xml: <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/NCT06018766</url>
    </required_header>
    <id_info>
      <org_study_id>LAM-001-BOS-CLN01</org_study_id>
      <nct_id>NCT06018766</nct_id>
    </id_info>
    <brief_title>Inhaled Sirolimus in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome.</brief_title>
    <acronym>INSPO-BOS</acronym>
    <official_title>A Randomized, Placebo-controlled Phase 2 Study to Demonstrate the Safety and Efficacy of the Addition of Inhaled Sirolimus to Standard Immunosuppression Therapy for Chronic Lung Allograft Dysfunction (BOS).</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Steven Hays, MD</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>AI Therapeutics, Inc.</agency>
        <agency_class>Industry</agency_class>
      </collaborator>
    </sponsors>
    <source>University of California, San Francisco</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>
        The goal of this clinical trial is to learn about the safety and effectiveness of inhaled&#xD;
        sirolimus in patients who have developed bronchiolitis obliterans syndrome (BOS), a form of&#xD;
        chronic rejection, after lung transplantation.&#xD;
  &#xD;
        The main questions it aims to answer are:&#xD;
  &#xD;
          -  Is inhaled sirolimus safe in these patients?&#xD;
  &#xD;
          -  Is inhaled sirolimus effective in slowing BOS progression?&#xD;
  &#xD;
        Participants will:&#xD;
  &#xD;
          -  Be randomly assigned to inhale either sirolimus or placebo (a look-alike substance that&#xD;
             contains no active drug) daily for 48 weeks&#xD;
  &#xD;
          -  Attend 10 study visits (mixture of in-person and telehealth) over the 48 week period&#xD;
  &#xD;
          -  Undergo pulmonary function testing, bronchoscopy, lab testing, and physical examination&#xD;
  &#xD;
          -  Submit weekly home spirometry monitoring&#xD;
  &#xD;
        Researchers will compare participants assigned to inhaled sirolimus versus placebo to see if&#xD;
        sirolimus is safely tolerated and to assess the effectiveness of inhaled sirolimus on slowing&#xD;
        BOS progression.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Chronic rejection, commonly denoted as bronchiolitis obliterans (BO), obliterative&#xD;
        bronchiolitis (OB), or bronchiolitis obliterans syndrome (BOS), is the leading cause of death&#xD;
        beyond the first year after lung transplantation. Whereas the development of BOS is rare&#xD;
        within the first year after lung transplantation, annual increments of approximately 10% are&#xD;
        recorded in subsequent years, resulting in a cumulative incidence range of 40-50% within the&#xD;
        first five years and 70-80% within 10 years of transplantation.&#xD;
  &#xD;
        No current effective treatment for BOS exists. BOS represents the leading cause of morbidity&#xD;
        and mortality after lung transplantation, limiting 5-year survival to well below other solid&#xD;
        organ transplants. BOS is characterized by an inexorable lung function decline despite&#xD;
        currently available immunomodulatory treatments. Sirolimus has been shown to block T-cell&#xD;
        proliferative effects induced by cytokines, alloantigens, and mitogens in a dose-dependent&#xD;
        manner(4, 5). Oral sirolimus has been shown in small studies to have a beneficial impact on&#xD;
        rapidly progressive BOS; however, administration in this patient population has been&#xD;
        challenged by a high degree of intolerance with the side effects. The development of inhaled&#xD;
        sirolimus for lung transplant related BOS, conceptually a T-cell driven process against&#xD;
        transplanted alloantigen, is based on the principal hypothesis that administration of a&#xD;
        sirolimus dose to the rejecting lung allograft(s) by inhalation will result in improved&#xD;
        efficacy by depositing higher drug concentrations directly within the allograft by inhalation&#xD;
        than would be achieved by oral administration due to systemic toxicities associated with&#xD;
        systemic sirolimus. Because of known reduced systemic bioavailability of inhaled sirolimus&#xD;
        compared to oral sirolimus dosing, amelioration of the substantial adverse event profile&#xD;
        compared to systemic drug is expected. Inhaled sirolimus is also expected to reduce serious&#xD;
        complication risks by obviating requirements for maintenance and augmented immune drugs used&#xD;
        to treat BOS.&#xD;
  &#xD;
        The primary objective is to assess the clinical efficacy of inhaled sirolimus in lung&#xD;
        transplant recipients with bronchiolitis obliterans syndrome as measured by progression free&#xD;
