<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/NCT04414098</url>
  </required_header>
  <id_info>
    <org_study_id>CZabala</org_study_id>
    <nct_id>NCT04414098</nct_id>
  </id_info>
  <brief_title>Ruxolitinib in the Treatment of Covid-19</brief_title>
  <official_title>Safety and Efficacy Study of Ruxolitinib in the Treatment of Severe Acute Respiratory Syndrome Due to SARS-COV-2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Marcelo Iastrebner</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Clinica Zabala</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</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>
      The treatment of COVID-19 severe acute respiratory syndrome with ruxolitinib 5 mg orally&#xD;
      every 12 hours during 14 days would stop the disproportionate inflammatory response, causing&#xD;
      a reduction in the proportion of patients who show a progression and worsening of the severe&#xD;
      acute respiratory syndrome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objective&#xD;
&#xD;
      Evaluate the efficacy of ruxolitinib in the treatment of COVID-19 severe acute respiratory&#xD;
      syndrome by means of measuring the proportion of patients with clinical worsening (defined by&#xD;
      a requirement of FIO2 50% and/or mechanical respiratory assistance) during 14 days after the&#xD;
      commencement of treatment.&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        1. Evaluate the median duration of hospitalization. Median duration after 45 days of&#xD;
           commencement of treatment.&#xD;
&#xD;
        2. Evaluate the evolution of systemic inflammation parameters. Evaluation at the beginning&#xD;
           (baseline), middle and end of the treatment with ruxolitinib of PCR, LDH, ESD, Ferritin&#xD;
           and IL-6.&#xD;
&#xD;
        3. Evaluate COVID-19 mortality rate after 45 days of treatment.&#xD;
&#xD;
        4. Evaluate the proportion of the requirement of mechanical ventilation.&#xD;
&#xD;
        5. Evaluate ruxolitinib adverse reactions with a total follow-up of 45 days.&#xD;
&#xD;
        6. Evaluate the proportion of secondary infections during the treatment with ruxolitinib.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">June 1, 2020</start_date>
  <completion_date type="Anticipated">September 15, 2020</completion_date>
  <primary_completion_date type="Anticipated">August 15, 2020</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>Experimental, open-label, prospective, single center, add-on (added to the standard treatment) study, compared with an historical control arm.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluate the efficacy of ruxolitinib in the treatment of COVID-19 severe acute respiratory syndrome</measure>
    <time_frame>during 14 days after the commencement of treatment</time_frame>
    <description>Measuring the proportion of patients with clinical worsening (defined by a requirement of FIO2 &gt;50% and/or mechanical respiratory assistance)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluate the median duration of hospitalization.</measure>
    <time_frame>after 45 days of commencement of treatment.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the evolution of systemic inflammation parameters.</measure>
    <time_frame>after 45 days of commencement of treatment.</time_frame>
    <description>Evaluation at the beginning (baseline), middle and end of the treatment with ruxolitinib of PCR, LDH, ESD, Ferritin and IL-6 (if available).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate COVID-19 mortality rate</measure>
    <time_frame>after 45 days of treatment.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the proportion of the requirement of mechanical ventilation.</measure>
    <time_frame>with a total follow-up of 45 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate ruxolitinib adverse reactions</measure>
    <time_frame>with a total follow-up of 45 days.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the proportion of secondary infections during the treatment with ruxolitinib</measure>
