<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/NCT03286556</url>
  </required_header>
  <id_info>
    <org_study_id>F170530011</org_study_id>
    <secondary_id>1U01HL133232-01A1</secondary_id>
    <nct_id>NCT03286556</nct_id>
  </id_info>
  <brief_title>Autoantibody Reduction for Acute Exacerbations of Idiopathic Pulmonary Fibrosis</brief_title>
  <acronym>STRIVE-IPF</acronym>
  <official_title>Study of Therapeutic Plasma Exchange, Rituximab and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis (STRIVE-IPF)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alabama at Birmingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Temple University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Alabama at Birmingham</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Acute exacerbations (AE) are a dreaded manifestation of idiopathic pulmonary fibrosis (IPF)&#xD;
      that presents with rapidly worsening respiratory function over days to weeks. AE account for&#xD;
      about 1/2 the deaths in IPF patients, and are refractory to all medical therapies attempted&#xD;
      to date.&#xD;
&#xD;
      Considerable preliminary data shows pathological B-cell abnormalities and autoantibodies are&#xD;
      present in AE-IPF and associated with disease severity.&#xD;
&#xD;
      The experimental therapy here (therapeutic plasma exchange plus rituximab plus intravenous&#xD;
      immunoglobulin) is mechanistically targeted to ameliorate autoantibody-mediated pulmonary&#xD;
      injury. Anecdotal pilot studies indicate these treatments have significant benefit for a&#xD;
      disease syndrome that has, until now, been almost invariably inexorable. This clinical trial&#xD;
      has the potential to profoundly affect current paradigms and treatment approaches to patients&#xD;
      with AE-IPF.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary goal of clinical trial is to determine effects of combined therapeutic plasma&#xD;
      exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) in comparison to effects of&#xD;
      treatment as usual (TAU), among AE-IPF patients.&#xD;
&#xD;
      Our central hypothesis is &quot;AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF PATIENTS.&quot; A&#xD;
      corollary of this hypothesis is that antibody-mediated autoimmunity can play an important&#xD;
      role in IPF exacerbations.&#xD;
&#xD;
      Following baseline screening assessments, hospitalized AE-IPF patients at the collaborating&#xD;
      sites that meet all inclusion/exclusion criteria will be randomly assigned to receive one of&#xD;
      the following treatments in a ratio of 2:1:&#xD;
&#xD;
      • Arm A (n=34) - Experimental Treatment:&#xD;
&#xD;
      Steroids: Prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and&#xD;
      16-19 (or the i.v. methylprednisolone equivalent). Methyl-prednisolone 100 mg i.v. will be&#xD;
      administered on days 6 and 15, as a premedication prior to the rituximab.&#xD;
&#xD;
      Insertion of a dialysis/apheresis catheter into a central vein, and initiation of therapeutic&#xD;
      plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) regimens:&#xD;
&#xD;
      Therapeutic Plasma Exchange (TPE) will consist of 1x estimated plasma volume exchanges for 3&#xD;
      successive days (1-3) and then, after a one day interval to enable equilibration of&#xD;
      autoantibodies between intra- and extra-vascular spaces, again on days 5, 6, 9, 11, 13, and&#xD;
      15.&#xD;
&#xD;
      Rituximab: One gm i.v. will be administered on day 6 and day 15 after completion of the TPE&#xD;
      on those days.&#xD;
&#xD;
      Intravenous immunoglobulin (IVIG): 0.5 gm/kg/day i.v. on days 16-19&#xD;
&#xD;
      • Arm B (n=17) - Treatment as Usual (TAU):&#xD;
&#xD;
      The same steroid regimen as described for Arm A, i.e., prednisone 60 mg (p.o.) on day 1,&#xD;
      followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone&#xD;
      equivalent), and methylprednisolone 100 mg i.v. administered on days 6 and 15.&#xD;
&#xD;
      All patients enrolled in both cohorts at all sites will also receive empiric broad-spectrum&#xD;
      antibiotics for 8 days. The empiric antibiotic regimen will be reassessed and tailored based&#xD;
      on any subsequent cultures and sensitivity results.&#xD;
&#xD;
      Patients will be monitored carefully for occurrences of adverse events, laboratory test&#xD;
      abnormalities, and changes in vital signs.&#xD;
&#xD;
      The respective treatment courses can be finished on an outpatient basis among enrolled&#xD;
      patients who are able to be discharged from the hospital, if medically indicated, and if&#xD;
