<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/NCT02258763</url>
  </required_header>
  <id_info>
    <org_study_id>RP026-14HTM</org_study_id>
    <nct_id>NCT02258763</nct_id>
  </id_info>
  <brief_title>Trial on the Ideal Duration of Oral Antibiotics in Children With Pneumonia</brief_title>
  <official_title>Pneumonia in Children: Aetiology, Ideal Antibiotic Duration, Quality of Life</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Malaya</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Menzies School of Health Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Malaya</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine, in children hospitalized with pneumonia, if an extended duration of oral&#xD;
      antibiotics (10 days) will be superior to a shorter duration (3 days) of antibiotics in&#xD;
      improving clinical outcomes.&#xD;
&#xD;
      Secondary Aims:&#xD;
&#xD;
        1. Describe the prevalence of respiratory viruses and bacteria at presentation.&#xD;
&#xD;
        2. Investigate the depression, anxiety and stress scores (DASS21) and quality of life&#xD;
           scored (QOL) by parents of the children during admission, pre-discharge and post&#xD;
           discharge and at follow-ups.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction:&#xD;
&#xD;
      Pneumonia is the single largest cause of death in children less than 5 years old and these&#xD;
      are preventable deaths.[1,2] It is also an important cause of morbidity , especially when it&#xD;
      is recurrent or severe as it may be linked with future adult lung disease.[3] Determining the&#xD;
      aetiology of pneumonia is difficult in children who cannot produce satisfactory sputum for&#xD;
      culture. Hence the reliance on molecular methods like polymerase chain reaction (PCR) and&#xD;
      Enzyme immunoassays(EIA) looking at serological rise to determine the true aetiology of&#xD;
      pneumonia is important especially in the era where mixed infections are common and may be&#xD;
      associated with severe infections.&#xD;
&#xD;
      There is currently no information on the suitable duration of antibiotics for uncomplicated&#xD;
      severe community acquired pneumonia (CAP). There is also rampant overuse of antibiotics that&#xD;
      results in poor compliance and significant side effects.&#xD;
&#xD;
      There is little information on the QOL of the child with severe pneumonia and his parent. It&#xD;
      is important to have a holistic approach to medicine hence the importance of analyzing the&#xD;
      burden and social issues associated with children admitted with pneumonia.&#xD;
&#xD;
      As opposed to adults, children cannot produce sputum (lower respiratory sample) appropriate&#xD;
      for culture which is the traditional method of identifying the causative bacteria.&#xD;
      Identification of bacteria in nasopharyngeal secretions (upper respiratory sample) does not&#xD;
      equate to that organism causing the infection as the upper airway of a child is often&#xD;
      colonized by bacteria. Detecting the organism in blood identifies it as the causative&#xD;
      organism. However, blood culture has a very low yield in children with pneumonia and&#xD;
      polymerase chain reaction (PCR) is much more sensitive at detecting bacteria in blood and&#xD;
      hence it will markedly improve the ability to determine infecting organism.&#xD;
&#xD;
      Development of our own in-house bacterial PCR kit which will detect several different&#xD;
      bacteria in blood is planned in this study. We already have an in-house viral PCR kit and the&#xD;
      ability to detect atypical bacteria via EIA. Currently there is an international study&#xD;
      (Pneumonia Etiology Research for Child Health [PERCH]) looking at aetiology of pneumonia, but&#xD;
      this study only involves 2 Asian countries (Thailand and Bangladesh)[5]. In Malaysia, in 2011&#xD;
      there was a study that looked at pneumococcal isolates and antibiotic sensitivity patterns on&#xD;
      invasive pneumococcal disease only[6]. There are also studies that look at viral aetiology of&#xD;
      pneumonia[7]. Hence information on aetiology of pneumonia is skewed to those involving&#xD;
      vaccine associated organisms and use of nasopharyngeal secretions(NPS) to detect viruses..&#xD;
&#xD;
      The evidence for appropriate duration of antibiotics that should be used in hospitalized&#xD;
      children with pneumonia is scarce. A randomized controlled trial comparing traditional&#xD;
