<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/NCT03238612</url>
  </required_header>
  <id_info>
    <org_study_id>UW 16-418</org_study_id>
    <nct_id>NCT03238612</nct_id>
  </id_info>
  <brief_title>Flufenamic Acid for Hospitalised Influenza Infection</brief_title>
  <official_title>A Double-blind Randomised Controlled Trial on Flufenamic Acid for Hospitalised Influenza Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <has_dmc>Yes</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>
      It is well recognized that respiratory viruses cause substantial disease burden every year.&#xD;
      Among all known respiratory viruses, influenza virus is the greatest cause of&#xD;
      disability-adjusted life years lost, excess hospitalizations, and deaths in the elderly and&#xD;
      patients with chronic illness. These patients are frequently hospitalized for pneumonia&#xD;
      secondary to these respiratory viral infection. Recently, macrolide antimicrobial&#xD;
      clarithromycin and flufenamic acid (FFA) have been shown to inhibit seasonal influenza virus&#xD;
      infection in human airway epithelial cells with additional anti-inflammatory effect.&#xD;
&#xD;
      The investigators therefore plan to conduct a 3-year prospective study among adult patients&#xD;
      hospitalized in Queen Mary Hospital for influenza with secondary pneumonia and randomized&#xD;
      them to receive a course of oseltamivir + FFA + clarithromycin (as treatment) vs. a course of&#xD;
      oseltamivir (current standard treatment as control). The objective of this prospective&#xD;
      double-blind randomized controlled trial is to evaluate the efficacy of clarithromycin and&#xD;
      FFA antiviral therapy in patients diagnosed to have pneumonia secondary to influenza&#xD;
      infection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This double blind randomized-controlled trial will assess the clinical efficacy, mortality&#xD;
      reduction and viral load reduction of clarithromycin and FFA in patients hospitalized for&#xD;
      pneumonia secondary to influenza infection.&#xD;
&#xD;
      The investigators plan to enroll at least 200 adult patients. Enrolled patients will be&#xD;
      randomized into 2 groups. Group 1: oseltamivir 75mg + clarithromycin 500mg + FFA 200mg all&#xD;
      twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days ; Group 2:&#xD;
      oseltamivir 75mg + two placebo capsules (identical in appearance to clarithromycin and FFA&#xD;
      capsules respectively) twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3&#xD;
      days. The placebo capsules will contain inactive starch. All patients will receive a 5-day&#xD;
      course of amoxicillin-clavulanate 1g bid for empirical coverage of community acquired&#xD;
      pneumonia and esomeprazole 20mg daily for prevention of non-steroidal anti-inflammatory drugs&#xD;
      related gastropathy.&#xD;
&#xD;
      Randomized treatment will be double blinded. Patients will be assigned to serial number by&#xD;
      the study-coordinator. Each serial number will be linked to a computer-generated&#xD;
      randomization list assigning the antiviral treatment regimens. The study medications will be&#xD;
      dispensed by the hospital pharmacy and then to the patients by the medical ward nurses who&#xD;
      will not know the treatment regimen of any subsequent patients. Enrolled patients could not&#xD;
      differentiate the study or the placebo medication capsule which will be identical in&#xD;
      appearance. The placebo capsules will contain inactive starch.&#xD;
&#xD;
      There will be 50% chance of random assignment into one of the treatment or control arms.&#xD;
&#xD;
      Clinical data, nasopharyngeal aspirate (NPA) and blood specimens will be collected daily if&#xD;
      possible from admission till discharge, transfer to convalescent hospitals or death. All&#xD;
      enrolled patients will be invited to the Infectious Disease outpatient clinic in Queen Mary&#xD;
      Hospital for follow-up at 1 and 3 months after discharge. The investigators will retrieve&#xD;
      your clinical information from the Clinical Medical System in the Queen Mary Hospital during&#xD;
      follow-up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 8, 2018</start_date>
  <completion_date type="Anticipated">October 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2020</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>Prospective Randomised Controlled Trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>30 days from commencement of treatment intervention</time_frame>
    <description>30-day mortality</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>NPA</measure>
    <time_frame>5 days post treatment</time_frame>
    <description>nasopharyngeal aspirate viral load changes post treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PSI</measure>
    <time_frame>5 days post treatment</time_frame>
    <description>Pneumonia severity index changes post treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalisation</measure>