      those treatment compliance can be assured.&#xD;
&#xD;
      Patients will be followed for the duration of their hospital admission after enrollment, and&#xD;
      then observed as either inpatients or outpatients on days 19, 60, 90, 180, 270, and 365. A&#xD;
      telephone contact will occur at monthly intervals, aside from those visits above. The total&#xD;
      observation/subject is 365 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 4, 2018</start_date>
  <completion_date type="Anticipated">September 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2024</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>
    <intervention_model_description>Open label randomized controlled trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Survival</measure>
    <time_frame>6 months</time_frame>
    <description>Actuarial survival</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Oxygen requirements</measure>
    <time_frame>6 months</time_frame>
    <description>Measures of oxygen required to maintain arterial oxygen concentration (SaO2) &gt;/=93%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Walk distance</measure>
    <time_frame>6 months</time_frame>
    <description>6 minute walk distance using standardized American Thoracic Society/European Respiratory Society (ATS/ERS) protocols.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>The presence of adverse events attributable to the trial intervention</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">51</enrollment>
  <condition>Idiopathic Pulmonary Fibrosis, Acute Fatal Form</condition>
  <arm_group>
    <arm_group_label>Autoantibody Reductive Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Therapeutic Plasma Exchange (TPE) consisting of 1x estimated plasma volume exchanges for 3 successive days (1-3) and then, after a one day interval to enable equilibration of autoantibodies between intra- and extra-vascular spaces, again on days 5, 6, 9, 11, 13, and 15.&#xD;
Rituximab: One gm i.v. will be administered on day 6 and day 15 after completion of the TPE on those days.&#xD;
Intravenous immunoglobulin (IVIG): 0.5 gm/kg/day i.v. on days 16-19&#xD;
All subjects in this trial, including patients in this arm, will receive identical empiric antibiotics and steroids. The steroid dose is: Prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent). Methylprednisolone 100 mg i.v. will be administered on days 6 and 15, as a premedication prior to the rituximab.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment as Usual (TAU)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The same steroid regimen as described for the experimental arm, i.e., prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent), and methylprednisolone 100 mg i.v. administered on days 6 and 15, as well as empiric antibiotics.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Autoantibody Reductive Therapy</intervention_name>
    <description>TPE x 9, rituximab x 2, IVIG x 4. See arm/group descriptions for additional details.</description>
    <arm_group_label>Autoantibody Reductive Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Treatment as Usual (TAU)</intervention_name>
    <description>Antibiotics and steroids</description>
    <arm_group_label>Treatment as Usual (TAU)</arm_group_label>
    <other_name>Antibiotics and steroids</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age between 40-85 years old.&#xD;
&#xD;
          2. A diagnosis of IPF that fulfills ATS/ERS Consensus Criteria.1&#xD;
&#xD;
          3. Worsening or new development of dyspnea or hypoxemia within the last 30 days.&#xD;
&#xD;
          4. Ground-glass abnormality and/or consolidation superimposed on a reticular or honeycomb&#xD;
             usual interstitial pneumonitis (UIP) pattern on locally read chest CT scan.&#xD;
&#xD;
          5. Ability and willingness to give informed consent (no surrogates) and adhere to study&#xD;
             requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Diagnoses of current infection per clinical or microbial assessments.&#xD;
&#xD;
          2. Diagnoses of an additional or alternative etiology for respiratory dysfunction based&#xD;
             upon clinical assessment, including congestive heart failure, sepsis, thromboembolism,&#xD;
             etc.&#xD;
&#xD;
          3. History or serologic evidence of hepatitis B or C infection.&#xD;
&#xD;
          4. Coagulopathy, defined as a International Normalized Ratio (INR) &gt;1.6, partial&#xD;
             thromboplastin time (PTT) &gt; 2x control, fibrinogen &lt;100 mg/dL, or platelet count &lt;50&#xD;
