<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/NCT03006146</url>
  </required_header>
  <id_info>
    <org_study_id>TPSC-110</org_study_id>
    <secondary_id>UL1TR001425</secondary_id>
    <nct_id>NCT03006146</nct_id>
  </id_info>
  <brief_title>Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis</brief_title>
  <official_title>Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rare Diseases Clinical Research Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Center for Advancing Translational Sciences (NCATS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital Medical Center, Cincinnati</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>
      Autoimmune PAP is a rare lung disease affecting less than 5,000 individuals in US with no&#xD;
      FDA-approved pharmacologic therapy. Results from &quot;off-label&quot; use in case reports and clinical&#xD;
      studies completed outside of the US indicate that inhaled rhGM-CSF may be a safe and&#xD;
      effective thera-py for autoimmune PAP. Preliminary clinical trials of inhaled rhGM-CSF in&#xD;
      autoimmune PAP patients show promising results, 62%-96% therapeutic response rate without any&#xD;
      identifiable drug-related adverse effects in at least 73 autoimmune PAP patients. However,&#xD;
      the pharmacokinetics (PK), pharmacodynamics (PD), optimal dose, and treatment duration to&#xD;
      maximize efficacy are unknown.&#xD;
&#xD;
      The goal is to begin to address these knowledge gaps for inhaled sargramostim for autoimmune&#xD;
      PAP patients with a pilot safety and PK/PD study (TPSC-110). TPSC-110, PharmPAP, which is a&#xD;
      self-controlled open-label, phase I study to evaluate the safety, PK, and PD of inhaled&#xD;
      sargra-mostim in autoimmune PAP patients. These results will impact the field by 1)&#xD;
      confirming existing published data, 2) monitoring the local effects of inhaled sargramostim&#xD;
      in autoimmune PAP patients, 3) potentially demonstrating a safe starting dose for a later&#xD;
      trial to evaluate the therapeutic efficacy of inhaled sargramostim for autoimmune PAP.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure&#xD;
      that occurs in a number of diseases classified pathogenically into three groups: primary PAP&#xD;
      (caused by disruption of GM-CSF signaling - autoimmune PAP, hereditary PAP), secondary PAP&#xD;
      (caused by reduction in alveolar macrophage numbers and/or functions), and surfactant&#xD;
      dysfunction-related PAP (caused by mutations in genes required for normal surfactant&#xD;
      production). In current clinical practice, PAP is diagnosed based on a lung biopsy; an&#xD;
      approach that is not able to identify the etiology of the PAP. Current therapy involves the&#xD;
      physical removal of surfactant by a procedure in which the lungs are repeatedly filled with&#xD;
      saline and emptied - whole lung lavage, which is invasive, inefficient, and not widely&#xD;
      available, especially for children. Importantly, research advances have elucidated the&#xD;
      pathogenesis of diseases causing PAP in most patients and have identified new diagnostic and&#xD;
      therapeutic approaches. Simple blood-based research tests can now identify the PAP-causing&#xD;
      disease in about 95% of patients. Further, several promising potential disease-specific&#xD;
      therapies are currently in development. Preliminary clinical trials of inhaled rhGM-CSF in&#xD;
      autoimmune PAP patients show promising results, 62%-96% therapeutic response rate at two&#xD;
      doses (250 and 500 mcg/day) without any identified safety concerns. At least 73 people with&#xD;
      autoimmune PAP have been reported to have received inhaled sargramostim with no identified&#xD;
      drug-related adverse effects. However, the PK, PD, optimal dose, and treatment duration&#xD;
      needed to maximize efficacy are unknown. The short-term goal is to address knowledge gaps for&#xD;
      inhaled sargramostim for autoimmune PAP patients in the following clinical study: a pilot&#xD;
      safety and PK/PD study (TPSC-110). A major goal of this protocol is to evaluate the local and&#xD;
      systemic safety, PK, and PD one dose of inhaled sargramostim in autoimmune PAP. The central&#xD;
      hypothesis is that in patients with autoimmune PAP, aerosol inhalation of sargramostim will&#xD;
      be well-tolerated and safe because the GM-CSF autoantibody will limit detection of free&#xD;
      GM-CSF thereby preventing local and systemic toxicity. The specific objectives of this study&#xD;
      are to: 1) evaluate the safety profile of one dose of inhaled sargramostim in patients with&#xD;
      autoimmune PAP 2) estimate the PK profile of inhaled sargramostim following single dose&#xD;
      administration in patients with autoimmune PAP 3) measure the PD effects of inhaled&#xD;
      sargramostim following single dose administration in patients with autoimmune PAP.&#xD;
&#xD;
      The target population is adults with autoimmune PAP who have measurable, clinically&#xD;
      significant disease satisfying all of the inclusion and exclusion criteria. The study design&#xD;
      will involve recruitment, screening, and enrollment of participants into a phase I,&#xD;
      open-label, multi-site study. Sargramostim will be administered to autoimmune PAP patients&#xD;