        survival and change in forced expiratory volume in one second (FEV1) over a 48-week period.&#xD;
        Another primary objective is to assess the safety and tolerability of inhaled sirolimus in&#xD;
        lung transplant recipients with bronchiolitis obliterans syndrome.&#xD;
  &#xD;
        Secondary objectives are:&#xD;
  &#xD;
          -  To determine the impact of inhaled sirolimus on genetic markers of bronchiolitis&#xD;
             obliterans syndrome and activation of the mammalian target of rapamycin (mTOR) pathway&#xD;
             by measuring chronic lung allograft dysfunction signature gene profiling and mTOR&#xD;
             pathway activation in bronchoalveolar lavage fluid&#xD;
  &#xD;
          -  To determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury&#xD;
             (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. %&#xD;
             ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and&#xD;
             re-transplantation for both randomized groups.&#xD;
  &#xD;
          -  To determine the levels of sirolimus in the blood and bronchoalveolar lavage (BAL)&#xD;
             fluid, the BAL as a surrogate for levels in the lung.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 17, 2023</start_date>
    <completion_date type="Anticipated">December 2025</completion_date>
    <primary_completion_date type="Anticipated">December 2025</primary_completion_date>
    <phase>Phase 2</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Time to Progression Free Survival (PFS), Level 1</measure>
      <time_frame>52 weeks</time_frame>
      <description>Time to Progression Free Survival (PFS) Level 1, defined as the earliest of the following:&#xD;
  Absolute decrease in FEV1 from baseline of &gt; 10%&#xD;
  Death from respiratory failure</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Change in FEV1</measure>
      <time_frame>48 weeks</time_frame>
      <description>Change in FEV1 from baseline</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in forced expiratory volume in one second/forced vital capacity (FEV1/FVC)</measure>
      <time_frame>48 weeks</time_frame>
      <description>Change in FEV1/FVC from baseline</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Time to Progression Free Survival (PFS), Level 2</measure>
      <time_frame>52 weeks</time_frame>
      <description>Time to Progression Free Survival (PFS) Level 2, defined as the earliest of the following:&#xD;
  Absolute decrease in the FEV1 from baseline of &gt;20%&#xD;
  Death from respiratory failure</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in Quality of Life</measure>
      <time_frame>48 weeks</time_frame>
      <description>Change in Quality of Life as measured by St. George's Respiratory Questionnaire -COPD (SGRQ-C). The range of scores is 0-100, with the higher scores representing more limitation in quality of life.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in six-minute walk distance (6MWD)</measure>
      <time_frame>48 weeks</time_frame>
      <description>Change in 6MWD from baseline</description>
    </other_outcome>
    <other_outcome>
      <measure>Donor-derived cell-free DNA: Ongoing lung injury</measure>
      <time_frame>52 weeks</time_frame>
      <description>Determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. %ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and re-transplantation for both randomized groups.</description>
    </other_outcome>
    <other_outcome>
      <measure>% Reduced donor-derived cell-free DNA</measure>
      <time_frame>48 weeks</time_frame>
      <description>Determine whether the inhaled sirolimus group will have a salutary effect on allograft injury in terms of reduced %ddcfDNA compared to standard therapy by measuring %ddcfDNA values at determined time points and comparing values between the inhaled sirolimus and placebo groups.</description>
    </other_outcome>
    <other_outcome>
      <measure>CLAD signature gene profiling</measure>
      <time_frame>3 months post randomization</time_frame>
      <description>Utilizing the endobronchial brush, we will quantify a metagene, or normalized sum of gene expression, from our previously published airway inflammation gene set, as described in our publication (PMID: 32885581). The metagene expression will be compared between randomized groups.</description>
    </other_outcome>
    <other_outcome>
      <measure>mTOR pathway activation</measure>
      <time_frame>3 months post randomization</time_frame>
      <description>Utilizing the bronchioalveolar lavage fluid, we will quantify pS6S235/235 in lymphocytes using flow cytometry, to quantify mTORC1 activity, as previously published (PMID: 36066491). We will compare pS6S235/235 between randomized groups.</description>
    </other_outcome>
    <other_outcome>
      <measure>Serum sirolimus levels</measure>
