<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/NCT03754686</url>
  </required_header>
  <id_info>
    <org_study_id>0520-18-RMB CTIL</org_study_id>
    <nct_id>NCT03754686</nct_id>
  </id_info>
  <brief_title>Oseltamivir Versus Paracetamol for Influenza-like Illness During the Influenza Season</brief_title>
  <official_title>Oseltamivir Versus Paracetamol for Influenza-like Illness During the Influenza Season: a Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rambam Health Care Campus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rambam Health Care Campus</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Parallel group, investigator initiated, 1:1, open-label, non-inferiority randomized&#xD;
      controlled trial, aiming to show that paracetamol is non-inferior to oseltamivir among&#xD;
      patients with serious acute respiratory infection (SARI).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study setting: a single tertiary hospital, containing 1,000 beds. Intervention: best medical&#xD;
      care and oral oseltamivir 75 mg twice daily for five days.&#xD;
&#xD;
      Control: best medical care and oral paracetamol twice daily for five days. Dose adjustments&#xD;
      of oseltamivir will be made according to manufacturer's instructions. Patients with&#xD;
      creatinine clearance between 30-60 ml/minute will receive 30 mg twice daily for five days.&#xD;
      Patients with creatinine clearance 10-30 ml/minute will receive 30 mg, once daily for 5 days.&#xD;
      Hemodialytic patients will receive 30 mg upon admission, and 30 mg after every session, for 5&#xD;
      days. Patients on peritoneal dialysis will receive 30 mg once, which suffices for 5 days.&#xD;
      Patients may withdraw participation from the trial at any time. The attending physician may&#xD;
      also be informed the treatment arm, and start antiviral treatment if deemed necessary.&#xD;
&#xD;
      A nasopharyngeal swab for influenza will be obtained upon enrollment. PCR testing will be&#xD;
      performed in-house. Administration of oseltamivir or paracetamol for patients with negative&#xD;
      swabs will be stopped, unless the sample was obtained after initiation of the study drug.&#xD;
      Patients may discontinue or refuse trial medications at any point. The reasons for&#xD;
      discontinuation will be documented.&#xD;
&#xD;
      Adverse effects: The investigators will monitor and document daily rate of nausea, vomiting,&#xD;
      and headache, deterioration in kidney function (defined as an increase in creatinine by &gt;0.3&#xD;
      mg/dl or by &gt;50% from baseline), and in-hospital delirium.&#xD;
&#xD;
      Participant timeline and follow-up: After signing informed consent (available in Hebrew,&#xD;
      Arabic or Russian), study personnel, will interview patients and review electronic medical&#xD;
      files.&#xD;
&#xD;
      Patients enrolled will be followed-up daily by study personnel in-hospital, until the first&#xD;
      of: achieving clinical improvement (defined below), hospital discharge, or 7 days from&#xD;
      randomization. During the follow-up patients will be assessed for clinical improvement and&#xD;
      for AE (detailed above). Patients discharged before day 7 will be assumed to have reached&#xD;
      clinical improvement by that time. Readmissions and deaths by day 30 will be monitored&#xD;
      through the electronic patient file (Prometheus), providing access to a national registry of&#xD;
      hospitalizations and updated from the national Health Ministry on deaths.&#xD;
&#xD;
      Recruitment: during the influenza high-season, ER nurses will fill in a check-box containing&#xD;
      the SARI criteria items. An electronic report of all cases filling SARI criteria, will be&#xD;
      sent to study personnel 5 times daily. An investigator will apply inclusion and exclusion&#xD;
      criteria on candidates, and obtain informed consent from patients or their legal guardians.&#xD;
      Enrollment will continue until reaching the predefined sample size.&#xD;
&#xD;
      Randomization and blinding methods: a computer-generated randomizer will be used, to assign&#xD;
      all patients into block sizes of 8, with a 1:1 randomization rate. Allocation codes will be&#xD;
      concealed in sealed opaque envelopes that will be opened consecutively by the randomization&#xD;
      code. The study is open-label. Outcome assessment will be performed blinded to the treatment&#xD;
      allocation.&#xD;
&#xD;
      Patients will be assessed once daily, by study personnel, for the clinical course of the&#xD;
      disease and for AE. Data will be entered into a case report form (CRF). Daily assessment will&#xD;