    <time_frame>after 45 days of commencement of treatment.</time_frame>
  </secondary_outcome>
  <enrollment type="Anticipated">100</enrollment>
  <condition>COVID-19</condition>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>INC424 / Ruxolitinib</intervention_name>
    <description>Ruxolitinib 5 mg orally every 12 hours during 14 days.&#xD;
Total Follow-up time will be of 45 days.&#xD;
The reduction of ruxolitinib dose will be considered in cases of drug-related cytopenias.&#xD;
During hospitalization, clinical and laboratory evolution parameters will be recorded daily in the medical history of the patient and in the data collection table of the study. Upon patient's discharge, a follow-up will be conducted until day +45&#xD;
During hospitalization, adverse events will be monitored daily by means of clinical assessment and laboratory data.&#xD;
After discharge, monitoring of adverse events will continue during the outpatient follow-up.&#xD;
Pro-inflammatory parameters will be assessed at baseline, after one week (day +7) and at the end of treatment (day +14)&#xD;
Ruxolitinib will be associated to the standard of care for COVID-19 of each center.&#xD;
In case of an adverse effect or a need to discontinue the treatment, ruxolitinib should be suspended.</description>
    <other_name>Jakavi</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients ≥ 18 years.&#xD;
&#xD;
          2. SARS-Cov2 infection confirmed by a validated method.&#xD;
&#xD;
          3. Presence of COVID-19 severe acute respiratory syndrome with:&#xD;
&#xD;
             Respiratory rate ≥ 20/min O2 saturation ≤93% with FiO2 of 0.21 Lung images by means of&#xD;
             computerized tomography or thorax radiography compatible with respiratory involvement&#xD;
             due to COVID-19.&#xD;
&#xD;
          4. Signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or breast-feeding.&#xD;
&#xD;
          2. Platelets &lt; 50,000/mm3.&#xD;
&#xD;
          3. Neutrophils &lt; 1,000/mm3.&#xD;
&#xD;
          4. Hemoglobin &lt; 6 g/dl&#xD;
&#xD;
          5. Creatinine ≥2 mg/dl or creatinine clearance ≤30 ml/min.&#xD;
&#xD;
          6. Total serum bilirubin &gt; 2.0 x upper limit of normal and/or aspartate aminotransferase&#xD;
             (AST) or alanine aminotransferase (ALT) &gt;5 times the upper limit of normal.&#xD;
&#xD;
          7. Known active infection due to HIV, HVC, HVB, Herpes Zoster or Micob Tuberculosis&#xD;
&#xD;
          8. Treatment with Tocilizumab, Baricitinib or Interferon.&#xD;
&#xD;
          9. History of hypersensitivity to ruxolitinib or to any medicine with similar chemical&#xD;
             compounds&#xD;
&#xD;
         10. Patients with mechanical respiratory assistance&#xD;
&#xD;
         11. Patients under treatment with Ruxolitinib due to hematological disease&#xD;
&#xD;
         12. Any condition that, according to the Investigator, may interfere with the complete&#xD;
             participation of the patient in the study, including the administration of the&#xD;
             medicinal product, the limitation of visits, the implication of a risk for the patient&#xD;
             or that prevents the correct interpretation of the results.&#xD;
&#xD;
        Treatment Suspension Criteria&#xD;
&#xD;
          1. Voluntary decision of the patient&#xD;
&#xD;
          2. Treating physician's decision to discontinue the treatment&#xD;
&#xD;
          3. Drug toxicity grade 3 or higher (CTCAE 5.0).&#xD;
&#xD;
        Study Design&#xD;
&#xD;
        Experimental, open-label, prospective, single center, add-on (added to the standard&#xD;
        treatment) study, compared with the historical control arm.&#xD;
&#xD;
        Control arm: It will include patients with COVID-19 Respiratory Syndrome who meet the&#xD;
        aforementioned selection criteria and have received the standard of care (SOC). Efforts&#xD;
        will be made so that both arms share similar demographic characteristics as regards gender&#xD;