             thousand (K) unless these abnormalities can be reversed safely.&#xD;
&#xD;
          5. Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes, or&#xD;
             uncontrolled hypertension (systolic BP &gt;160 mm Hg and diastolic BP &gt;100 mm Hg) that&#xD;
             would contraindicate use of corticosteroids.&#xD;
&#xD;
          6. Hemodynamic instability, defined as an inotrope or vasopressor requirement.&#xD;
&#xD;
          7. History of reaction to blood products or murine-derived products or prior rituximab&#xD;
             use.&#xD;
&#xD;
          8. History of malignancy, excluding basal or squamous cell skin cancer and low-risk&#xD;
             prostate cancer, the latter defined as stage T1 or T2a, with prostate specific antigen&#xD;
             (PSA) less than 10 ng/dl. The experimental treatments are not known to promote cancer&#xD;
             progression, and these criteria are within current guidelines.&#xD;
&#xD;
          9. Unwillingness to accept blood product transfusion.&#xD;
&#xD;
         10. Diagnosis of major comorbidities expected to interfere with study participation.&#xD;
&#xD;
         11. 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 immuno-suppressant&#xD;
             (e.g., cyclophosphamide, methotrexate, calcineurin inhibitors, mycophenolate,&#xD;
             azathioprine, etc.). An exception will be made if the patient has a bronchoalveolar&#xD;
             lavage (BAL) negative for pathogens.&#xD;
&#xD;
         12. Current treatment with an angiotensin converting enzyme inhibitor that cannot be&#xD;
             discontinued and/or substituted (to obviate hemodynamic complications during TPE).&#xD;
&#xD;
         13. Concurrent participation in other experimental trials.&#xD;
&#xD;
         14. Fertile females who do not agree to contraception or abstinence, or have a positive&#xD;
             pregnancy test (urine or blood). IPF is a disease of older adults, and male&#xD;
             predominant, so this will not be a frequent consideration.&#xD;
&#xD;
         15. Presence of positive (abnormal) classical autoimmune tests: anti-nuclear antibody&#xD;
             (ANA), rheumatoid factor (RF), Anti- Sjögren's-syndrome-related antigen (SSA) , and&#xD;
             Anti-Cyclic Citrullinated Peptide (CCP). This criterion will eliminate patients with&#xD;
             confounding classical autoimmune syndromes. Many IPF patients will have already had&#xD;
             these tests, which are standard of practice (SOP) at many IPF centers, and these prior&#xD;
             results will suffice if the tests were performed within the last year. Otherwise,&#xD;
             these tests need to be performed prior to enrollment and they can usually be procured&#xD;
             in 1-2 days. Based on experience, we anticipate ~10% of patients who fulfill all other&#xD;
             IPF criteria will nonetheless be positive for one of these classical autoantibody&#xD;
             tests.&#xD;
&#xD;
         16. IgA deficiency (IgA level &lt;7 mg/dL)- to preclude IVIG reactions.&#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>Steven R Duncan, MD</last_name>
    <phone>205-934-5018</phone>
    <email>srduncan@uabmc.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Melissa D Garner, RN</last_name>
    <phone>205-934-6229</phone>
    <email>mdgarnder@uabmc.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Steve Duncan, MD</last_name>
      <phone>205-934-5018</phone>
      <email>srduncan@uabmc.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Dan Dilling</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dan Dilling</last_name>
      <phone>708-216-5744</phone>
      <email>ddillin@lumc.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Thomas Jefferson University Medical Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ross Summer, MD</last_name>
      <phone>215-955-5161</phone>
      <email>ross.summer@jefferson.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Temple University Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19140</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gerard J Criner, MD</last_name>
      <phone>215-707-5864</phone>
      <email>gerard.criner@tuhs.temple.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Medical Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Daniel J Kass, MD</last_name>
      <phone>412-802-3275</phone>
      <email>kassd2@upmc.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Baylor University Medical Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Fernando M Poli</last_name>
