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/NCT05976217</url>
    </required_header>
    <id_info>
      <org_study_id>IRB-300010757</org_study_id>
      <nct_id>NCT05976217</nct_id>
    </id_info>
    <brief_title>Safety and Efficacy of Venetoclax in Idiopathic Pulmonary Fibrosis</brief_title>
    <official_title>Safety and Efficacy of Venetoclax in Idiopathic Pulmonary Fibrosis</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Alabama at Birmingham</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of Alabama at Birmingham</source>
    <oversight_info>
      <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>
        Based on preclinical data, investigators hypothesize that apoptosis resistance in&#xD;
        monocyte-derived macrophages (MDMs) have a decisive role in the development of idiopathic&#xD;
        pulmonary fibrosis (IPF). Specifically, macrophages from subjects with IPF have increased&#xD;
        expression of Bcl-2 in mitochondria. In preclinical models of IPF, a conditional deletion of&#xD;
        Bcl-2 in MDMs reverses established fibrosis by inducing apoptosis. Additional evidence to&#xD;
        suggest that Bcl-2 expression in MDM mitochondria is a therapeutic target for IPF as&#xD;
        administration of the Bcl-2 inhibitor, ABT-199 (Venetoclax), showed marked efficacy in&#xD;
        preclinical models of IPF by inducing apoptosis of MDMs and reversing established fibrosis.&#xD;
        ABT-199 is an orally available mimetic of the BH3 domain of Bcl-2, which is the domain the&#xD;
        anchors Bcl-2 in the mitochondria to inhibit apoptosis. ABT-199 has shown therapeutic&#xD;
        efficacy and good safety and tolerability in patients with chronic lymphocytic leukemia.&#xD;
        Investigators anticipate that treatment with ABT-199 could result in significant benefit for&#xD;
        IPF patients that have a life expectancy of 3-5 years. As there is no curative therapy for&#xD;
        IPF, this clinical trial has the potential to substantially alter treatment approaches in&#xD;
        patients with IPF.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">November 15, 2023</completion_date>
    <primary_completion_date type="Anticipated">November 1, 2023</primary_completion_date>
    <phase>Early 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>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Number of participants with treatment-related adverse events as assessed by measuring liver function.</measure>
      <time_frame>3 weeks</time_frame>
      <description>complete metabolic panel</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Number of participants with treatment-related adverse events as assessed by measuring blood counts.</measure>
      <time_frame>3 weeks</time_frame>
      <description>complete blood count</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Percentage of monocyte-derived macrophages that undergoing apoptosis.</measure>
      <time_frame>3 weeks</time_frame>
      <description>flow cytometry</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">5</enrollment>
    <condition>Idiopathic Pulmonary Fibrosis</condition>
    <arm_group>
      <arm_group_label>treatment</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Venetoclax 100 mg daily for 3 weeks</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Venetoclax</intervention_name>
      <description>100 mg daily by mouth for 3 weeks This drug inhibits a protein (Bcl-2) that protects cells from undergoing programmed cell death.</description>
      <arm_group_label>treatment</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Age between 40-85 years old, male and female.&#xD;
  &#xD;
            2. A diagnosis of IPF that fulfills current ATS/ERS Consensus Criteria (1).&#xD;
  &#xD;
            3. IPF duration &lt;5 years, based on the date of definitive diagnosis.&#xD;
  &#xD;
            4. Ability and willingness to give informed consent and adhere to study requirements.&#xD;
  &#xD;
            5. Forced Vital Capacity (FVC) &gt; 50% predicted values.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Diagnosis of major comorbidities expected to interfere with study participation.&#xD;
  &#xD;
            2. History of malignancy within the last 5 years, excluding basal or squamous cell skin&#xD;
               cancer.&#xD;
  &#xD;
            3. The occurrence of any acute infection requiring systemic antibiotic therapy within 2&#xD;
               weeks prior to Screening (Visit 1).&#xD;
  &#xD;
            4. Treatment for &gt;14 days within the preceding month with &gt;20 mg. prednisone (or&#xD;
               equivalent) or any treatment during the last month with a cellular immunosuppressant&#xD;
               (e.g., cyclophosphamide, methotrexate, calcineurin inhibitors, azathioprine, etc.),&#xD;
               given increased risks of opportunistic infections.&#xD;
  &#xD;
            5. Concurrent participation in other experimental trials.&#xD;
  &#xD;
            6. Fertile women who do not agree to abstinence or an effective form of contraception (as&#xD;
               approved by the investigator), or who are breast feeding, for 4 weeks before&#xD;
               randomization until 90 days after the last administration of study medication (or&#xD;
               placebo).&#xD;
  &#xD;
            7. Men who are not surgically sterile and do not agree to remain abstinent from&#xD;
               heterosexual intercourse or use effective contraception (as approved by the&#xD;
               investigator), and refrain from donating sperm, from the time of giving informed&#xD;
               consent until 90 days after the last administration of study medication (or placebo).&#xD;
  &#xD;
            8. Subjects with known hypersensitivity to capsule &quot;bulking&quot; agents.&#xD;