      via aerosol inhalation one time at a dose of 125 mcg or 250 mcg. Adverse events (AEs),&#xD;
      serious AEs (SAEs), PK, and PD parameters will be evaluated (see Appendix 3 Schedule of&#xD;
      Events). The experimental approach will evaluate 1) safety of inhaled sargramostim by&#xD;
      documenting occurrence of treatment-emergent AEs and SAEs, 2) PK profile of GM-CSF in serum&#xD;
      and BAL fluid, 3) local and systemic PD effects of inhaled GM-CSF and 4) effects of inhaled&#xD;
      GM-CSF on the quality of life for participants. Anticipated results will determine the safety&#xD;
      profile of inhaled sargramostim in patients with autoimmune PAP, will evaluate total and free&#xD;
      GM-CSF levels in blood and lung, effects of sargramostim on blood and BAL cell counts,&#xD;
      differentials, baseline- and GM-CSF-responsiveness of blood leukocytes and BAL cells, and&#xD;
      biomarkers of PAP in patients with autoimmune PAP after single dose administration. These&#xD;
      results will impact the field by 1) confirming existing published data, 2) monitoring local&#xD;
      effects of inhaled sargramostim in autoimmune PAP patients, 3) demonstrating a safe starting&#xD;
      dose to evaluate the efficacy of inhaled sargramostim for autoimmune PAP.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 13, 2017</start_date>
  <completion_date type="Actual">June 7, 2021</completion_date>
  <primary_completion_date type="Actual">June 7, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of any treatment-emergent adverse events and serious adverse events</measure>
    <time_frame>1 year</time_frame>
    <description>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum plasma GM-CSF Concentration (Cmax)</measure>
    <time_frame>1 year</time_frame>
    <description>Maximum concentration of free and toal GM-CSF in the plasma following a single administration of inhaled sargramostim</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to maximum plasma GM-CSF concentration (TMax)</measure>
    <time_frame>1 year</time_frame>
    <description>Time to maximum plasma concentrations of free and total GM-CSF following a single administration of inhaled sargramostim</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GM-CSF Area Under the Curve (AUC)</measure>
    <time_frame>1 year</time_frame>
    <description>Systemic exposure to GM-CSF in plasma samples collected at regular intervals following a single administration of inhaled sargramostim</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-life of inhaled GM-CSF (t1/2)</measure>
    <time_frame>1 year</time_frame>
    <description>Half-life of GM-CSF following a single administration of inhaled sargramostim</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete cell counts and differentials in blood and BAL fluid</measure>
    <time_frame>1 year</time_frame>
    <description>Cell Counts and differentials in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GM-CSF autoantibody levels in blood and BAL fluid</measure>
    <time_frame>1 year</time_frame>
    <description>GM-CSF autoantibody concentrations in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GM-CSF signaling levels in blood and BAL fluid</measure>
    <time_frame>1 year</time_frame>
    <description>Responsiveness of blood and BAL cells to in vitro stimulation with GM-CSF in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Autoimmune Pulmonary Alveolar Proteinosis</condition>
  <arm_group>
    <arm_group_label>Sargramostim</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sargramostim</intervention_name>
    <description>Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)</description>
    <arm_group_label>Sargramostim</arm_group_label>
    <other_name>Leukine</other_name>
    <other_name>recombinant human GM-CSF</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Male or female&#xD;
&#xD;
        Age ≥ 18 years and ≤ 80 years&#xD;
&#xD;
        Able to understand and willing to sign a written informed consent document&#xD;
&#xD;
        Able and willing to use hand held nebulizer&#xD;
&#xD;
        Able and willing to adhere to study visit schedule and study procedures&#xD;
&#xD;
        Diagnosis of autoimmune PAP determined by:&#xD;
&#xD;
          -  History of a diagnosis of PAP with or without supporting lung histology or&#xD;
             BAL/cytology&#xD;
&#xD;
        and&#xD;
&#xD;
          -  Abnormal serum GM-CSF autoantibody test (GMAb ELISA Test)&#xD;
&#xD;
        and&#xD;
&#xD;
          -  Chest CT findings compatible with a diagnosis of autoimmune PAP&#xD;
&#xD;
        Evidence of impaired GM-CSF signaling demonstrated by an abnormal STAT5 phosphorylation&#xD;
        index (STAT5-PI) test measured in heparinized whole blood at the time screening&#xD;
&#xD;
        A-aDO2 ≥ 15 mm Hg&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Diagnosis of any other PAP-causing disease&#xD;
&#xD;
        Autoimmune PAP complicated by:&#xD;
&#xD;
          -  Severe disease at screening/enrollment (A-aD02&lt;50)&#xD;
&#xD;
          -  Clinically significant pulmonary fibrosis&#xD;
&#xD;
        History of any clinically significant:&#xD;
&#xD;
          -  Other lung disease&#xD;
&#xD;
          -  Cardiovascular disease&#xD;
&#xD;
          -  Disease requiring use of systemic steroids in past year&#xD;
&#xD;
          -  Coagulopathy or other hematologic disease&#xD;
&#xD;
          -  Active / serious lung or systemic infection&#xD;