      duration of antibiotics (≥ 7 days) versus shorter duration of antibiotics &lt; 7 days) is what&#xD;
      we think is necessary. There are no studies looking at duration of antibiotics in children&#xD;
      with severe uncomplicated pneumonia. We hypothesize that there is no need for a longer&#xD;
      duration of antibiotics which are only associated with poor compliance and unnecessary&#xD;
      side-effects.&#xD;
&#xD;
      Finally, there is little data on quality of life in children and parents during and after a&#xD;
      pneumonic episode. It is important to measure the impact of such a common disease on both&#xD;
      parent and patient as well as to assess the impact of medical management on QOL so as to have&#xD;
      a more holistic approach to medicine. Two previous studies have looked at QOL. One was a&#xD;
      study comparing all acute diseases to chronic diseases[8]. The other looked at CAP but&#xD;
      without the use of structured questionnaires[9]&#xD;
&#xD;
      Methodology&#xD;
&#xD;
      Randomized, Double Blind, Placebo Controlled Trial Children aged 3 months till &lt;5 years old&#xD;
      Admitted to University Malaya Medical Centre (UMMC) hospital with a severe community acquired&#xD;
      pneumonia Eligibility Ages Eligible for Study: 3 Months to 59 Months Genders Eligible for&#xD;
      Study: Both&#xD;
&#xD;
      Inclusion Criteria:&#xD;
&#xD;
      Children admitted with severe pneumonia as defined by the presence of all the following as&#xD;
      defined as below:&#xD;
&#xD;
        -  3 months to 59 months old&#xD;
&#xD;
        -  History of cough and/or shortness of breath Unwell for &lt;= 7 days&#xD;
&#xD;
        -  Increased respiratory rate ( ≥ 50/min if ≤12 months old, ≥ 40/min)&#xD;
&#xD;
        -  Any of the following signs/symptoms are present at examination that would necessitate&#xD;
           admission: chest retractions, cyanosis, saturation&lt; 92% on air, poor feeding or lethargy&#xD;
&#xD;
        -  Documented fever (axillary /central temp ≥ 38/38.5°C) within 24 hrs of admission&#xD;
&#xD;
        -  Abnormal chest radio graph(CXR) with presence of alveolar infiltrates&#xD;
&#xD;
        -  Responds to IV antibiotics by the first 72 hrs and able to go home with oral antibiotics&#xD;
           i.e. no more hypoxia and afebrile and reduced respiratory symptoms&#xD;
&#xD;
      Exclusion Criteria:&#xD;
&#xD;
      Children who (a) are transferred from another hospital (b) refuse blood taking (c) have a&#xD;
      doctor diagnosis of asthma or recurrent wheezing illness (d) have a diagnosis of&#xD;
      bronchiolitis i.e. wheezing in a child with a CXR with no consolidation (e) do not have an&#xD;
      acute illness ( ie &gt;7 days) (f) are unable to come for follow-up (g) do not have community&#xD;
      acquired pneumonia e.g. aspiration pneumonia (h)have a complicated pneumonia with effusion,&#xD;
      pneumothorax, clinical suspicion of necrotizing pneumonia (i)require paediatric intensive&#xD;
      care unit (PICU) admission or use of non-invasive ventilation (j)significant comorbidities&#xD;
      that can increase the risk of having a complicated pneumonia- (k) need other antibiotics like&#xD;
      anti-staph or macrolides (l)have an extra-pulmonary infection e.g. meningitis (m)are allergic&#xD;
      to penicillin (n) are unable to tolerate oral antibiotics and (o)have underlying illness that&#xD;
      can predispose to recurrent pneumonia&#xD;
&#xD;
      Randomized, Double Blind, Placebo Controlled Trial Children aged 3 months till &lt;5 years old&#xD;
      Admitted to UMMC hospital with a severe community acquired pneumonia Informed signed consent&#xD;
      will be obtained from parents first. All children will have full blood count and CXR taken&#xD;
&#xD;
      Additional blood and urine as detailed below will also be taken:&#xD;
&#xD;
      a. Blood for PCR -streptococcus pneumoniae, staphylococcus aureus, Haemophilus influenzae,&#xD;
      Mycoplasma pnuemoniae, Chlamydia pneumoniae will be taken.&#xD;
&#xD;
      NPS for respiratory bacteria and viruses (by culture and PCT-similar as above) All these&#xD;
      samples will be tested in our hospital laboratory. If samples cannot be processed&#xD;
      immediately, they will be stored in a -80 deg C freezer except for the NPS for bacterial&#xD;
      culture.&#xD;
&#xD;
      All data will be collected at enrollment and at each follow-up visit on a standardized data&#xD;