      <phone>786-642-2332</phone>
      <email>fernando.polidefrias@bcm.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Utah Medical Center</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tyler Suciu</last_name>
      <phone>801-581-5864</phone>
      <email>tyler.suciu@hsc.utah.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, Gadgil A, George MP, Gibson KF, Choi AM, Kaminski N, Zhang Y, Duncan SR. Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol. 2007 Aug 15;179(4):2592-9. doi: 10.4049/jimmunol.179.4.2592.</citation>
    <PMID>17675522</PMID>
  </results_reference>
  <results_reference>
    <citation>Gilani SR, Vuga LJ, Lindell KO, Gibson KF, Xue J, Kaminski N, Valentine VG, Lindsay EK, George MP, Steele C, Duncan SR. CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis. PLoS One. 2010 Jan 29;5(1):e8959. doi: 10.1371/journal.pone.0008959.</citation>
    <PMID>20126467</PMID>
  </results_reference>
  <results_reference>
    <citation>Xue J, Gochuico BR, Alawad AS, Feghali-Bostwick CA, Noth I, Nathan SD, Rosen GD, Rosas IO, Dacic S, Ocak I, Fuhrman CR, Cuenco KT, Smith MA, Jacobs SS, Zeevi A, Morel PA, Pilewski JM, Valentine VG, Gibson KF, Kaminski N, Sciurba FC, Zhang Y, Duncan SR. The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS One. 2011 Feb 23;6(2):e14715. doi: 10.1371/journal.pone.0014715.</citation>
    <PMID>21373184</PMID>
  </results_reference>
  <results_reference>
    <citation>Kahloon RA, Xue J, Bhargava A, Csizmadia E, Otterbein L, Kass DJ, Bon J, Soejima M, Levesque MC, Lindell KO, Gibson KF, Kaminski N, Banga G, Oddis CV, Pilewski JM, Sciurba FC, Donahoe M, Zhang Y, Duncan SR. Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses. Am J Respir Crit Care Med. 2013 Apr 1;187(7):768-75. doi: 10.1164/rccm.201203-0506OC.</citation>
    <PMID>23262513</PMID>
  </results_reference>
  <results_reference>
    <citation>Xue J, Kass DJ, Bon J, Vuga L, Tan J, Csizmadia E, Otterbein L, Soejima M, Levesque MC, Gibson KF, Kaminski N, Pilewski JM, Donahoe M, Sciurba FC, Duncan SR. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients. J Immunol. 2013 Sep 1;191(5):2089-95. doi: 10.4049/jimmunol.1203476. Epub 2013 Jul 19.</citation>
    <PMID>23872052</PMID>
  </results_reference>
  <results_reference>
    <citation>Vuga LJ, Tedrow JR, Pandit KV, Tan J, Kass DJ, Xue J, Chandra D, Leader JK, Gibson KF, Kaminski N, Sciurba FC, Duncan SR. C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014 Apr 15;189(8):966-74. doi: 10.1164/rccm.201309-1592OC.</citation>
    <PMID>24628285</PMID>
  </results_reference>
  <results_reference>
    <citation>Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, Xue J, Zhang Y, Duncan SR. Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis. PLoS One. 2015 Jun 17;10(6):e0127771. doi: 10.1371/journal.pone.0127771. eCollection 2015. Erratum In: PLoS One. 2015;10(7):e0133684.</citation>
    <PMID>26083430</PMID>
  </results_reference>
  <results_reference>
    <citation>Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, Loyd JE, Noth I, Olman MA, Raghu G, Roman J, Ryu JH, Zisman DA, Hunninghake GW, Colby TV, Egan JJ, Hansell DM, Johkoh T, Kaminski N, Kim DS, Kondoh Y, Lynch DA, Muller-Quernheim J, Myers JL, Nicholson AG, Selman M, Toews GB, Wells AU, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007 Oct 1;176(7):636-43. doi: 10.1164/rccm.200703-463PP. Epub 2007 Jun 21.</citation>
    <PMID>17585107</PMID>
  </results_reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>September 12, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 18, 2017</study_first_posted>
  <last_update_submitted>August 4, 2023</last_update_submitted>
  <last_update_submitted_qc>August 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 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>Steven R. Duncan, MD</investigator_full_name>
    <investigator_title>Prinicpal Investigator</investigator_title>
  </responsible_party>
  <keyword>Acute Exacerbation of Idiopathic Pulmonary Fibrosis</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>Anti-Bacterial Agents</mesh_term>
    <mesh_term>Autoantibodies</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/NCT03286556
org study id: F170530011
secondary id: 1U01HL133232-01A1
nct id: NCT03286556
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Acute exacerbations (AE) are a dreaded manifestation of idiopathic pulmonary fibrosis (IPF)
      that presents with rapidly worsening respiratory function over days to weeks. AE account for
      about 1/2 the deaths in IPF patients, and are refractory to all medical therapies attempted
      to date.