&#xD;
          -  Persistent or unexplained fever &gt;101oF within 2 months of study&#xD;
&#xD;
          -  Use of any immunosuppressive medication within 3-6 months of screening&#xD;
&#xD;
          -  Women who are pregnant or plan to become pregnant&#xD;
&#xD;
          -  History of active tobacco/e-cig/marijuana use&#xD;
&#xD;
          -  Concomitant or recent use of specific medicines&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bruce Trapnell</last_name>
    <role>Study Chair</role>
    <affiliation>Children's Hospital Medical Center, Cincinnati</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, Los Angeles</name>
      <address>
        <city>Los Altos</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>November 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 30, 2016</study_first_posted>
  <last_update_submitted>August 2, 2021</last_update_submitted>
  <last_update_submitted_qc>August 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Alveolar Proteinosis</mesh_term>
    <mesh_term>Autoimmune Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Molgramostim</mesh_term>
    <mesh_term>Sargramostim</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/NCT03006146
org study id: TPSC-110
secondary id: UL1TR001425
nct id: NCT03006146
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Autoimmune PAP is a rare lung disease affecting less than 5,000 individuals in US with no
      FDA-approved pharmacologic therapy. Results from "off-label" use in case reports and clinical
      studies completed outside of the US indicate that inhaled rhGM-CSF may be a safe and
      effective thera-py for autoimmune PAP. Preliminary clinical trials of inhaled rhGM-CSF in
      autoimmune PAP patients show promising results, 62%-96% therapeutic response rate without any
      identifiable drug-related adverse effects in at least 73 autoimmune PAP patients. However,
      the pharmacokinetics (PK), pharmacodynamics (PD), optimal dose, and treatment duration to
      maximize efficacy are unknown.

      The goal is to begin to address these knowledge gaps for inhaled sargramostim for autoimmune
      PAP patients with a pilot safety and PK/PD study (TPSC-110). TPSC-110, PharmPAP, which is a
      self-controlled open-label, phase I study to evaluate the safety, PK, and PD of inhaled
      sargra-mostim in autoimmune PAP patients. These results will impact the field by 1)
      confirming existing published data, 2) monitoring the local effects of inhaled sargramostim
      in autoimmune PAP patients, 3) potentially demonstrating a safe starting dose for a later
      trial to evaluate the therapeutic efficacy of inhaled sargramostim for autoimmune PAP.
PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure
      that occurs in a number of diseases classified pathogenically into three groups: primary PAP
      (caused by disruption of GM-CSF signaling - autoimmune PAP, hereditary PAP), secondary PAP
      (caused by reduction in alveolar macrophage numbers and/or functions), and surfactant
      dysfunction-related PAP (caused by mutations in genes required for normal surfactant
      production). In current clinical practice, PAP is diagnosed based on a lung biopsy; an
      approach that is not able to identify the etiology of the PAP. Current therapy involves the
      physical removal of surfactant by a procedure in which the lungs are repeatedly filled with
      saline and emptied - whole lung lavage, which is invasive, inefficient, and not widely
      available, especially for children. Importantly, research advances have elucidated the
      pathogenesis of diseases causing PAP in most patients and have identified new diagnostic and
      therapeutic approaches. Simple blood-based research tests can now identify the PAP-causing
      disease in about 95% of patients. Further, several promising potential disease-specific
      therapies are currently in development. Preliminary clinical trials of inhaled rhGM-CSF in
      autoimmune PAP patients show promising results, 62%-96% therapeutic response rate at two
      doses (250 and 500 mcg/day) without any identified safety concerns. At least 73 people with
      autoimmune PAP have been reported to have received inhaled sargramostim with no identified
      drug-related adverse effects. However, the PK, PD, optimal dose, and treatment duration
      needed to maximize efficacy are unknown. The short-term goal is to address knowledge gaps for
      inhaled sargramostim for autoimmune PAP patients in the following clinical study: a pilot
      safety and PK/PD study (TPSC-110). A major goal of this protocol is to evaluate the local and
      systemic safety, PK, and PD one dose of inhaled sargramostim in autoimmune PAP. The central
      hypothesis is that in patients with autoimmune PAP, aerosol inhalation of sargramostim will
      be well-tolerated and safe because the GM-CSF autoantibody will limit detection of free
      GM-CSF thereby preventing local and systemic toxicity. The specific objectives of this study
      are to: 1) evaluate the safety profile of one dose of inhaled sargramostim in patients with
      autoimmune PAP 2) estimate the PK profile of inhaled sargramostim following single dose
      administration in patients with autoimmune PAP 3) measure the PD effects of inhaled
      sargramostim following single dose administration in patients with autoimmune PAP.