    <time_frame>Days of the subject hospitalised for the current admission up to 30 days</time_frame>
    <description>Length of hospitalisation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AE</measure>
    <time_frame>2 weeks from subjects received treatment intervention</time_frame>
    <description>Adverse events during treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Long-term mortality</measure>
    <time_frame>90 days from commencement of treatment intervention</time_frame>
    <description>90-day mortality</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Influenza A</condition>
  <arm_group>
    <arm_group_label>FFA, clarithromycin, oseltamivir</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>oseltamivir 75mg + clarithromycin 500mg + FFA 200mg all twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oseltamivir alone</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>oseltamivir 75mg + two placebo capsules (identical in appearance to clarithromycin and FFA capsules respectively) twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>FFA, clarithromycin, oseltamivir</intervention_name>
    <description>2-day course of triple combination of clarithromycin 500mg, flufenamic acid 200mg and oseltamivir 75mg twice daily followed by oseltamivir 75mg twice daily for 3 days</description>
    <arm_group_label>FFA, clarithromycin, oseltamivir</arm_group_label>
    <other_name>Antiviral combo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oseltamivir alone</intervention_name>
    <description>2-day course of oseltamivir 75mg plus placebo capsules twice daily followed by oseltamivir 75mg twice daily for 3 days as control</description>
    <arm_group_label>Oseltamivir alone</arm_group_label>
    <other_name>Antiviral</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Recruited subjects include all adult patients ≥18 years hospitalised for virologically&#xD;
             confirmed influenza infection.&#xD;
&#xD;
          2. Auditory temperature ≥38°C with at least one of the following symptoms (cough, sputum&#xD;
             production, sore-throat, nasal discharge, myalgia, headache or fatigue) upon admission&#xD;
&#xD;
          3. Symptom duration ≤72 hours&#xD;
&#xD;
          4. Radiological changes of pulmonary infiltrate by chest radiography or computerised&#xD;
             tomography&#xD;
&#xD;
          5. All subjects give written informed consent. Subjects must be available to complete the&#xD;
             study and comply with study procedures. Willingness to allow for serum samples to be&#xD;
             stored beyond the study period, for potential additional future testing to better&#xD;
             characterise immune response.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Inability to comprehend and to follow all required study procedures.&#xD;
&#xD;
          2. Allergy or severe reactions including renal or hepatic dysfunctions to clarithromycin,&#xD;
             FFA, oseltamivir, amoxicillin-clavulanate or esomeprazole will be excluded&#xD;
&#xD;
          3. Patient with moderate renal impairment (creatinine clearance &lt;30mL/min)&#xD;
&#xD;
          4. Prolonged QT or ventricular cardiac arrhythmias, including torsade de pointes.&#xD;
&#xD;
          5. Patient with a history of cholestatic jaundice and/or liver dysfunction associated&#xD;
             with prior clarithromycin use&#xD;
&#xD;
          6. Patient on cisapride, pimozide, astemizole, terfenadine, ergotamine, dihyroergotamine,&#xD;
             or statins medications which could not be stopped&#xD;
&#xD;
          7. Patient on colchicine with renal or hepatic impairment.&#xD;
&#xD;
          8. Pregnant or lactating women&#xD;
&#xD;
          9. Inability to comprehend and to follow all required study procedures&#xD;
&#xD;
         10. Have known human immunodeficiency virus infection&#xD;
&#xD;
         11. Received an experimental agent (vaccine, drug, biologic, device, blood product, or&#xD;
             medication) within 1 month prior to recruitment in this study or expect to receive an&#xD;
             experimental agent during this study. Unwilling to refuse participation in another&#xD;
             clinical study through the end of this study.&#xD;
&#xD;
         12. Have a history of alcohol or drug abuse in the last 5 years. Have any condition that&#xD;
             the investigator believes may interfere with successful completion of the study.&#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_official>
    <last_name>Ivan Hung, MD FRCP</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Deborah Ho, BSc MSc</last_name>
    <phone>22554049</phone>
    <email>tipyin@yahoo.com.hk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Teresa Tong, BSc</last_name>
    <phone>22551674</phone>
    <email>tongsma@hkucc.hku.hk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Ivan Hung</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ivan FN Hung, MD FRCP</last_name>
      <phone>852 22554049</phone>