      Considerable preliminary data shows pathological B-cell abnormalities and autoantibodies are
      present in AE-IPF and associated with disease severity.

      The experimental therapy here (therapeutic plasma exchange plus rituximab plus intravenous
      immunoglobulin) is mechanistically targeted to ameliorate autoantibody-mediated pulmonary
      injury. Anecdotal pilot studies indicate these treatments have significant benefit for a
      disease syndrome that has, until now, been almost invariably inexorable. This clinical trial
      has the potential to profoundly affect current paradigms and treatment approaches to patients
      with AE-IPF.
The primary goal of clinical trial is to determine effects of combined therapeutic plasma
      exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) in comparison to effects of
      treatment as usual (TAU), among AE-IPF patients.

      Our central hypothesis is "AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF PATIENTS." A
      corollary of this hypothesis is that antibody-mediated autoimmunity can play an important
      role in IPF exacerbations.

      Following baseline screening assessments, hospitalized AE-IPF patients at the collaborating
      sites that meet all inclusion/exclusion criteria will be randomly assigned to receive one of
      the following treatments in a ratio of 2:1:

      • Arm A (n=34) - Experimental Treatment:

      Steroids: Prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and
      16-19 (or the i.v. methylprednisolone equivalent). Methyl-prednisolone 100 mg i.v. will be
      administered on days 6 and 15, as a premedication prior to the rituximab.

      Insertion of a dialysis/apheresis catheter into a central vein, and initiation of therapeutic
      plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) regimens:

      Therapeutic Plasma Exchange (TPE) will consist of 1x estimated plasma volume exchanges for 3
      successive days (1-3) and then, after a one day interval to enable equilibration of
      autoantibodies between intra- and extra-vascular spaces, again on days 5, 6, 9, 11, 13, and
      15.

      Rituximab: One gm i.v. will be administered on day 6 and day 15 after completion of the TPE
      on those days.

      Intravenous immunoglobulin (IVIG): 0.5 gm/kg/day i.v. on days 16-19

      • Arm B (n=17) - Treatment as Usual (TAU):

      The same steroid regimen as described for Arm A, i.e., prednisone 60 mg (p.o.) on day 1,
      followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone
      equivalent), and methylprednisolone 100 mg i.v. administered on days 6 and 15.

      All patients enrolled in both cohorts at all sites will also receive empiric broad-spectrum
      antibiotics for 8 days. The empiric antibiotic regimen will be reassessed and tailored based
      on any subsequent cultures and sensitivity results.

      Patients will be monitored carefully for occurrences of adverse events, laboratory test
      abnormalities, and changes in vital signs.

      The respective treatment courses can be finished on an outpatient basis among enrolled
      patients who are able to be discharged from the hospital, if medically indicated, and if
      those treatment compliance can be assured.