      The target population is adults with autoimmune PAP who have measurable, clinically
      significant disease satisfying all of the inclusion and exclusion criteria. The study design
      will involve recruitment, screening, and enrollment of participants into a phase I,
      open-label, multi-site study. Sargramostim will be administered to autoimmune PAP patients
      via aerosol inhalation one time at a dose of 125 mcg or 250 mcg. Adverse events (AEs),
      serious AEs (SAEs), PK, and PD parameters will be evaluated (see Appendix 3 Schedule of
      Events). The experimental approach will evaluate 1) safety of inhaled sargramostim by
      documenting occurrence of treatment-emergent AEs and SAEs, 2) PK profile of GM-CSF in serum
      and BAL fluid, 3) local and systemic PD effects of inhaled GM-CSF and 4) effects of inhaled
      GM-CSF on the quality of life for participants. Anticipated results will determine the safety
      profile of inhaled sargramostim in patients with autoimmune PAP, will evaluate total and free
      GM-CSF levels in blood and lung, effects of sargramostim on blood and BAL cell counts,
      differentials, baseline- and GM-CSF-responsiveness of blood leukocytes and BAL cells, and
      biomarkers of PAP in patients with autoimmune PAP after single dose administration. These
      results will impact the field by 1) confirming existing published data, 2) monitoring local
      effects of inhaled sargramostim in autoimmune PAP patients, 3) demonstrating a safe starting
      dose to evaluate the efficacy of inhaled sargramostim for autoimmune PAP.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Occurrence of any treatment-emergent adverse events and serious adverse events
time frame: 1 year
description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
measure: Maximum plasma GM-CSF Concentration (Cmax)
time frame: 1 year
description: Maximum concentration of free and toal GM-CSF in the plasma following a single administration of inhaled sargramostim
measure: Time to maximum plasma GM-CSF concentration (TMax)
time frame: 1 year
description: Time to maximum plasma concentrations of free and total GM-CSF following a single administration of inhaled sargramostim
measure: GM-CSF Area Under the Curve (AUC)
time frame: 1 year
description: Systemic exposure to GM-CSF in plasma samples collected at regular intervals following a single administration of inhaled sargramostim
measure: Half-life of inhaled GM-CSF (t1/2)
time frame: 1 year
description: Half-life of GM-CSF following a single administration of inhaled sargramostim
measure: Complete cell counts and differentials in blood and BAL fluid
time frame: 1 year
description: Cell Counts and differentials in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
measure: GM-CSF autoantibody levels in blood and BAL fluid
time frame: 1 year
description: GM-CSF autoantibody concentrations in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
measure: GM-CSF signaling levels in blood and BAL fluid
time frame: 1 year
description: Responsiveness of blood and BAL cells to in vitro stimulation with GM-CSF in blood and BAL fluid following a single administration of inhaled sargramostim will be compared to baseline values (pre-study drug administration)
arm group label: Sargramostim
arm group type: Experimental
description: Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)
intervention type: Drug
intervention name: Sargramostim
description: Participants will receive a single administration of inhaled sargramostim (either 125 mcg or 250 mcg dose)
arm group label: Sargramostim
other name: Leukine
other name: recombinant human GM-CSF
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Bruce Trapnell
role: Study Chair
affiliation: Children's Hospital Medical Center, Cincinnati
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Pulmonary Alveolar Proteinosis
mesh term: Autoimmune Diseases
mesh term: Molgramostim
mesh term: Sargramostim
sharing ipd: No