<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/NCT03824847</url>
  </required_header>
  <id_info>
    <org_study_id>DKMI010.1</org_study_id>
    <nct_id>NCT03824847</nct_id>
  </id_info>
  <brief_title>Immunomodulatory Effect of Macrolides in Naturally Occurring Influenza Virus Infections in the Community</brief_title>
  <official_title>Immunomodulatory Effect of Macrolides in Naturally Occurring Influenza Virus Infections in the Community</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>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>
      The investigators propose a double-blind randomised placebo-controlled study in naturally&#xD;
      occurring influenza virus infections in the community setting to compare the impact of a&#xD;
      short course of clarithromycin versus placebo, on the clinical course, viral shedding,&#xD;
      immunomodulation, and the antimicrobial resistance pattern of respiratory bacterial carriage&#xD;
      of the patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Influenza continues to pose an imminent threat to public health through seasonal&#xD;
      epidemics and occasion pandemics with significant impact on morbidity and mortality.&#xD;
      Increasing attention has also been paid in recent years to the potential benefit of&#xD;
      immunomodulatory effect of macrolide antibiotics in the management of influenza virus&#xD;
      infection.&#xD;
&#xD;
      Aims: To study the immunomodulatory effects of a short course of clarithromycin in naturally&#xD;
      occurring influenza virus infection.&#xD;
&#xD;
      Design and subjects: The study is a double-blind, randomised controlled trial. One hundred&#xD;
      adults aged 18-60 years will be recruited when they present with symptoms of acute&#xD;
      respiratory infection within 48 hours of symptoms onset to university health clinics, and&#xD;
      being tested positive with a QuickVue/Sofia (Quidel Corp., San Diego, CA) rapid influenza&#xD;
      test. Consented patients tested positive with the rapid test will receive their clinical&#xD;
      consultation and prescriptions as indicated as usual, and being randomised to receive either&#xD;
      clarithromycin (250mg) or placebo (in a ratio of 1:1) taken twice daily orally for three&#xD;
      days. Blood specimen, nasal and throat swabs will be collected on the same day (day 1). They&#xD;
      will be followed-up on day 4, day 7 and day 10 for further collection of nasal and throat&#xD;
      swabs, and serum samples. A symptom diary will be kept by each participant for 10 days for&#xD;
      monitoring the clinical course of the infection.&#xD;
&#xD;
      Study instruments: QuickVue/Sofia (Quidel Corp., San Diego, CA) rapid influenza test, symptom&#xD;
      diary, blood specimen, nasal and throat swabs.&#xD;
&#xD;
      Interventions: Intervention group: clarithromycin; placebo group: placebo in identical&#xD;
      packaging.&#xD;
&#xD;
      Main outcome measures: The primary outcomes of the study will compare the duration of&#xD;
      illness, viral shedding, patterns of plasma cytokine/chemokine and antimicrobial resistance&#xD;
      pattern of respiratory bacterial carriage between patients who were randomised to&#xD;
      clarithromycin or placebo.&#xD;
&#xD;
      Analysis: Intention to treat.&#xD;
&#xD;
      Potential significance: This will be the first placebo-controlled RCT to investigate the&#xD;
      immunomodulatory effect of macrolide antibiotics in the management of influenza virus&#xD;
      infection, in terms of its impact on the duration of illness, viral shedding, patterns of&#xD;
      plasma cytokine/chemokine and antimicrobial resistance pattern of respiratory bacterial&#xD;
      carriage. Findings from this study will have important contribution to our understanding on&#xD;
      the potential immunomodulatory effect of macrolides, and help to inform the appropriate&#xD;
      clinical management approach, and the potential&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    Community recruitment suspended due to COVID-19&#xD;
  </why_stopped>
  <start_date type="Anticipated">June 1, 2023</start_date>
  <completion_date type="Anticipated">September 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">March 1, 2024</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>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time from recruitment to cessation of clinical illness</measure>
    <time_frame>10 days</time_frame>
    <description>Defined as the time when all relevant clinical symptoms are resolved.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time from recruitment to cessation of viral shedding</measure>
    <time_frame>10 days</time_frame>
    <description>Defined as the time when no virus is detected by RT-PCR from both nasal and throat swabs.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration and severity of individual symptoms</measure>
    <time_frame>10 days</time_frame>
    <description>Participants will keep symptom diary twice daily for 10 days (from D1-D10), using 4-point scale of 0, 1, 2, or 3 for absent, mild, moderate, or severe symptoms respectively. Mild symptoms are easily tolerated and do not interfere with any usual activities; moderate symptoms interfere with usual activities; Severe symptoms are such that the individual cannot carry out usual activities. Ten common influenza symptoms (including feverishness, chills, cough, rhinorrhea, sore throat, general fatigue, headache, myalgia/arthralgia, vomiting, and diarrhea) will be recorded for ten days (D1-D10) and the duration of individual symptoms will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of secondary complications</measure>
    <time_frame>28 days</time_frame>
