels 5-12 ng/ml Prednisone:20 mg/day PO if >40 kg and 10 mg/day if <40 kg, adjust based on adverse effects.
Arm 2) Standard Therapy Tacrolimus:0.1 to 0.15 mg/kg/day PO in 2 divided doses Adjust trough blood 8-12 ng/ml Mycophenolate mofetil:750-1250 mg bid PO and adjust to tolerance (WBCs and GI side effects Sirolimus: NA Prednisone: Prednisone dose 20 mg/day PO if >40 kg and 10 mg/day if <40 kg, adjust based on adverse effect
intervention type: Drug
intervention name: Assigned Interventions
description: This is a prospective single-center, open-label, randomized, controlled pilot study in the treatment of chronic rejection (CR), defined as grade 1 and 2 BOS, in adult recipients of a pulmonary allograft (single or double lungs). Patients meeting entry criteria shall demonstrate a sustained decline in FEV1 having met stage 1 or 2 BOS. Patients randomized to the study arm, will be treated with Sirolimus (S) orally in place of MMF in addition to tacrolimus and prednisone compared to those patients randomized to defined ST alone (tacrolimus, MMF and prednisone). The trial duration will be approximately 2 years for each subject randomized. Treatment compliance and safety will be monitored by clinic visits at 4-6 week intervals for the 2 year subject duration and will include standard physical examinations and monitoring of routine clinical and laboratory parameters including cause of hospitalizations and rate of adverse events including death in each group. T
arm group label: Sirolimus and Tacrolimus and prednisone
arm group label: Standard of Care
other name: Tacrolimus
other name: Mycophenolate mofetil
other name: Prednisone
other name: Sirolimus
other name: Prograft
other name: Cellcept
other name: Deltasone
other name: Prednicot
other name: Rayos
other name: Sterapred
other name: Rapamune
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Aldo T Iacono, MD
role: Principal Investigator
affiliation: University of Maryland, Baltimore
citation: Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, Fung JJ, Burckart GJ, McCurry KR, Griffith BP. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med. 2006 Jan 12;354(2):141-50. doi: 10.1056/NEJMoa043204.
PMID: 16407509
responsible party type: Sponsor
mesh term: Mycophenolic Acid
mesh term: Sirolimus
mesh term: Prednisone
mesh term: Tacrolimus
sharing ipd: No