      sheet. Baseline demographic data( age, gender, address, ethnicity, household size, income,&#xD;
      parent education, caregivers, household appliances) and medical information( birth history,&#xD;
      breastfeeding and weaning, growth, immunization, smoke exposure, co-morbidity, daily&#xD;
      hospitalization information) will be obtained from parents and medical charts. CXRs and&#xD;
      routine blood test results will also be recorded.&#xD;
&#xD;
      Quality of life, stress level, severity of illness , of parents and children with pneumonia,&#xD;
      will be assessed at these time points too: during their admission (average of 3-5 days) and&#xD;
      during follow-ups( average at, 4 weeks, 3 months(phone call only with no questionnaire&#xD;
      administered), 6 months, 1 year post their pneumonic episode) using the following&#xD;
      questionnaires-Paediatric proxy cough quality of life-8 (PCQOL-8), Canadian Acute Respiratory&#xD;
      Illness and Flu Scale (CARIFS) (in hospital only), cough diary( at home, daily for 1&#xD;
      month),Depression Anxiety Stress Scale 21( DASS21).&#xD;
&#xD;
      The PCQOL-8 and DASS21 have been translated and validated in Bahasa Melayu. The CARIFS and&#xD;
      the cough diary was recently translated in Bahasa Melayu and piloted for the purpose of this&#xD;
      study.&#xD;
&#xD;
      Treatments will be administered only after at least 48-72 hrs of intravenous(IV) antibiotics&#xD;
      ( penicillin/ampicillin/ amoxicillin-clavulanate acid/cefuroxime) and the patients are ready&#xD;
      for discharge : afebrile, improved respiratory symptoms and signs, saturation &gt; 92% in air&#xD;
      and ready to be converted to oral antibiotics.&#xD;
&#xD;
      Arm 1: Twice a day oral amoxicillin-clavulanate (22.5mg/kg/dose) for 10 days Arm 2: Twice a&#xD;
      day oral amoxicillin-clavulanate (22.5mg/kg/dose) for 3 days followed by oral placebo for 7&#xD;
      days The random treatments will be allocated via computer generated number sequence and will&#xD;
      be supervised by a statistician.&#xD;
&#xD;
      All medications will be prepared and dispensed by the pharmacy department in suspension form.&#xD;
      The appearance of the placebo will be similar to the active medication. Investigators and&#xD;
      subjects will be blinded.&#xD;
&#xD;
      At discharge, parents will be asked to fill up a daily cough diary at home. Treatment&#xD;
      failure/exit criteria will be fulfilled if any of the following occur: death, recrudescence&#xD;
      of fever ≥38 °C (axilla) with respiratory signs of pneumonia, hypoxaemia &lt; 92% on air), need&#xD;
      for antibiotic treatment, new CXR changes.&#xD;
&#xD;
      On discharge, children will be followed up at regular intervals of 4 weeks, 3 moths(phone&#xD;
      call), 6 months and 1 year, to ensure they are well and also to detect residual or recurring&#xD;
      respiratory symptoms i.e. presence of cough/breathlessness/fever, recrudescence of pneumonia&#xD;
      and other respiratory illness, fever and upper respiratory tract infection(URTI), growth,&#xD;
      need for unscheduled healthcare visits for respiratory symptoms, need for antibiotic&#xD;
      treatments for respiratory/upper airway symptoms, abnormal physical findings, over a period&#xD;
      of 1 year post-discharge from hospital. Adverse effects of antibiotics e.g. vomiting,&#xD;
      diarrhoea, rash and adherence (returned empty bottles) to medication will be recorded.&#xD;
&#xD;
      CXR will be repeated at 4 weeks and at 1 year(if clinically indicated). These will be scored&#xD;
      by a radiologist who will be masked to allotted treatment.&#xD;
&#xD;
      At 12 months, if the age allows it, children will be asked to perform lung function tests.&#xD;
&#xD;
      During these follow-ups they will be given questionnaires: PCQOL-8, DASS21. At the 4 week&#xD;
      discharge, CXR as well as blood and NPS will be collected for testing for bacterial and viral&#xD;
      organisms. At 4 weeks, daily cough diaries will be collected back and reviewed.&#xD;
&#xD;
      Sample size calculation is based on the primary aim. We expect a 20% superiority difference&#xD;
      in the extended antibiotic regime and assuming a 20% drop-out, sample size should be 204&#xD;
      children (102 in each arm).&#xD;
&#xD;
      Data will be presented in accordance with the CONSORT guidelines on reporting on RCTs.&#xD;
      Analysis will be done by Dr. Rafdzah, a statistician. An intention to treat approach will be&#xD;