    <description>The symptom diary will be checked on each follow-up (D4, D7, and D10) and collected on D10 by our research staff when the patient returns for follow-up. Symptoms of possible side effects related to treatment (including skin rashes, nausea, vomiting, jaundice, dark urine) will be recorded. The occurrence of any complications including otitis media, bronchitis, sinusitis, and pneumonia will be enquired during all follow-up sessions and recorded, and cross checking with the attending doctor will be done where necessary.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related quality of life</measure>
    <time_frame>28 days</time_frame>
    <description>A simple quality of life (QOL) assessment based on two simple validated 11- point visual analog scales will also be done daily by all participants form D1 - D10, one to rate their own ability for performing normal daily activities (0 = unable to perform normal activity to 10 = fully able to perform normal activity) , and the other for a self-perceived overall health status over a 24-hour (0 = worst health to 10 = best possible health), both of which will be compared to an initial assessment of their normal pre-influenza state reported on the D1 baseline. All participants will also be required to complete the Acute Form of the Short Form-36, version 2 (SF-36), in D1, D10 and D28, for a more details assessment on the changes of Health-related quality of life (HRQL) related to the episode of the influenza infection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean rise in antibody titre against the infecting type or subtype of influenza virus</measure>
    <time_frame>28 days</time_frame>
    <description>Paired sera will be collected on D1 and D28 for measuring the humoral antibody titres against the infecting type or subtype and other circulating strains of influenza viruses, and for evaluating the geometric mean titer rise from baseline to convalescence.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in blood immunity (Cytokine/chemokine and pro-inflammatory mediators)</measure>
    <time_frame>7 days</time_frame>
    <description>Plasma concentrations of 20+ cytokines/chemokines and proinflammatory mediators (e.g. IL-6, IL-8, TNFα, IFN-γ, IL-12p70 etc.) will be measured in each collected blood sample using cytokines bead assay by Flow cytometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the carriage rate of common respiratory bacterial pathogen</measure>
    <time_frame>7 days</time_frame>
    <description>change in the carriage rate of five common respiratory bacterial pathogen and the proportion of each that were macrolide resistant.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Influenza, Human</condition>
  <arm_group>
    <arm_group_label>Intervention group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intervention group: clarithromycin 1 tablet (250mg) twice daily for three days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo group: (identical-looking) placebo 1 tablet twice daily for three days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clarithromycin 250 MG</intervention_name>
    <description>Clarithromycin 1 tablet (250mg) twice daily for three days</description>
    <arm_group_label>Intervention group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Placebo group: (identical-looking) placebo 1 tablet twice daily for three days</description>
    <arm_group_label>Placebo group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults aged between 18-60&#xD;
&#xD;
          -  Presenting with symptoms of acute URTI (at least two among the following symptoms:&#xD;
             body temperature ≥37.8°C, cough, rhinorrhea, sore throat, headache,&#xD;
             myalgia/arthralgia) to university health clinics within 48 hours of illness onset.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Allergy to clarithromycin or any other macrolides or the ingredients in the tablets,&#xD;
             which include microcrystalline cellulose, croscarmelose sodium, magnesium stearate and&#xD;
             povidon will be excluded.&#xD;
&#xD;
          -  Patients with a history of chronic liver disease, or any active lung, heart or renal&#xD;
             diseases requiring regular medication, or any underlying immunocompromised condition&#xD;
             or receiving immunosuppressive agents will also be excluded.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dennis KM Ip, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>School of Public Health, The University of Hong Kong</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>School of Public Health, The University of Hong Kong</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>January 29, 2019</study_first_submitted>
  <study_first_submitted_qc>January 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>November 1, 2022</last_update_submitted>
  <last_update_submitted_qc>November 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Dr. Dennis Kai-Ming Ip</investigator_full_name>
    <investigator_title>Clinical Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Macrolides</keyword>
  <keyword>Immunomodulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Influenza, Human</mesh_term>
    <mesh_term>Virus Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clarithromycin</mesh_term>
  </intervention_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/NCT03824847
org study id: DKMI010.1
nct id: NCT03824847
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The investigators propose a double-blind randomised placebo-controlled study in naturally
      occurring influenza virus infections in the community setting to compare the impact of a
      short course of clarithromycin versus placebo, on the clinical course, viral shedding,
      immunomodulation, and the antimicrobial resistance pattern of respiratory bacterial carriage
      of the patients.
Background: Influenza continues to pose an imminent threat to public health through seasonal
      epidemics and occasion pandemics with significant impact on morbidity and mortality.
      Increasing attention has also been paid in recent years to the potential benefit of
      immunomodulatory effect of macrolide antibiotics in the management of influenza virus
      infection.