      end when patients are released from hospitalization, or at the end of 7 days from admission.&#xD;
      During hospitalization, medical files will be reviewed for administration of antibiotics,&#xD;
      respiratory deterioration (defined as new requirement of oxygen supplementation or&#xD;
      requirement for mechanical ventilation, either invasive or non-invasive). Duration of&#xD;
      hospitalization, as well as re-hospitalization within one month after enrollment, and 30 days&#xD;
      mortality, available from the hospital computerized medical records, will be noted.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 10, 2019</start_date>
  <completion_date type="Anticipated">July 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>the composite of failure to reach clinical stability at day 7 after randomization OR transfer to the ICU until day 7 after randomization OR re-admission within 30 days of randomization OR death within 30 days of randomization.</measure>
    <time_frame>30 days</time_frame>
    <description>Clinical stability will be defined as: heart rate &lt; 100/min AND systolic blood pressure &gt; 90 mmHG AND temperature ≤ 38.00 AND respiratory rate ≤ 24 AND oxygen saturation ≥ 90.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>include time to clinical stability (defined earlier), and duration of hospitalization.</measure>
    <time_frame>30 days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">436</enrollment>
  <condition>Influenza</condition>
  <arm_group>
    <arm_group_label>Oseltamivir</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>best medical care and oral oseltamivir 75 mg twice daily for five days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Paracetamol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>best medical care and oral paracetamol twice daily for five days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oseltamivir</intervention_name>
    <description>Best medical care and oral oseltamivir 75 mg twice daily for five days. Dose adjustments of oseltamivir will be made according to manufacturer's instructions.</description>
    <arm_group_label>Oseltamivir</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paracetamol</intervention_name>
    <description>Best medical care and oral paracetamol twice daily for five days</description>
    <arm_group_label>Paracetamol</arm_group_label>
    <other_name>Best medical care and oral paracetamol twice daily for five days.</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  admitted to the hospital during the influenza &quot;high season&quot; with SARI.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Severe disease on admission, defined as any of the following: patients deemed to&#xD;
             require intensive care immediately upon admission, a high probability of imminent&#xD;
             respiratory failure as judged by the ER physician.&#xD;
&#xD;
          2. Pregnancy.&#xD;
&#xD;
          3. Severe immunosuppression including: Acquired immunodeficiency syndrome (AIDS) or Human&#xD;
             immunodeficiency virus (HIV) with unknown CD4 or with CD4 &lt; 200/mL, solid organ and&#xD;
             stem cell transplant recipients, or neutrophil count of less than 100 per µliter.&#xD;
&#xD;
          4. Patients with decompensated cirrhosis.&#xD;
&#xD;
          5. Patients discharged home from the ER.&#xD;
&#xD;
          6. Patients unable to sign informed consent with no legal guardian.&#xD;
&#xD;
          7. Patients who received at least 2 doses of oseltamivir prior to randomization.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>November 25, 2018</study_first_submitted>
  <study_first_submitted_qc>November 25, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 27, 2018</study_first_posted>
  <last_update_submitted>January 29, 2019</last_update_submitted>
  <last_update_submitted_qc>January 29, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 30, 2019</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>Influenza, Human</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
    <mesh_term>Oseltamivir</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/NCT03754686
org study id: 0520-18-RMB CTIL
nct id: NCT03754686
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Parallel group, investigator initiated, 1:1, open-label, non-inferiority randomized
      controlled trial, aiming to show that paracetamol is non-inferior to oseltamivir among
      patients with serious acute respiratory infection (SARI).
Study setting: a single tertiary hospital, containing 1,000 beds. Intervention: best medical
      care and oral oseltamivir 75 mg twice daily for five days.