      used for all analyses. For the primary aim i.e. the clinical outcome of the different&#xD;
      antibiotic durations, the main outcomes being looked at are (a) clinical cure-complete&#xD;
      resolution of symptoms and signs at 4 weeks ,(b) proportion of children without chronic&#xD;
      respiratory symptoms or signs at the 12 month follow-up , using odds ratio(95%CI) with&#xD;
      logistic regression and linear regression. For continuous variables, t-tests and Mann-Whitney&#xD;
      tests will be used depending on the normality of the data. A Kaplan-Meier curve will be&#xD;
      constructed for each group for the time to next respiratory illness and hospitalization and&#xD;
      proportions will be compared by regression models. For prevalence of respiratory pathogens,&#xD;
      point prevalence will be reported on and multivariable logistic regression adjusting for&#xD;
      baseline carriage and antibiotic resistance will examine the effects of treatment duration on&#xD;
      the different organisms particularly Streptococcus pneumoniae and Haemophilus influenzae and&#xD;
      Staph aureus.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2014</start_date>
  <completion_date type="Actual">October 2018</completion_date>
  <primary_completion_date type="Actual">November 2017</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical cure</measure>
    <time_frame>30 days</time_frame>
    <description>Complete resolution of symptoms. No treatment failure or exit failure i.e. need for antibiotics or readmission into hospital for a respiratory condition</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quality of life of child and parent</measure>
    <time_frame>on admission, at discharge, at follow-ups( 4 weeks, 6 months and 1 year)</time_frame>
    <description>Severity of cough by using the translated and validated PCQOL-8 to assess impact of cough on the child and parent.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of pneumonia on the parent</measure>
    <time_frame>on admission, at discharge, at follow-ups(average 1 week, 4 weeks, 6 months and 1 year)</time_frame>
    <description>Using the translated and validated DASS21 on parents</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of pneumonia</measure>
    <time_frame>during the admission which expected duration will be 5 days, daily twice a day to do the questionnaires</time_frame>
    <description>Using the translated and validated the Canadian Acute Respiratory Influenza Scale(CARIFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse effects</measure>
    <time_frame>at 4 weeks follow-up</time_frame>
    <description>Treatment related adverse effects of antibiotics e.g. diarrhoea, vomiting</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to next hospitalisation or visit to healthcare unit</measure>
    <time_frame>during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 year</time_frame>
    <description>Time to the next hospitalization or visit to the doctor for respiratory symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number hospitalised for pneumonia or unscheduled healthcare visits</measure>
    <time_frame>during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 year</time_frame>
    <description>proportion of children hospitalised for respiratory illness or need for unscheduled healthcare visits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bacterial isolates</measure>
    <time_frame>at the 4 weeks appointment</time_frame>
    <description>Bacterial isolates: resistance pattern, resolution or persistence. Viral isolates: positive or negative These will be assessed at admission and 4 weeks post-discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiological resolution</measure>
    <time_frame>at the 4 weeks appointment</time_frame>
    <description>Radiological resolution and correlation with respiratory symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of chronic respiratory symptoms and signs post pneumonia</measure>
    <time_frame>during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 yea</time_frame>
    <description>Presence of respiratory symptoms and signs e.g. cough, failure to thrive, reduced effort tolerance, clubbing, persistent respiratory signs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of cough during 4 weeks post-discharge</measure>
    <time_frame>at the 4 weeks appointment, cough diary which will be done by parents daily from discharge</time_frame>