      <email>ivanfn@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Kelvin To, MD FRCPath</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>KY Yuen, MD FRCPath</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <reference>
    <citation>Hung IFN, To KKW, Chan JFW, Cheng VCC, Liu KSH, Tam A, Chan TC, Zhang AJ, Li P, Wong TL, Zhang R, Cheung MKS, Leung W, Lau JYN, Fok M, Chen H, Chan KH, Yuen KY. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012. Epub 2016 Nov 22.</citation>
    <PMID>27884765</PMID>
  </reference>
  <reference>
    <citation>Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CCY, Liu SH, Chan KH, Lin CK, Yuen KY. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013 Aug;144(2):464-473. doi: 10.1378/chest.12-2907.</citation>
    <PMID>23450336</PMID>
  </reference>
  <reference>
    <citation>Li IW, Hung IF, To KK, Chan KH, Wong SS, Chan JF, Cheng VC, Tsang OT, Lai ST, Lau YL, Yuen KY. The natural viral load profile of patients with pandemic 2009 influenza A(H1N1) and the effect of oseltamivir treatment. Chest. 2010 Apr;137(4):759-68. doi: 10.1378/chest.09-3072. Epub 2010 Jan 8.</citation>
    <PMID>20061398</PMID>
  </reference>
  <reference>
    <citation>Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, Liu R, Watt CL, Chan WM, Lai KY, Koo CK, Buckley T, Chow FL, Wong KK, Chan HS, Ching CK, Tang BS, Lau CC, Li IW, Liu SH, Chan KH, Lin CK, Yuen KY. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56. doi: 10.1093/cid/ciq106. Epub 2011 Jan 19.</citation>
    <PMID>21248066</PMID>
  </reference>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>July 27, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>October 21, 2019</last_update_submitted>
  <last_update_submitted_qc>October 21, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>influenza</keyword>
  <keyword>FFA</keyword>
  <keyword>clarithromycin</keyword>
  <keyword>mortality</keyword>
  <keyword>hospitalisation</keyword>
  <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>Clarithromycin</mesh_term>
    <mesh_term>Oseltamivir</mesh_term>
    <mesh_term>Antiviral Agents</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03238612
org study id: UW 16-418
nct id: NCT03238612
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
It is well recognized that respiratory viruses cause substantial disease burden every year.
      Among all known respiratory viruses, influenza virus is the greatest cause of
      disability-adjusted life years lost, excess hospitalizations, and deaths in the elderly and
      patients with chronic illness. These patients are frequently hospitalized for pneumonia
      secondary to these respiratory viral infection. Recently, macrolide antimicrobial
      clarithromycin and flufenamic acid (FFA) have been shown to inhibit seasonal influenza virus
      infection in human airway epithelial cells with additional anti-inflammatory effect.

      The investigators therefore plan to conduct a 3-year prospective study among adult patients
      hospitalized in Queen Mary Hospital for influenza with secondary pneumonia and randomized
      them to receive a course of oseltamivir + FFA + clarithromycin (as treatment) vs. a course of
      oseltamivir (current standard treatment as control). The objective of this prospective
      double-blind randomized controlled trial is to evaluate the efficacy of clarithromycin and
      FFA antiviral therapy in patients diagnosed to have pneumonia secondary to influenza
      infection.
This double blind randomized-controlled trial will assess the clinical efficacy, mortality
      reduction and viral load reduction of clarithromycin and FFA in patients hospitalized for
      pneumonia secondary to influenza infection.

      The investigators plan to enroll at least 200 adult patients. Enrolled patients will be
      randomized into 2 groups. Group 1: oseltamivir 75mg + clarithromycin 500mg + FFA 200mg all
      twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days ; Group 2:
      oseltamivir 75mg + two placebo capsules (identical in appearance to clarithromycin and FFA
      capsules respectively) twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3
      days. The placebo capsules will contain inactive starch. All patients will receive a 5-day
      course of amoxicillin-clavulanate 1g bid for empirical coverage of community acquired
      pneumonia and esomeprazole 20mg daily for prevention of non-steroidal anti-inflammatory drugs
      related gastropathy.

      Randomized treatment will be double blinded. Patients will be assigned to serial number by
      the study-coordinator. Each serial number will be linked to a computer-generated
      randomization list assigning the antiviral treatment regimens. The study medications will be
      dispensed by the hospital pharmacy and then to the patients by the medical ward nurses who
      will not know the treatment regimen of any subsequent patients. Enrolled patients could not
      differentiate the study or the placebo medication capsule which will be identical in
      appearance. The placebo capsules will contain inactive starch.