      Patients will be followed for the duration of their hospital admission after enrollment, and
      then observed as either inpatients or outpatients on days 19, 60, 90, 180, 270, and 365. A
      telephone contact will occur at monthly intervals, aside from those visits above. The total
      observation/subject is 365 days.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Open label randomized controlled trial.
primary purpose: Treatment
masking: None (Open Label)
measure: Survival
time frame: 6 months
description: Actuarial survival
measure: Oxygen requirements
time frame: 6 months
description: Measures of oxygen required to maintain arterial oxygen concentration (SaO2) >/=93%
measure: Walk distance
time frame: 6 months
description: 6 minute walk distance using standardized American Thoracic Society/European Respiratory Society (ATS/ERS) protocols.
measure: Adverse Events
time frame: Through study completion, an average of 1 year
description: The presence of adverse events attributable to the trial intervention
arm group label: Autoantibody Reductive Therapy
arm group type: Experimental
description: Therapeutic Plasma Exchange (TPE) consisting of 1x estimated plasma volume exchanges for 3 successive days (1-3) and then, after a one day interval to enable equilibration of autoantibodies between intra- and extra-vascular spaces, again on days 5, 6, 9, 11, 13, and 15.
Rituximab: One gm i.v. will be administered on day 6 and day 15 after completion of the TPE on those days.
Intravenous immunoglobulin (IVIG): 0.5 gm/kg/day i.v. on days 16-19
All subjects in this trial, including patients in this arm, will receive identical empiric antibiotics and steroids. The steroid dose is: Prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent). Methylprednisolone 100 mg i.v. will be administered on days 6 and 15, as a premedication prior to the rituximab.
arm group label: Treatment as Usual (TAU)
arm group type: Active Comparator
description: The same steroid regimen as described for the experimental arm, i.e., prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent), and methylprednisolone 100 mg i.v. administered on days 6 and 15, as well as empiric antibiotics.
intervention type: Drug
intervention name: Autoantibody Reductive Therapy
description: TPE x 9, rituximab x 2, IVIG x 4. See arm/group descriptions for additional details.
arm group label: Autoantibody Reductive Therapy
intervention type: Drug
intervention name: Treatment as Usual (TAU)
description: Antibiotics and steroids
arm group label: Treatment as Usual (TAU)
other name: Antibiotics and steroids
criteria: 
gender: All
minimum age: 40 Years
maximum age: 85 Years
healthy volunteers: No
last name: Steven R Duncan, MD
phone: 205-934-5018
email: srduncan@uabmc.edu
last name: Melissa D Garner, RN
phone: 205-934-6229
email: mdgarnder@uabmc.edu
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: United States
citation: Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, Gadgil A, George MP, Gibson KF, Choi AM, Kaminski N, Zhang Y, Duncan SR. Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol. 2007 Aug 15;179(4):2592-9. doi: 10.4049/jimmunol.179.4.2592.
PMID: 17675522
citation: Gilani SR, Vuga LJ, Lindell KO, Gibson KF, Xue J, Kaminski N, Valentine VG, Lindsay EK, George MP, Steele C, Duncan SR. CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis. PLoS One. 2010 Jan 29;5(1):e8959. doi: 10.1371/journal.pone.0008959.
PMID: 20126467
citation: Xue J, Gochuico BR, Alawad AS, Feghali-Bostwick CA, Noth I, Nathan SD, Rosen GD, Rosas IO, Dacic S, Ocak I, Fuhrman CR, Cuenco KT, Smith MA, Jacobs SS, Zeevi A, Morel PA, Pilewski JM, Valentine VG, Gibson KF, Kaminski N, Sciurba FC, Zhang Y, Duncan SR. The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS One. 2011 Feb 23;6(2):e14715. doi: 10.1371/journal.pone.0014715.
PMID: 21373184
citation: Kahloon RA, Xue J, Bhargava A, Csizmadia E, Otterbein L, Kass DJ, Bon J, Soejima M, Levesque MC, Lindell KO, Gibson KF, Kaminski N, Banga G, Oddis CV, Pilewski JM, Sciurba FC, Donahoe M, Zhang Y, Duncan SR. Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses. Am J Respir Crit Care Med. 2013 Apr 1;187(7):768-75. doi: 10.1164/rccm.201203-0506OC.
PMID: 23262513
citation: Xue J, Kass DJ, Bon J, Vuga L, Tan J, Csizmadia E, Otterbein L, Soejima M, Levesque MC, Gibson KF, Kaminski N, Pilewski JM, Donahoe M, Sciurba FC, Duncan SR. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients. J Immunol. 2013 Sep 1;191(5):2089-95. doi: 10.4049/jimmunol.1203476. Epub 2013 Jul 19.
PMID: 23872052
citation: Vuga LJ, Tedrow JR, Pandit KV, Tan J, Kass DJ, Xue J, Chandra D, Leader JK, Gibson KF, Kaminski N, Sciurba FC, Duncan SR. C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014 Apr 15;189(8):966-74. doi: 10.1164/rccm.201309-1592OC.
PMID: 24628285
citation: Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, Xue J, Zhang Y, Duncan SR. Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis. PLoS One. 2015 Jun 17;10(6):e0127771. doi: 10.1371/journal.pone.0127771. eCollection 2015. Erratum In: PLoS One. 2015;10(7):e0133684.
PMID: 26083430
citation: Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, Loyd JE, Noth I, Olman MA, Raghu G, Roman J, Ryu JH, Zisman DA, Hunninghake GW, Colby TV, Egan JJ, Hansell DM, Johkoh T, Kaminski N, Kim DS, Kondoh Y, Lynch DA, Muller-Quernheim J, Myers JL, Nicholson AG, Selman M, Toews GB, Wells AU, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007 Oct 1;176(7):636-43. doi: 10.1164/rccm.200703-463PP. Epub 2007 Jun 21.
PMID: 17585107
responsible party type: Principal Investigator
investigator affiliation: University of Alabama at Birmingham
investigator full name: Steven R. Duncan, MD
investigator title: Prinicpal Investigator
mesh term: Pulmonary Fibrosis
mesh term: Idiopathic Pulmonary Fibrosis
mesh term: Fibrosis
mesh term: Anti-Bacterial Agents
mesh term: Autoantibodies
sharing ipd: No