    <description>Using the visual scale cough diary</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Cost effective analysis of long vs short course of antibiotics for pneumonia</measure>
    <time_frame>at the 4 weeks appointment</time_frame>
    <description>To see if the extended antibiotic course is cost effective</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Pneumonia</condition>
  <arm_group>
    <arm_group_label>Amoxicillin-Potassium Clavulanate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient will be on amoxicillin-clavulanate 22.5mg/kg/dose bd for 10 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patient will be on amoxicillin-clavulanate 22.5mg/kg/bd for 3 days followed by another 7 days of placebo medication given at the same dose and frequency</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amoxicillin-Potassium Clavulanate Combination</intervention_name>
    <description>Oral antibiotic for 10 days</description>
    <arm_group_label>Amoxicillin-Potassium Clavulanate</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Augmentin</other_name>
    <other_name>Clomovid</other_name>
    <other_name>Co-amoxiclav</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo made to look like the study drug-main ingredient sugar syrup made by the pharmacy department in the hospital In the placebo arm, patient will be given 3 days of antibiotic followed by 7 days of placebo</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo arm</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Children admitted with severe pneumonia as defined by the presence of all the following as&#xD;
        defined as below:&#xD;
&#xD;
          -  3 months to 59 months old&#xD;
&#xD;
          -  History of cough and/or shortness of breath&#xD;
&#xD;
          -  Unwell for &lt;= 7 days -Increased respiratory rate ( ≥ 50/min if ≤12 months old, ≥&#xD;
             40/min) or retractions,-&#xD;
&#xD;
          -  Any of the following signs/symptoms are present at examination that would necessitate&#xD;
             admission: chest retractions, cyanosis, saturation&lt; 92% on air, poor feeding or&#xD;
             lethargy&#xD;
&#xD;
          -  Documented fever (axillary /central temp ≥ 38/38.5°C) within 24 hrs of admission&#xD;
&#xD;
          -  Abnormal CXR with presence of alveolar infiltrates&#xD;
&#xD;
          -  Responds to IV antibiotics by the first 72 hrs and able to go home with oral&#xD;
             antibiotics i.e. no more hypoxia and afebrile and reduced respiratory symptoms&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Children who (a) are transferred from another hospital (b) refuse blood taking (c) have a&#xD;
        doctor diagnosis of asthma or recurrent wheezing illness (d) have a diagnosis of&#xD;
        bronchiolitis i.e. wheezing in a child with a CXR with no consolidation (e) not acute&#xD;
        illness ( ie &gt;7 days) (f) unable to come for follow-up (g) not community acquired pneumonia&#xD;
        e.g. aspiration pneumonia (h)complicated pneumonia with effusion, pneumothorax, clinical&#xD;
        suspicion of necrotizing pneumonia (i)PICU admission or use of Non-invasive ventilation&#xD;
        (j)significant comorbidities that can increase the risk of having a complicated pneumonia-&#xD;
        (k) need for use of other antibiotics like anti-staph or macrolides (l)extra-pulmonary&#xD;
        infection e.g. meningitis (m)allergy to penicillin (n) unable to tolerate oral antibiotics&#xD;
        (o) underlying illness that can predispose to recurrent pneumonia&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>59 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University Malaya Medical Centre</name>
      <address>
        <city>Kuala Lumpur</city>
        <state>Lembah Pantai</state>
        <zip>59100</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Malaysia</country>
  </location_countries>
  <results_reference>
    <citation>Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ. 2008 May;86(5):408-16. doi: 10.2471/blt.07.048769.</citation>
    <PMID>18545744</PMID>
  </results_reference>
  <results_reference>
    <citation>Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O'Brien KL, Campbell H, Black RE. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013 Apr 20;381(9875):1405-1416. doi: 10.1016/S0140-6736(13)60222-6. Epub 2013 Apr 12.</citation>
    <PMID>23582727</PMID>
  </results_reference>
  <results_reference>