      <time_frame>Assessed pre-inhalation at in-person study visits over 48 weeks and post-inhalation at 3 months post randomization</time_frame>
      <description>Measured serum sirolimus levels</description>
    </other_outcome>
    <other_outcome>
      <measure>Tolerability of inhaled therapy</measure>
      <time_frame>Baseline Study Visit (Week 0)</time_frame>
      <description>Measurement of FEV1 pre-inhalation and 4 hours following study drug inhalation.</description>
    </other_outcome>
    <other_outcome>
      <measure>Adverse events</measure>
      <time_frame>52 weeks</time_frame>
      <description>Incidence and severity of treatment emergent adverse events (AE) and serious adverse events (SAE).</description>
    </other_outcome>
    <other_outcome>
      <measure>Adverse events of special interest</measure>
      <time_frame>52 weeks</time_frame>
      <description>Incidence of local and systemic adverse events of special interest (AESI) including oral or dental lesions, pharyngeal soreness, cough, and dyspnea associated with inhalation will be recorded using a specific case report form and standard examination</description>
    </other_outcome>
    <other_outcome>
      <measure>White blood cell (WBC) count</measure>
      <time_frame>52 weeks</time_frame>
      <description>WBC will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Hemoglobin</measure>
      <time_frame>52 weeks</time_frame>
      <description>Hemoglobin will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Platelet count</measure>
      <time_frame>52 weeks</time_frame>
      <description>Platelet count will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Aspartate Aminotransferase (AST)</measure>
      <time_frame>52 weeks</time_frame>
      <description>AST will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Alanine Aminotransferase (ALT)</measure>
      <time_frame>52 weeks</time_frame>
      <description>ALT will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Alkaline Phosphatase</measure>
      <time_frame>52 weeks</time_frame>
      <description>Alkaline Phosphatase will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Total Bilirubin</measure>
      <time_frame>52 weeks</time_frame>
      <description>Total Bilirubin will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Triglycerides</measure>
      <time_frame>52 weeks</time_frame>
      <description>Triglycerides will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Creatinine</measure>
      <time_frame>52 weeks</time_frame>
      <description>Creatinine will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Urine protein/creatinine ratio</measure>
      <time_frame>52 weeks</time_frame>
      <description>Urine protein/creatinine ratio will be monitored and compared between randomized groups</description>
    </other_outcome>
    <other_outcome>
      <measure>Mortality</measure>
      <time_frame>52 weeks</time_frame>
      <description>Overall mortality in each group will be compared</description>
    </other_outcome>
    <other_outcome>
      <measure>Infections</measure>
      <time_frame>52 weeks</time_frame>
      <description>Incidence of infections including pneumonia, bronchitis, viral infections (including COVID-19) in each group will be compared</description>
    </other_outcome>
    <other_outcome>
      <measure>Malignancies</measure>
      <time_frame>52 weeks</time_frame>
      <description>Incidence of malignancies in each group will be compared</description>
    </other_outcome>
    <other_outcome>
      <measure>Wound healing complications</measure>
      <time_frame>52 weeks</time_frame>
      <description>Wound healing complications in each group will be compared</description>
    </other_outcome>
    <other_outcome>
      <measure>Hospitalization rates</measure>
      <time_frame>52 weeks</time_frame>
      <description>Hospitalization rates in each group will be compared</description>
    </other_outcome>
    <other_outcome>
      <measure>Interstitial pneumonitis</measure>
      <time_frame>52 weeks</time_frame>
      <description>Incidence of interstitial pneumonitis in each group will be compared</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">30</enrollment>
    <condition>Bronchiolitis Obliterans Syndrome Due to and After Lung Transplantation (Disorder)</condition>
    <condition>Chronic Lung Allograft Dysfunction</condition>
    <arm_group>
      <arm_group_label>Sirolimus</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>100 ug sirolimus capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Lactose capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sirolimus</intervention_name>
      <description>Inhaled sirolimus administered via dry powder inhaler</description>
      <arm_group_label>Sirolimus</arm_group_label>