  &#xD;
            9. A history of bone marrow disorder including aplastic anemia, or marked anemia defined&#xD;
               as hemoglobin &lt; 10.0 g/dL (or 6.2 mmol/L).&#xD;
  &#xD;
           10. Severe cardiovascular disease, defined as any of the following within the preceding 12&#xD;
               weeks: acute myocardial infarction or unstable angina, a coronary revascularization&#xD;
               procedure, congestive heart failure (NYHA Class III or IV), or stroke, including a&#xD;
               transient ischemic attack.&#xD;
  &#xD;
           11. Evidence of cardiac conducting abnormalities, defined as second- or third-degree AV&#xD;
               block not successfully treated with a pacemaker, or a personal or family history of&#xD;
               long QT syndrome (QTc interval &gt;450 msec for males or 470 msec for females).&#xD;
  &#xD;
           12. End-stage renal disease requiring dialysis.&#xD;
  &#xD;
           13. Undergoing transplantation evaluation or listed with the United Network for Organ&#xD;
               Sharing (UNOS) as a lung transplantation candidate at the time of enrollment in this&#xD;
               trial.&#xD;
  &#xD;
           14. Liver function tests (transaminases, alkaline phosphatase, direct and total bilirubin)&#xD;
               &gt;2x upper limit of normal values.&#xD;
  &#xD;
           15. Systemically administered potent CYP3A4 inhibitors or inducers are prohibited during&#xD;
               the 24-week treatment period.&#xD;
  &#xD;
          Inhibitors include: pirfenidone, boceprevir, cobicistat, conivaptan, ritonavir,&#xD;
          itraconazole, ketoconazole, telaprevir, troleandomycin, voriconazole, clarithromycin,&#xD;
          diltiazem, idelalisib, nefazodone, nelfinavir.&#xD;
  &#xD;
          Inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>40 Years</minimum_age>
      <maximum_age>85 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>A. Brent Carter, MD</last_name>
      <phone>(205) 934-5018</phone>
      <email>BCARTER1@UAB.EDU</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Steven R Duncan, MD</last_name>
      <phone>(205) 934-5018</phone>
      <email>srduncan@uabmc.edu</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>A. Brent Carter</name>
        <address>
          <city>Birmingham</city>
          <state>Alabama</state>
          <zip>35214</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <results_reference>
      <citation>Larson-Casey JL, Deshane JS, Ryan AJ, Thannickal VJ, Carter AB. Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis. Immunity. 2016 Mar 15;44(3):582-596. doi: 10.1016/j.immuni.2016.01.001. Epub 2016 Feb 23.</citation>
      <PMID>26921108</PMID>
    </results_reference>
    <results_reference>
      <citation>Larson-Casey JL, Murthy S, Ryan AJ, Carter AB. Modulation of the mevalonate pathway by akt regulates macrophage survival and development of pulmonary fibrosis. J Biol Chem. 2014 Dec 26;289(52):36204-19. doi: 10.1074/jbc.M114.593285. Epub 2014 Nov 5.</citation>
      <PMID>25378391</PMID>
    </results_reference>
    <results_reference>
      <citation>Larson-Casey JL, Gu L, Kang J, Dhyani A, Carter AB. NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression. J Biol Chem. 2021 Jul;297(1):100810. doi: 10.1016/j.jbc.2021.100810. Epub 2021 May 21.</citation>
      <PMID>34023385</PMID>
    </results_reference>
    <results_reference>
      <citation>Larson-Casey JL, Gu L, Davis D, Cai GQ, Ding Q, He C, Carter AB. Post-translational regulation of PGC-1alpha modulates fibrotic repair. FASEB J. 2021 Jun;35(6):e21675. doi: 10.1096/fj.202100339R.</citation>
      <PMID>34038004</PMID>
    </results_reference>
    <results_reference>
      <citation>Gu L, Surolia R, Larson-Casey JL, He C, Davis D, Kang J, Antony VB, Carter AB. Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling. Cell Death Differ. 2022 Jan;29(1):118-132. doi: 10.1038/s41418-021-00840-w. Epub 2021 Aug 20.</citation>
      <PMID>34413485</PMID>
    </results_reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>July 26, 2023</study_first_submitted>
    <study_first_submitted_qc>August 3, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 4, 2023</study_first_posted>
    <last_update_submitted>September 8, 2023</last_update_submitted>
    <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 11, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of Alabama at Birmingham</investigator_affiliation>
      <investigator_full_name>A. Brent Carter, MD</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <keyword>monocyte-derived macrophages</keyword>
    <keyword>apoptosis resistance</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Pulmonary Fibrosis</mesh_term>
      <mesh_term>Idiopathic Pulmonary Fibrosis</mesh_term>
      <mesh_term>Fibrosis</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Venetoclax</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/NCT05976217
  org study id: IRB-300010757
  nct id: NCT05976217
  lead sponsor: 
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: No
  Based on preclinical data, investigators hypothesize that apoptosis resistance in
        monocyte-derived macrophages (MDMs) have a decisive role in the development of idiopathic
        pulmonary fibrosis (IPF). Specifically, macrophages from subjects with IPF have increased
        expression of Bcl-2 in mitochondria. In preclinical models of IPF, a conditional deletion of
        Bcl-2 in MDMs reverses established fibrosis by inducing apoptosis. Additional evidence to
        suggest that Bcl-2 expression in MDM mitochondria is a therapeutic target for IPF as
        administration of the Bcl-2 inhibitor, ABT-199 (Venetoclax), showed marked efficacy in
        preclinical models of IPF by inducing apoptosis of MDMs and reversing established fibrosis.