      Aims: To study the immunomodulatory effects of a short course of clarithromycin in naturally
      occurring influenza virus infection.

      Design and subjects: The study is a double-blind, randomised controlled trial. One hundred
      adults aged 18-60 years will be recruited when they present with symptoms of acute
      respiratory infection within 48 hours of symptoms onset to university health clinics, and
      being tested positive with a QuickVue/Sofia (Quidel Corp., San Diego, CA) rapid influenza
      test. Consented patients tested positive with the rapid test will receive their clinical
      consultation and prescriptions as indicated as usual, and being randomised to receive either
      clarithromycin (250mg) or placebo (in a ratio of 1:1) taken twice daily orally for three
      days. Blood specimen, nasal and throat swabs will be collected on the same day (day 1). They
      will be followed-up on day 4, day 7 and day 10 for further collection of nasal and throat
      swabs, and serum samples. A symptom diary will be kept by each participant for 10 days for
      monitoring the clinical course of the infection.

      Study instruments: QuickVue/Sofia (Quidel Corp., San Diego, CA) rapid influenza test, symptom
      diary, blood specimen, nasal and throat swabs.

      Interventions: Intervention group: clarithromycin; placebo group: placebo in identical
      packaging.

      Main outcome measures: The primary outcomes of the study will compare the duration of
      illness, viral shedding, patterns of plasma cytokine/chemokine and antimicrobial resistance
      pattern of respiratory bacterial carriage between patients who were randomised to
      clarithromycin or placebo.

      Analysis: Intention to treat.