      <other_name>LAM-001</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Inhaled lactose administered via dry powder inhaler</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age &gt; 18 years old&#xD;
  &#xD;
            -  Recipient of a double pulmonary allograft at least 12 months before study entry&#xD;
  &#xD;
            -  Subjects with clinically diagnosed CLAD-BOS phenotype (all 3 required)&#xD;
  &#xD;
                 -  BOS defined as screening FEV1 between 85-51% of the baseline as defined by the 2&#xD;
                    highest FEV1 measures at least 3 weeks apart.&#xD;
  &#xD;
                 -  Diagnosis within 12 months of screening visit.&#xD;
  &#xD;
                 -  FEV1 decline is persistent as defined by decline sustained for &gt; 30 days.&#xD;
  &#xD;
            -  Currently receiving Standard Immunosuppression. This is defined as a combination of 3&#xD;
               medications including Prednisone, Mycophenolate or Azathioprine, and Tacrolimus or&#xD;
               Cyclosporine. The dosing should be stable for 4 weeks prior to screening.&#xD;
  &#xD;
            -  Absence of oral sirolimus or everolimus treatment for at least 4 weeks prior to&#xD;
               screening based on the half-life and resolution of the tissue effects&#xD;
  &#xD;
            -  Stable enough to enable routine post-transplant bronchoscopy with BAL and biopsy when&#xD;
               indicated&#xD;
  &#xD;
            -  Capable of understanding the purposes and risks of the study&#xD;
  &#xD;
            -  Written informed consent (and assent when applicable) obtained from subject or&#xD;
               subject's legal representative and ability for subject to comply with the requirements&#xD;
               of the study.&#xD;
  &#xD;
            -  Women of childbearing potential must have a negative serum pregnancy test within 7&#xD;
               days prior to study entry&#xD;
  &#xD;
            -  Women of childbearing potential if sexually active must agree to using highly&#xD;
               effective contraception during study and for 90 days after discontinuation of study&#xD;
               treatment&#xD;
  &#xD;
            -  Women of childbearing potential must refrain from breast feeding or donating eggs for&#xD;
               the duration of the study and for 90 days after the last dose of study treatment&#xD;
  &#xD;
            -  Male participants must agree to use a condom during sexual contact with a female of&#xD;
               childbearing potential while participating in the study and for 90 days following&#xD;
               discontinuation of investigational product use&#xD;
  &#xD;
            -  Male participants must refrain from donating sperm for the duration of the study and&#xD;
               for 90 days after the last dose of study treatment&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Pregnant, breastfeeding, or unwilling to practice birth control during participation&#xD;
               in the study.&#xD;
  &#xD;
            -  Presence of a condition or abnormality that in the opinion of the Investigator would&#xD;
               compromise the safety of the patient or the quality of the data.&#xD;
  &#xD;
            -  Patients with re-transplantation or currently listed for re-transplantation&#xD;
  &#xD;
            -  Patients with confirmed other causes for loss of lung function, such as acute&#xD;
               infection, acute rejection, restrictive allograft syndrome (CLAD - RAS phenotype, see&#xD;
               Protocol Specific Definition), etc.&#xD;
  &#xD;
            -  Patients with acute antibody-mediated rejection at Screening. In this context,&#xD;
               clinically stable patients (as judged by the Investigator) with detectable&#xD;
               donor-specific antibodies (DSA) levels at the Screening Visit are eligible for the&#xD;
               study&#xD;
  &#xD;
            -  Active acute bacterial, viral, or fungal infection that has not successfully resolved&#xD;
               in at least 4 weeks prior to the Screening Visit. Patients with chronic infection or&#xD;
               colonization who are clinically stable as per judgement of the investigator are&#xD;
               eligible.&#xD;
  &#xD;
            -  Mechanical ventilation within 12 weeks prior to the randomization&#xD;
  &#xD;
            -  Patient has baseline resting oxygen saturation of &lt; 89% on room air or use of&#xD;
               supplemental oxygen at rest at screening&#xD;
  &#xD;
            -  Evidence of functional airway stenosis (i.e., bronchomalacia/ tracheomalacia, airway&#xD;
               stents, or airways requiring balloon dilatations to maintain patency) with onset after&#xD;
               the initial diagnosis of BOS and ongoing at Screening and/or Baseline Visit&#xD;
  &#xD;