      Control: best medical care and oral paracetamol twice daily for five days. Dose adjustments
      of oseltamivir will be made according to manufacturer's instructions. Patients with
      creatinine clearance between 30-60 ml/minute will receive 30 mg twice daily for five days.
      Patients with creatinine clearance 10-30 ml/minute will receive 30 mg, once daily for 5 days.
      Hemodialytic patients will receive 30 mg upon admission, and 30 mg after every session, for 5
      days. Patients on peritoneal dialysis will receive 30 mg once, which suffices for 5 days.
      Patients may withdraw participation from the trial at any time. The attending physician may
      also be informed the treatment arm, and start antiviral treatment if deemed necessary.

      A nasopharyngeal swab for influenza will be obtained upon enrollment. PCR testing will be
      performed in-house. Administration of oseltamivir or paracetamol for patients with negative
      swabs will be stopped, unless the sample was obtained after initiation of the study drug.
      Patients may discontinue or refuse trial medications at any point. The reasons for
      discontinuation will be documented.

      Adverse effects: The investigators will monitor and document daily rate of nausea, vomiting,
      and headache, deterioration in kidney function (defined as an increase in creatinine by >0.3
      mg/dl or by >50% from baseline), and in-hospital delirium.

      Participant timeline and follow-up: After signing informed consent (available in Hebrew,
      Arabic or Russian), study personnel, will interview patients and review electronic medical
      files.

      Patients enrolled will be followed-up daily by study personnel in-hospital, until the first
      of: achieving clinical improvement (defined below), hospital discharge, or 7 days from
      randomization. During the follow-up patients will be assessed for clinical improvement and
      for AE (detailed above). Patients discharged before day 7 will be assumed to have reached
      clinical improvement by that time. Readmissions and deaths by day 30 will be monitored
      through the electronic patient file (Prometheus), providing access to a national registry of
      hospitalizations and updated from the national Health Ministry on deaths.

      Recruitment: during the influenza high-season, ER nurses will fill in a check-box containing
      the SARI criteria items. An electronic report of all cases filling SARI criteria, will be
      sent to study personnel 5 times daily. An investigator will apply inclusion and exclusion
      criteria on candidates, and obtain informed consent from patients or their legal guardians.
      Enrollment will continue until reaching the predefined sample size.

      Randomization and blinding methods: a computer-generated randomizer will be used, to assign
      all patients into block sizes of 8, with a 1:1 randomization rate. Allocation codes will be
      concealed in sealed opaque envelopes that will be opened consecutively by the randomization
      code. The study is open-label. Outcome assessment will be performed blinded to the treatment
      allocation.

      Patients will be assessed once daily, by study personnel, for the clinical course of the
      disease and for AE. Data will be entered into a case report form (CRF). Daily assessment will
      end when patients are released from hospitalization, or at the end of 7 days from admission.
      During hospitalization, medical files will be reviewed for administration of antibiotics,
      respiratory deterioration (defined as new requirement of oxygen supplementation or
      requirement for mechanical ventilation, either invasive or non-invasive). Duration of
      hospitalization, as well as re-hospitalization within one month after enrollment, and 30 days
      mortality, available from the hospital computerized medical records, will be noted.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: the composite of failure to reach clinical stability at day 7 after randomization OR transfer to the ICU until day 7 after randomization OR re-admission within 30 days of randomization OR death within 30 days of randomization.
time frame: 30 days
description: Clinical stability will be defined as: heart rate < 100/min AND systolic blood pressure > 90 mmHG AND temperature ≤ 38.00 AND respiratory rate ≤ 24 AND oxygen saturation ≥ 90.
measure: include time to clinical stability (defined earlier), and duration of hospitalization.
time frame: 30 days
arm group label: Oseltamivir
arm group type: Active Comparator
description: best medical care and oral oseltamivir 75 mg twice daily for five days.
arm group label: Paracetamol
arm group type: Active Comparator
description: best medical care and oral paracetamol twice daily for five days.
intervention type: Drug
intervention name: Oseltamivir
description: Best medical care and oral oseltamivir 75 mg twice daily for five days. Dose adjustments of oseltamivir will be made according to manufacturer's instructions.
arm group label: Oseltamivir
intervention type: Drug
intervention name: Paracetamol
description: Best medical care and oral paracetamol twice daily for five days
arm group label: Paracetamol
other name: Best medical care and oral paracetamol twice daily for five days.
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
responsible party type: Sponsor
mesh term: Influenza, Human
mesh term: Acetaminophen
mesh term: Oseltamivir
sharing ipd: No