        and age group. Ten centers will participate, which will share the same protocol and their&#xD;
        results may be jointly analyzed. The expected n per center is 10-15 patients.&#xD;
&#xD;
        For the safety assessment as part of the objective, the following parameters will be taken&#xD;
        into account:&#xD;
&#xD;
          1. Biochemical changes: (day 1, 8 and 14) Leukocytes, Formula, Hemoglobin, platelets,&#xD;
             creatinine, glycemia, PT, Bilirubin, GOT/GPT.&#xD;
&#xD;
          2. Grade 3/4 Toxicity, SAE (Serious Adverse Event)&#xD;
&#xD;
          3. Incidence of discontinuation, suspension or dose-reduction of the study drug.&#xD;
&#xD;
          4. Incidence of secondary infections.&#xD;
&#xD;
        Efficacy Assessment:&#xD;
&#xD;
          1. Efficacy will be graded according to the ordinal scale of 8 points.&#xD;
&#xD;
          2. Time to Improvement&#xD;
&#xD;
          3. Time of response consolidation&#xD;
&#xD;
          4. Changes in NEWS table&#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_contact>
    <last_name>Marcelo Iastrebner, MD</last_name>
    <phone>+5491169816300</phone>
    <email>miastrebner@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Joaquin Castro, MD</last_name>
    <phone>+5491153880811</phone>
    <email>drjoaquincastro@gmail.com</email>
  </overall_contact_backup>
  <reference>
    <citation>Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2023 Aug 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/</citation>
    <PMID>32150360</PMID>
  </reference>
  <reference>
    <citation>McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020 Jun;19(6):102537. doi: 10.1016/j.autrev.2020.102537. Epub 2020 Apr 3.</citation>
    <PMID>32251717</PMID>
  </reference>
  <reference>
    <citation>Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 2017 Apr;77(5):521-546. doi: 10.1007/s40265-017-0701-9. Erratum In: Drugs. 2017 May;77(8):939. Drugs. 2017 Jun 12;:</citation>
    <PMID>28255960</PMID>
  </reference>
  <reference>
    <citation>Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14. doi: 10.1038/s41421-020-0153-3. eCollection 2020.</citation>
    <PMID>32194980</PMID>
  </reference>
  <reference>
    <citation>Slostad J, Hoversten P, Haddox CL, Cisak K, Paludo J, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A single patient experience. Am J Hematol. 2018 Feb;93(2):E47-E49. doi: 10.1002/ajh.24971. Epub 2017 Dec 4. No abstract available.</citation>
    <PMID>29134683</PMID>
  </reference>
  <reference>
    <citation>Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, Cervantes F, Jones MM, Sun K, McQuitty M, Stalbovskaya V, Gopalakrishna P, Barbui T. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016 Aug;30(8):1701-7. doi: 10.1038/leu.2016.148. Epub 2016 May 23. Erratum In: Leukemia. 2017 Mar;31(3):775.</citation>
    <PMID>27211272</PMID>
  </reference>
  <reference>
    <citation>Gadina M, Le MT, Schwartz DM, Silvennoinen O, Nakayamada S, Yamaoka K, O'Shea JJ. Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology (Oxford). 2019 Feb 1;58(Suppl 1):i4-i16. doi: 10.1093/rheumatology/key432.</citation>
    <PMID>30806710</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>June 1, 2020</last_update_submitted>
  <last_update_submitted_qc>June 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Clinica Zabala</investigator_affiliation>
    <investigator_full_name>Marcelo Iastrebner</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Ruxolitinib</keyword>
  <keyword>Covid-19</keyword>
  <keyword>SARS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <!-- 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/NCT04414098
org study id: CZabala
nct id: NCT04414098
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
The treatment of COVID-19 severe acute respiratory syndrome with ruxolitinib 5 mg orally
      every 12 hours during 14 days would stop the disproportionate inflammatory response, causing
      a reduction in the proportion of patients who show a progression and worsening of the severe
      acute respiratory syndrome.
Primary Objective