            -  Known hypersensitivity to sirolimus or everolimus&#xD;
  &#xD;
            -  Currently enrolled in another investigational trial for obstructive chronic lung&#xD;
               allograft dysfunction (BOS)&#xD;
  &#xD;
            -  Patients with chronic renal failure, defined as serum creatinine &gt; 2.5 mg/dL at&#xD;
               screening, or requiring chronic dialysis&#xD;
  &#xD;
            -  Patients with liver disease and serum bilirubin &gt; 3-fold upper limit of normal range&#xD;
               or transaminases &gt; 2.5 upper limit of normal range&#xD;
  &#xD;
            -  Patients with active malignancy within the previous 2 years, including post-transplant&#xD;
               lymphoproliferative disorder, except for treated, localized basal and squamous cell&#xD;
               carcinomas&#xD;
  &#xD;
            -  Any history of malignancy likely to result in significant disability or likely to&#xD;
               require significant medical or surgical intervention within the next 6 months. This&#xD;
               does not include minor surgical procedures for localized skin cancer.&#xD;
  &#xD;
            -  History of severe allergic reaction to lactose (patients with lactose intolerance are&#xD;
               eligible)&#xD;
  &#xD;
            -  Patients with uncontrolled hypertension&#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>Steven Hays, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University of California, San Francisco</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Steven Hays, MD</last_name>
      <phone>415-336-4141</phone>
      <email>steven.hays@ucsf.edu</email>
    </overall_contact>
    <location>
      <facility>
        <name>University of California, San Francisco</name>
        <address>
          <city>San Francisco</city>
          <state>California</state>
          <zip>94143</zip>
          <country>United States</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Steven Hays, MD</last_name>
        <phone>415-353-4141</phone>
        <email>steven.hays@ucsf.edu</email>
      </contact>
      <investigator>
        <last_name>Steven Hays, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Julia Maheshwari, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <reference>
      <citation>Gillen JR, Zhao Y, Harris DA, LaPar DJ, Kron IL, Lau CL. Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans. Ann Thorac Surg. 2013 Aug;96(2):464-72. doi: 10.1016/j.athoracsur.2013.04.068. Epub 2013 Jun 24.</citation>
      <PMID>23806229</PMID>
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    <reference>
      <citation>Gillen JR, Zhao Y, Harris DA, Lapar DJ, Stone ML, Fernandez LG, Kron IL, Lau CL. Rapamycin blocks fibrocyte migration and attenuates bronchiolitis obliterans in a murine model. Ann Thorac Surg. 2013 May;95(5):1768-75. doi: 10.1016/j.athoracsur.2013.02.021. Epub 2013 Apr 2.</citation>
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    <reference>
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    </reference>
    <reference>
      <citation>de Oliveira MA, Martins E Martins F, Wang Q, Sonis S, Demetri G, George S, Butrynski J, Treister NS. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol. 2011 Oct;47(10):998-1003. doi: 10.1016/j.oraloncology.2011.08.009. Epub 2011 Sep 3.</citation>
      <PMID>21890398</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>June 1, 2023</study_first_submitted>
    <study_first_submitted_qc>August 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 31, 2023</study_first_posted>
    <last_update_submitted>August 28, 2023</last_update_submitted>
    <last_update_submitted_qc>August 28, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 31, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
      <investigator_full_name>Steven Hays, MD</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <keyword>Bronchiolitis Obliterans Syndrome</keyword>
    <keyword>Chronic Lung Allograft Dysfunction</keyword>
    <keyword>Lung Transplant Rejection</keyword>
    <keyword>Sirolimus</keyword>
    <keyword>mTOR inhibitor</keyword>
    <keyword>CLAD</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Bronchiolitis</mesh_term>
      <mesh_term>Bronchiolitis Obliterans</mesh_term>
      <mesh_term>Bronchiolitis Obliterans Syndrome</mesh_term>
      <mesh_term>Syndrome</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sirolimus</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06018766
  org study id: LAM-001-BOS-CLN01
  nct id: NCT06018766
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  The goal of this clinical trial is to learn about the safety and effectiveness of inhaled
        sirolimus in patients who have developed bronchiolitis obliterans syndrome (BOS), a form of
        chronic rejection, after lung transplantation.
  