        ABT-199 is an orally available mimetic of the BH3 domain of Bcl-2, which is the domain the
        anchors Bcl-2 in the mitochondria to inhibit apoptosis. ABT-199 has shown therapeutic
        efficacy and good safety and tolerability in patients with chronic lymphocytic leukemia.
        Investigators anticipate that treatment with ABT-199 could result in significant benefit for
        IPF patients that have a life expectancy of 3-5 years. As there is no curative therapy for
        IPF, this clinical trial has the potential to substantially alter treatment approaches in
        patients with IPF.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Number of participants with treatment-related adverse events as assessed by measuring liver function.
  time frame: 3 weeks
  description: complete metabolic panel
  measure: Number of participants with treatment-related adverse events as assessed by measuring blood counts.
  time frame: 3 weeks
  description: complete blood count
  measure: Percentage of monocyte-derived macrophages that undergoing apoptosis.
  time frame: 3 weeks
  description: flow cytometry
  arm group label: treatment
  arm group type: Experimental
  description: Venetoclax 100 mg daily for 3 weeks
  intervention type: Drug
  intervention name: Venetoclax
  description: 100 mg daily by mouth for 3 weeks This drug inhibits a protein (Bcl-2) that protects cells from undergoing programmed cell death.
  arm group label: treatment
  criteria: 
  gender: All
  minimum age: 40 Years
  maximum age: 85 Years
  healthy volunteers: No
  last name: A. Brent Carter, MD
  phone: (205) 934-5018
  email: BCARTER1@UAB.EDU
  last name: Steven R Duncan, MD
  phone: (205) 934-5018
  email: srduncan@uabmc.edu
  facility: 
  country: United States
  citation: Larson-Casey JL, Deshane JS, Ryan AJ, Thannickal VJ, Carter AB. Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis. Immunity. 2016 Mar 15;44(3):582-596. doi: 10.1016/j.immuni.2016.01.001. Epub 2016 Feb 23.
  PMID: 26921108
  citation: Larson-Casey JL, Murthy S, Ryan AJ, Carter AB. Modulation of the mevalonate pathway by akt regulates macrophage survival and development of pulmonary fibrosis. J Biol Chem. 2014 Dec 26;289(52):36204-19. doi: 10.1074/jbc.M114.593285. Epub 2014 Nov 5.
  PMID: 25378391
  citation: Larson-Casey JL, Gu L, Kang J, Dhyani A, Carter AB. NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression. J Biol Chem. 2021 Jul;297(1):100810. doi: 10.1016/j.jbc.2021.100810. Epub 2021 May 21.
  PMID: 34023385
  citation: Larson-Casey JL, Gu L, Davis D, Cai GQ, Ding Q, He C, Carter AB. Post-translational regulation of PGC-1alpha modulates fibrotic repair. FASEB J. 2021 Jun;35(6):e21675. doi: 10.1096/fj.202100339R.
  PMID: 34038004
  citation: Gu L, Surolia R, Larson-Casey JL, He C, Davis D, Kang J, Antony VB, Carter AB. Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling. Cell Death Differ. 2022 Jan;29(1):118-132. doi: 10.1038/s41418-021-00840-w. Epub 2021 Aug 20.
  PMID: 34413485
  responsible party type: Principal Investigator
  investigator affiliation: University of Alabama at Birmingham
  investigator full name: A. Brent Carter, MD
  investigator title: Professor
  mesh term: Pulmonary Fibrosis
  mesh term: Idiopathic Pulmonary Fibrosis
  mesh term: Fibrosis
  mesh term: Venetoclax
  sharing ipd: No