      Evaluate the efficacy of ruxolitinib in the treatment of COVID-19 severe acute respiratory
      syndrome by means of measuring the proportion of patients with clinical worsening (defined by
      a requirement of FIO2 50% and/or mechanical respiratory assistance) during 14 days after the
      commencement of treatment.

      Secondary Objectives

        1. Evaluate the median duration of hospitalization. Median duration after 45 days of
           commencement of treatment.

        2. Evaluate the evolution of systemic inflammation parameters. Evaluation at the beginning
           (baseline), middle and end of the treatment with ruxolitinib of PCR, LDH, ESD, Ferritin
           and IL-6.

        3. Evaluate COVID-19 mortality rate after 45 days of treatment.

        4. Evaluate the proportion of the requirement of mechanical ventilation.

        5. Evaluate ruxolitinib adverse reactions with a total follow-up of 45 days.

        6. Evaluate the proportion of secondary infections during the treatment with ruxolitinib.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Experimental, open-label, prospective, single center, add-on (added to the standard treatment) study, compared with an historical control arm.
primary purpose: Treatment
masking: None (Open Label)
measure: Evaluate the efficacy of ruxolitinib in the treatment of COVID-19 severe acute respiratory syndrome
time frame: during 14 days after the commencement of treatment
description: Measuring the proportion of patients with clinical worsening (defined by a requirement of FIO2 >50% and/or mechanical respiratory assistance)
measure: Evaluate the median duration of hospitalization.
time frame: after 45 days of commencement of treatment.
measure: Evaluate the evolution of systemic inflammation parameters.
time frame: after 45 days of commencement of treatment.
description: Evaluation at the beginning (baseline), middle and end of the treatment with ruxolitinib of PCR, LDH, ESD, Ferritin and IL-6 (if available).
measure: Evaluate COVID-19 mortality rate
time frame: after 45 days of treatment.
measure: Evaluate the proportion of the requirement of mechanical ventilation.
time frame: with a total follow-up of 45 days
measure: Evaluate ruxolitinib adverse reactions
time frame: with a total follow-up of 45 days.
measure: Evaluate the proportion of secondary infections during the treatment with ruxolitinib
time frame: after 45 days of commencement of treatment.
intervention type: Drug
intervention name: INC424 / Ruxolitinib
description: Ruxolitinib 5 mg orally every 12 hours during 14 days.
Total Follow-up time will be of 45 days.
The reduction of ruxolitinib dose will be considered in cases of drug-related cytopenias.
During hospitalization, clinical and laboratory evolution parameters will be recorded daily in the medical history of the patient and in the data collection table of the study. Upon patient's discharge, a follow-up will be conducted until day +45
During hospitalization, adverse events will be monitored daily by means of clinical assessment and laboratory data.
After discharge, monitoring of adverse events will continue during the outpatient follow-up.
Pro-inflammatory parameters will be assessed at baseline, after one week (day +7) and at the end of treatment (day +14)
Ruxolitinib will be associated to the standard of care for COVID-19 of each center.
In case of an adverse effect or a need to discontinue the treatment, ruxolitinib should be suspended.
other name: Jakavi
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marcelo Iastrebner, MD
phone: +5491169816300
email: miastrebner@gmail.com
last name: Joaquin Castro, MD
phone: +5491153880811
email: drjoaquincastro@gmail.com
citation: Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2023 Aug 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/
PMID: 32150360
citation: McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020 Jun;19(6):102537. doi: 10.1016/j.autrev.2020.102537. Epub 2020 Apr 3.
PMID: 32251717
citation: Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 2017 Apr;77(5):521-546. doi: 10.1007/s40265-017-0701-9. Erratum In: Drugs. 2017 May;77(8):939. Drugs. 2017 Jun 12;:
PMID: 28255960
citation: Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14. doi: 10.1038/s41421-020-0153-3. eCollection 2020.
PMID: 32194980
citation: Slostad J, Hoversten P, Haddox CL, Cisak K, Paludo J, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A single patient experience. Am J Hematol. 2018 Feb;93(2):E47-E49. doi: 10.1002/ajh.24971. Epub 2017 Dec 4. No abstract available.
PMID: 29134683
citation: Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, Cervantes F, Jones MM, Sun K, McQuitty M, Stalbovskaya V, Gopalakrishna P, Barbui T. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016 Aug;30(8):1701-7. doi: 10.1038/leu.2016.148. Epub 2016 May 23. Erratum In: Leukemia. 2017 Mar;31(3):775.
PMID: 27211272
citation: Gadina M, Le MT, Schwartz DM, Silvennoinen O, Nakayamada S, Yamaoka K, O'Shea JJ. Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology (Oxford). 2019 Feb 1;58(Suppl 1):i4-i16. doi: 10.1093/rheumatology/key432.
PMID: 30806710
responsible party type: Sponsor-Investigator
investigator affiliation: Clinica Zabala
investigator full name: Marcelo Iastrebner
investigator title: Principal Investigator
mesh term: COVID-19