        The main questions it aims to answer are:
  
          -  Is inhaled sirolimus safe in these patients?
  
          -  Is inhaled sirolimus effective in slowing BOS progression?
  
        Participants will:
  
          -  Be randomly assigned to inhale either sirolimus or placebo (a look-alike substance that
             contains no active drug) daily for 48 weeks
  
          -  Attend 10 study visits (mixture of in-person and telehealth) over the 48 week period
  
          -  Undergo pulmonary function testing, bronchoscopy, lab testing, and physical examination
  
          -  Submit weekly home spirometry monitoring
  
        Researchers will compare participants assigned to inhaled sirolimus versus placebo to see if
        sirolimus is safely tolerated and to assess the effectiveness of inhaled sirolimus on slowing
        BOS progression.
  Chronic rejection, commonly denoted as bronchiolitis obliterans (BO), obliterative
        bronchiolitis (OB), or bronchiolitis obliterans syndrome (BOS), is the leading cause of death
        beyond the first year after lung transplantation. Whereas the development of BOS is rare
        within the first year after lung transplantation, annual increments of approximately 10% are
        recorded in subsequent years, resulting in a cumulative incidence range of 40-50% within the
        first five years and 70-80% within 10 years of transplantation.
  
        No current effective treatment for BOS exists. BOS represents the leading cause of morbidity
        and mortality after lung transplantation, limiting 5-year survival to well below other solid
        organ transplants. BOS is characterized by an inexorable lung function decline despite
        currently available immunomodulatory treatments. Sirolimus has been shown to block T-cell
        proliferative effects induced by cytokines, alloantigens, and mitogens in a dose-dependent
        manner(4, 5). Oral sirolimus has been shown in small studies to have a beneficial impact on
        rapidly progressive BOS; however, administration in this patient population has been
        challenged by a high degree of intolerance with the side effects. The development of inhaled
        sirolimus for lung transplant related BOS, conceptually a T-cell driven process against
        transplanted alloantigen, is based on the principal hypothesis that administration of a
        sirolimus dose to the rejecting lung allograft(s) by inhalation will result in improved
        efficacy by depositing higher drug concentrations directly within the allograft by inhalation
        than would be achieved by oral administration due to systemic toxicities associated with
        systemic sirolimus. Because of known reduced systemic bioavailability of inhaled sirolimus
        compared to oral sirolimus dosing, amelioration of the substantial adverse event profile
        compared to systemic drug is expected. Inhaled sirolimus is also expected to reduce serious
        complication risks by obviating requirements for maintenance and augmented immune drugs used
        to treat BOS.
  
        The primary objective is to assess the clinical efficacy of inhaled sirolimus in lung
        transplant recipients with bronchiolitis obliterans syndrome as measured by progression free
        survival and change in forced expiratory volume in one second (FEV1) over a 48-week period.
        Another primary objective is to assess the safety and tolerability of inhaled sirolimus in
        lung transplant recipients with bronchiolitis obliterans syndrome.
  
        Secondary objectives are:
  
          -  To determine the impact of inhaled sirolimus on genetic markers of bronchiolitis
             obliterans syndrome and activation of the mammalian target of rapamycin (mTOR) pathway
             by measuring chronic lung allograft dysfunction signature gene profiling and mTOR
             pathway activation in bronchoalveolar lavage fluid
  
          -  To determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury
             (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. %
             ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and
             re-transplantation for both randomized groups.
  