      Potential significance: This will be the first placebo-controlled RCT to investigate the
      immunomodulatory effect of macrolide antibiotics in the management of influenza virus
      infection, in terms of its impact on the duration of illness, viral shedding, patterns of
      plasma cytokine/chemokine and antimicrobial resistance pattern of respiratory bacterial
      carriage. Findings from this study will have important contribution to our understanding on
      the potential immunomodulatory effect of macrolides, and help to inform the appropriate
      clinical management approach, and the potential
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
measure: Time from recruitment to cessation of clinical illness
time frame: 10 days
description: Defined as the time when all relevant clinical symptoms are resolved.
measure: Time from recruitment to cessation of viral shedding
time frame: 10 days
description: Defined as the time when no virus is detected by RT-PCR from both nasal and throat swabs.
measure: Duration and severity of individual symptoms
time frame: 10 days
description: Participants will keep symptom diary twice daily for 10 days (from D1-D10), using 4-point scale of 0, 1, 2, or 3 for absent, mild, moderate, or severe symptoms respectively. Mild symptoms are easily tolerated and do not interfere with any usual activities; moderate symptoms interfere with usual activities; Severe symptoms are such that the individual cannot carry out usual activities. Ten common influenza symptoms (including feverishness, chills, cough, rhinorrhea, sore throat, general fatigue, headache, myalgia/arthralgia, vomiting, and diarrhea) will be recorded for ten days (D1-D10) and the duration of individual symptoms will be assessed.
measure: Incidence of secondary complications
time frame: 28 days
description: The symptom diary will be checked on each follow-up (D4, D7, and D10) and collected on D10 by our research staff when the patient returns for follow-up. Symptoms of possible side effects related to treatment (including skin rashes, nausea, vomiting, jaundice, dark urine) will be recorded. The occurrence of any complications including otitis media, bronchitis, sinusitis, and pneumonia will be enquired during all follow-up sessions and recorded, and cross checking with the attending doctor will be done where necessary.
measure: Health-related quality of life
time frame: 28 days
description: A simple quality of life (QOL) assessment based on two simple validated 11- point visual analog scales will also be done daily by all participants form D1 - D10, one to rate their own ability for performing normal daily activities (0 = unable to perform normal activity to 10 = fully able to perform normal activity) , and the other for a self-perceived overall health status over a 24-hour (0 = worst health to 10 = best possible health), both of which will be compared to an initial assessment of their normal pre-influenza state reported on the D1 baseline. All participants will also be required to complete the Acute Form of the Short Form-36, version 2 (SF-36), in D1, D10 and D28, for a more details assessment on the changes of Health-related quality of life (HRQL) related to the episode of the influenza infection.
measure: Geometric mean rise in antibody titre against the infecting type or subtype of influenza virus
time frame: 28 days
description: Paired sera will be collected on D1 and D28 for measuring the humoral antibody titres against the infecting type or subtype and other circulating strains of influenza viruses, and for evaluating the geometric mean titer rise from baseline to convalescence.
measure: Changes in blood immunity (Cytokine/chemokine and pro-inflammatory mediators)
time frame: 7 days
description: Plasma concentrations of 20+ cytokines/chemokines and proinflammatory mediators (e.g. IL-6, IL-8, TNFα, IFN-γ, IL-12p70 etc.) will be measured in each collected blood sample using cytokines bead assay by Flow cytometry.
measure: Change in the carriage rate of common respiratory bacterial pathogen
time frame: 7 days
description: change in the carriage rate of five common respiratory bacterial pathogen and the proportion of each that were macrolide resistant.
arm group label: Intervention group
arm group type: Active Comparator
description: Intervention group: clarithromycin 1 tablet (250mg) twice daily for three days
arm group label: Placebo group
arm group type: Placebo Comparator
description: Placebo group: (identical-looking) placebo 1 tablet twice daily for three days.
intervention type: Drug
intervention name: Clarithromycin 250 MG
description: Clarithromycin 1 tablet (250mg) twice daily for three days
arm group label: Intervention group
intervention type: Drug
intervention name: Placebos
description: Placebo group: (identical-looking) placebo 1 tablet twice daily for three days
arm group label: Placebo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Dennis KM Ip, MD
role: Principal Investigator
affiliation: School of Public Health, The University of Hong Kong
facility: 
country: Hong Kong
responsible party type: Principal Investigator
investigator affiliation: The University of Hong Kong
investigator full name: Dr. Dennis Kai-Ming Ip
investigator title: Clinical Associate Professor
mesh term: Influenza, Human
mesh term: Virus Diseases
mesh term: Clarithromycin