      There will be 50% chance of random assignment into one of the treatment or control arms.

      Clinical data, nasopharyngeal aspirate (NPA) and blood specimens will be collected daily if
      possible from admission till discharge, transfer to convalescent hospitals or death. All
      enrolled patients will be invited to the Infectious Disease outpatient clinic in Queen Mary
      Hospital for follow-up at 1 and 3 months after discharge. The investigators will retrieve
      your clinical information from the Clinical Medical System in the Queen Mary Hospital during
      follow-up.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Prospective Randomised Controlled Trial
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: Double-blind
measure: Mortality
time frame: 30 days from commencement of treatment intervention
description: 30-day mortality
measure: NPA
time frame: 5 days post treatment
description: nasopharyngeal aspirate viral load changes post treatment
measure: PSI
time frame: 5 days post treatment
description: Pneumonia severity index changes post treatment
measure: Hospitalisation
time frame: Days of the subject hospitalised for the current admission up to 30 days
description: Length of hospitalisation
measure: AE
time frame: 2 weeks from subjects received treatment intervention
description: Adverse events during treatment
measure: Long-term mortality
time frame: 90 days from commencement of treatment intervention
description: 90-day mortality
arm group label: FFA, clarithromycin, oseltamivir
arm group type: Experimental
description: oseltamivir 75mg + clarithromycin 500mg + FFA 200mg all twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days
arm group label: Oseltamivir alone
arm group type: Placebo Comparator
description: oseltamivir 75mg + two placebo capsules (identical in appearance to clarithromycin and FFA capsules respectively) twice daily for 2 days, followed by oseltamivir 75mg twice daily for 3 days
intervention type: Drug
intervention name: FFA, clarithromycin, oseltamivir
description: 2-day course of triple combination of clarithromycin 500mg, flufenamic acid 200mg and oseltamivir 75mg twice daily followed by oseltamivir 75mg twice daily for 3 days
arm group label: FFA, clarithromycin, oseltamivir
other name: Antiviral combo
intervention type: Drug
intervention name: Oseltamivir alone
description: 2-day course of oseltamivir 75mg plus placebo capsules twice daily followed by oseltamivir 75mg twice daily for 3 days as control
arm group label: Oseltamivir alone
other name: Antiviral
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ivan Hung, MD FRCP
role: Principal Investigator
affiliation: The University of Hong Kong
last name: Deborah Ho, BSc MSc
phone: 22554049
email: tipyin@yahoo.com.hk
last name: Teresa Tong, BSc
phone: 22551674
email: tongsma@hkucc.hku.hk
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Hong Kong
citation: Hung IFN, To KKW, Chan JFW, Cheng VCC, Liu KSH, Tam A, Chan TC, Zhang AJ, Li P, Wong TL, Zhang R, Cheung MKS, Leung W, Lau JYN, Fok M, Chen H, Chan KH, Yuen KY. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012. Epub 2016 Nov 22.
PMID: 27884765
citation: Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CCY, Liu SH, Chan KH, Lin CK, Yuen KY. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013 Aug;144(2):464-473. doi: 10.1378/chest.12-2907.
PMID: 23450336
citation: Li IW, Hung IF, To KK, Chan KH, Wong SS, Chan JF, Cheng VC, Tsang OT, Lai ST, Lau YL, Yuen KY. The natural viral load profile of patients with pandemic 2009 influenza A(H1N1) and the effect of oseltamivir treatment. Chest. 2010 Apr;137(4):759-68. doi: 10.1378/chest.09-3072. Epub 2010 Jan 8.
PMID: 20061398
citation: Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, Liu R, Watt CL, Chan WM, Lai KY, Koo CK, Buckley T, Chow FL, Wong KK, Chan HS, Ching CK, Tang BS, Lau CC, Li IW, Liu SH, Chan KH, Lin CK, Yuen KY. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56. doi: 10.1093/cid/ciq106. Epub 2011 Jan 19.
PMID: 21248066
responsible party type: Sponsor
mesh term: Influenza, Human
mesh term: Clarithromycin
mesh term: Oseltamivir
mesh term: Antiviral Agents
sharing ipd: Undecided