          -  To determine the levels of sirolimus in the blood and bronchoalveolar lavage (BAL)
             fluid, the BAL as a surrogate for levels in the lung.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: Time to Progression Free Survival (PFS), Level 1
  time frame: 52 weeks
  description: Time to Progression Free Survival (PFS) Level 1, defined as the earliest of the following:
  Absolute decrease in FEV1 from baseline of > 10%
  Death from respiratory failure
  measure: Change in FEV1
  time frame: 48 weeks
  description: Change in FEV1 from baseline
  measure: Change in forced expiratory volume in one second/forced vital capacity (FEV1/FVC)
  time frame: 48 weeks
  description: Change in FEV1/FVC from baseline
  measure: Time to Progression Free Survival (PFS), Level 2
  time frame: 52 weeks
  description: Time to Progression Free Survival (PFS) Level 2, defined as the earliest of the following:
  Absolute decrease in the FEV1 from baseline of >20%
  Death from respiratory failure
  measure: Change in Quality of Life
  time frame: 48 weeks
  description: Change in Quality of Life as measured by St. George's Respiratory Questionnaire -COPD (SGRQ-C). The range of scores is 0-100, with the higher scores representing more limitation in quality of life.
  measure: Change in six-minute walk distance (6MWD)
  time frame: 48 weeks
  description: Change in 6MWD from baseline
  measure: Donor-derived cell-free DNA: Ongoing lung injury
  time frame: 52 weeks
  description: Determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. %ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and re-transplantation for both randomized groups.
  measure: % Reduced donor-derived cell-free DNA
  time frame: 48 weeks
  description: Determine whether the inhaled sirolimus group will have a salutary effect on allograft injury in terms of reduced %ddcfDNA compared to standard therapy by measuring %ddcfDNA values at determined time points and comparing values between the inhaled sirolimus and placebo groups.
  measure: CLAD signature gene profiling
  time frame: 3 months post randomization
  description: Utilizing the endobronchial brush, we will quantify a metagene, or normalized sum of gene expression, from our previously published airway inflammation gene set, as described in our publication (PMID: 32885581). The metagene expression will be compared between randomized groups.
  measure: mTOR pathway activation
  time frame: 3 months post randomization
  description: Utilizing the bronchioalveolar lavage fluid, we will quantify pS6S235/235 in lymphocytes using flow cytometry, to quantify mTORC1 activity, as previously published (PMID: 36066491). We will compare pS6S235/235 between randomized groups.
  measure: Serum sirolimus levels
  time frame: Assessed pre-inhalation at in-person study visits over 48 weeks and post-inhalation at 3 months post randomization
  description: Measured serum sirolimus levels
  measure: Tolerability of inhaled therapy
  time frame: Baseline Study Visit (Week 0)
  description: Measurement of FEV1 pre-inhalation and 4 hours following study drug inhalation.
  measure: Adverse events
  time frame: 52 weeks
  description: Incidence and severity of treatment emergent adverse events (AE) and serious adverse events (SAE).
  measure: Adverse events of special interest
  time frame: 52 weeks
  description: Incidence of local and systemic adverse events of special interest (AESI) including oral or dental lesions, pharyngeal soreness, cough, and dyspnea associated with inhalation will be recorded using a specific case report form and standard examination
  measure: White blood cell (WBC) count
  time frame: 52 weeks
  description: WBC will be monitored and compared between randomized groups
  measure: Hemoglobin
  time frame: 52 weeks
  description: Hemoglobin will be monitored and compared between randomized groups
  measure: Platelet count
  time frame: 52 weeks
  description: Platelet count will be monitored and compared between randomized groups
  measure: Aspartate Aminotransferase (AST)
  time frame: 52 weeks
  description: AST will be monitored and compared between randomized groups
  measure: Alanine Aminotransferase (ALT)
  time frame: 52 weeks
  description: ALT will be monitored and compared between randomized groups
  measure: Alkaline Phosphatase
  time frame: 52 weeks
  description: Alkaline Phosphatase will be monitored and compared between randomized groups
  measure: Total Bilirubin
  time frame: 52 weeks
  description: Total Bilirubin will be monitored and compared between randomized groups
  measure: Triglycerides
  time frame: 52 weeks
  description: Triglycerides will be monitored and compared between randomized groups
  measure: Creatinine