    <citation>Chang AB, Byrnes CA, Everard ML. Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis. Paediatr Respir Rev. 2011 Jun;12(2):97-103. doi: 10.1016/j.prrv.2010.10.008. Epub 2010 Dec 4.</citation>
    <PMID>21458737</PMID>
  </results_reference>
  <results_reference>
    <citation>Trenholme AA, Byrnes CA, McBride C, Lennon DR, Chan-Mow F, Vogel AM, Stewart JM, Percival T. Respiratory health outcomes 1 year after admission with severe lower respiratory tract infection. Pediatr Pulmonol. 2013 Aug;48(8):772-9. doi: 10.1002/ppul.22661. Epub 2012 Sep 19.</citation>
    <PMID>22997178</PMID>
  </results_reference>
  <results_reference>
    <citation>Gilani Z, Kwong YD, Levine OS, Deloria-Knoll M, Scott JA, O'Brien KL, Feikin DR. A literature review and survey of childhood pneumonia etiology studies: 2000-2010. Clin Infect Dis. 2012 Apr;54 Suppl 2(Suppl 2):S102-8. doi: 10.1093/cid/cir1053.</citation>
    <PMID>22403223</PMID>
  </results_reference>
  <results_reference>
    <citation>Yasin RM, Zin NM, Hussin A, Nawi SH, Hanapiah SM, Wahab ZA, Raj G, Shafie N, Peng NP, Chu KK, Aziz MN, Maning N, Mohamad JS, Benjamin A, Salleh MA, Zahari SS, Francis A, Ahmad N, Karunakaran R. Current trend of pneumococcal serotypes distribution and antibiotic susceptibility pattern in Malaysian hospitals. Vaccine. 2011 Aug 5;29(34):5688-93. doi: 10.1016/j.vaccine.2011.06.004. Epub 2011 Jun 30.</citation>
    <PMID>21723357</PMID>
  </results_reference>
  <results_reference>
    <citation>Chan PW, Goh AY, Chua KB, Kharullah NS, Hooi PS. Viral aetiology of lower respiratory tract infection in young Malaysian children. J Paediatr Child Health. 1999 Jun;35(3):287-90. doi: 10.1046/j.1440-1754.1999.00359.x.</citation>
    <PMID>10404452</PMID>
  </results_reference>
  <results_reference>
    <citation>Kulpeng W, Sornsrivichai V, Chongsuvivatwong V, Rattanavipapong W, Leelahavarong P, Cairns J, Lubell Y, Teerawattananon Y. Variation of health-related quality of life assessed by caregivers and patients affected by severe childhood infections. BMC Pediatr. 2013 Aug 13;13:122. doi: 10.1186/1471-2431-13-122.</citation>
    <PMID>23941314</PMID>
  </results_reference>
  <results_reference>
    <citation>Shoham Y, Dagan R, Givon-Lavi N, Liss Z, Shagan T, Zamir O, Greenberg D. Community-acquired pneumonia in children: quantifying the burden on patients and their families including decrease in quality of life. Pediatrics. 2005 May;115(5):1213-9. doi: 10.1542/peds.2004-1285.</citation>
    <PMID>15867027</PMID>
  </results_reference>
  <results_reference>
    <citation>Edmond K, Scott S, Korczak V, Ward C, Sanderson C, Theodoratou E, Clark A, Griffiths U, Rudan I, Campbell H. Long term sequelae from childhood pneumonia; systematic review and meta-analysis. PLoS One. 2012;7(2):e31239. doi: 10.1371/journal.pone.0031239. Epub 2012 Feb 22.</citation>
    <PMID>22384005</PMID>
  </results_reference>
  <results_reference>
    <citation>Jimenez Ortega AI, Lopez-Neyra A, Sanz Santiago V, Alvarez-Coca J, Villa Asensi JR. [Pulmonary function in children following community-acquired pneumonia contracted at pre-school age]. An Pediatr (Barc). 2011 Nov;75(5):314-9. doi: 10.1016/j.anpedi.2011.05.002. Epub 2011 Jul 31. Spanish.</citation>
    <PMID>21684825</PMID>
  </results_reference>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>October 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 7, 2014</study_first_posted>
  <last_update_submitted>April 22, 2019</last_update_submitted>
  <last_update_submitted_qc>April 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 23, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Malaya</investigator_affiliation>
    <investigator_full_name>Anna Marie Nathan</investigator_full_name>
    <investigator_title>Consultant and Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Pneumonia</keyword>
  <keyword>Child</keyword>
  <keyword>Outcome</keyword>
  <keyword>Antibiotics</keyword>
  <keyword>Etiology</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pneumonia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Amoxicillin</mesh_term>
    <mesh_term>Clavulanic Acid</mesh_term>
    <mesh_term>Clavulanic Acids</mesh_term>
    <mesh_term>Amoxicillin-Potassium Clavulanate Combination</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/NCT02258763
org study id: RP026-14HTM
nct id: NCT02258763
lead sponsor: 
collaborator: 
has dmc: No
To determine, in children hospitalized with pneumonia, if an extended duration of oral
      antibiotics (10 days) will be superior to a shorter duration (3 days) of antibiotics in
      improving clinical outcomes.