  time frame: 52 weeks
  description: Creatinine will be monitored and compared between randomized groups
  measure: Urine protein/creatinine ratio
  time frame: 52 weeks
  description: Urine protein/creatinine ratio will be monitored and compared between randomized groups
  measure: Mortality
  time frame: 52 weeks
  description: Overall mortality in each group will be compared
  measure: Infections
  time frame: 52 weeks
  description: Incidence of infections including pneumonia, bronchitis, viral infections (including COVID-19) in each group will be compared
  measure: Malignancies
  time frame: 52 weeks
  description: Incidence of malignancies in each group will be compared
  measure: Wound healing complications
  time frame: 52 weeks
  description: Wound healing complications in each group will be compared
  measure: Hospitalization rates
  time frame: 52 weeks
  description: Hospitalization rates in each group will be compared
  measure: Interstitial pneumonitis
  time frame: 52 weeks
  description: Incidence of interstitial pneumonitis in each group will be compared
  arm group label: Sirolimus
  arm group type: Experimental
  description: 100 ug sirolimus capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.
  arm group label: Placebo
  arm group type: Placebo Comparator
  description: Lactose capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.
  intervention type: Drug
  intervention name: Sirolimus
  description: Inhaled sirolimus administered via dry powder inhaler
  arm group label: Sirolimus
  other name: LAM-001
  intervention type: Drug
  intervention name: Placebo
  description: Inhaled lactose administered via dry powder inhaler
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Steven Hays, MD
  role: Principal Investigator
  affiliation: University of California, San Francisco
  last name: Steven Hays, MD
  phone: 415-336-4141
  email: steven.hays@ucsf.edu
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  investigator: 
  country: United States
  citation: Gillen JR, Zhao Y, Harris DA, LaPar DJ, Kron IL, Lau CL. Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans. Ann Thorac Surg. 2013 Aug;96(2):464-72. doi: 10.1016/j.athoracsur.2013.04.068. Epub 2013 Jun 24.
  PMID: 23806229
  citation: Gillen JR, Zhao Y, Harris DA, Lapar DJ, Stone ML, Fernandez LG, Kron IL, Lau CL. Rapamycin blocks fibrocyte migration and attenuates bronchiolitis obliterans in a murine model. Ann Thorac Surg. 2013 May;95(5):1768-75. doi: 10.1016/j.athoracsur.2013.02.021. Epub 2013 Apr 2.
  PMID: 23561805
  citation: Zhao Y, Gillen JR, Meher AK, Burns JA, Kron IL, Lau CL. Rapamycin prevents bronchiolitis obliterans through increasing infiltration of regulatory B cells in a murine tracheal transplantation model. J Thorac Cardiovasc Surg. 2016 Feb;151(2):487-96.e3. doi: 10.1016/j.jtcvs.2015.08.116. Epub 2015 Sep 7.
  PMID: 26481278
  citation: Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998 Jul;31(5):335-40. doi: 10.1016/s0009-9120(98)00045-9.
  PMID: 9721431
  citation: Bak S, Tischer S, Dragon A, Ravens S, Pape L, Koenecke C, Oelke M, Blasczyk R, Maecker-Kolhoff B, Eiz-Vesper B. Selective Effects of mTOR Inhibitor Sirolimus on Naive and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression. Front Immunol. 2018 Dec 17;9:2953. doi: 10.3389/fimmu.2018.02953. eCollection 2018.
  PMID: 30619313
  citation: Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer. 2010 Jan 1;116(1):210-5. doi: 10.1002/cncr.24696.
  PMID: 19862817
  citation: Boers-Doets CB, Raber-Durlacher JE, Treister NS, Epstein JB, Arends AB, Wiersma DR, Lalla RV, Logan RM, van Erp NP, Gelderblom H. Mammalian target of rapamycin inhibitor-associated stomatitis. Future Oncol. 2013 Dec;9(12):1883-92. doi: 10.2217/fon.13.141.
  PMID: 24295418
  citation: Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer. 2017 May;25(5):1713-1739. doi: 10.1007/s00520-017-3629-4. Epub 2017 Feb 22.
  PMID: 28224235
  citation: Pilotte AP, Hohos MB, Polson KM, Huftalen TM, Treister N. Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs. 2011 Oct;15(5):E83-9. doi: 10.1188/11.CJON.E83-E89.
  PMID: 21951751
  citation: de Oliveira MA, Martins E Martins F, Wang Q, Sonis S, Demetri G, George S, Butrynski J, Treister NS. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol. 2011 Oct;47(10):998-1003. doi: 10.1016/j.oraloncology.2011.08.009. Epub 2011 Sep 3.
  PMID: 21890398
  responsible party type: Sponsor-Investigator
  investigator affiliation: University of California, San Francisco
  investigator full name: Steven Hays, MD
  investigator title: Professor
  mesh term: Bronchiolitis
  mesh term: Bronchiolitis Obliterans
  mesh term: Bronchiolitis Obliterans Syndrome
  mesh term: Syndrome
  mesh term: Sirolimus
  sharing ipd: No