      Secondary Aims:

        1. Describe the prevalence of respiratory viruses and bacteria at presentation.

        2. Investigate the depression, anxiety and stress scores (DASS21) and quality of life
           scored (QOL) by parents of the children during admission, pre-discharge and post
           discharge and at follow-ups.
Introduction:

      Pneumonia is the single largest cause of death in children less than 5 years old and these
      are preventable deaths.[1,2] It is also an important cause of morbidity , especially when it
      is recurrent or severe as it may be linked with future adult lung disease.[3] Determining the
      aetiology of pneumonia is difficult in children who cannot produce satisfactory sputum for
      culture. Hence the reliance on molecular methods like polymerase chain reaction (PCR) and
      Enzyme immunoassays(EIA) looking at serological rise to determine the true aetiology of
      pneumonia is important especially in the era where mixed infections are common and may be
      associated with severe infections.

      There is currently no information on the suitable duration of antibiotics for uncomplicated
      severe community acquired pneumonia (CAP). There is also rampant overuse of antibiotics that
      results in poor compliance and significant side effects.

      There is little information on the QOL of the child with severe pneumonia and his parent. It
      is important to have a holistic approach to medicine hence the importance of analyzing the
      burden and social issues associated with children admitted with pneumonia.

      As opposed to adults, children cannot produce sputum (lower respiratory sample) appropriate
      for culture which is the traditional method of identifying the causative bacteria.
      Identification of bacteria in nasopharyngeal secretions (upper respiratory sample) does not
      equate to that organism causing the infection as the upper airway of a child is often
      colonized by bacteria. Detecting the organism in blood identifies it as the causative
      organism. However, blood culture has a very low yield in children with pneumonia and
      polymerase chain reaction (PCR) is much more sensitive at detecting bacteria in blood and
      hence it will markedly improve the ability to determine infecting organism.

      Development of our own in-house bacterial PCR kit which will detect several different
      bacteria in blood is planned in this study. We already have an in-house viral PCR kit and the
      ability to detect atypical bacteria via EIA. Currently there is an international study
      (Pneumonia Etiology Research for Child Health [PERCH]) looking at aetiology of pneumonia, but
      this study only involves 2 Asian countries (Thailand and Bangladesh)[5]. In Malaysia, in 2011
      there was a study that looked at pneumococcal isolates and antibiotic sensitivity patterns on
      invasive pneumococcal disease only[6]. There are also studies that look at viral aetiology of
      pneumonia[7]. Hence information on aetiology of pneumonia is skewed to those involving
      vaccine associated organisms and use of nasopharyngeal secretions(NPS) to detect viruses..

      The evidence for appropriate duration of antibiotics that should be used in hospitalized
      children with pneumonia is scarce. A randomized controlled trial comparing traditional
      duration of antibiotics (≥ 7 days) versus shorter duration of antibiotics < 7 days) is what
      we think is necessary. There are no studies looking at duration of antibiotics in children
      with severe uncomplicated pneumonia. We hypothesize that there is no need for a longer
      duration of antibiotics which are only associated with poor compliance and unnecessary
      side-effects.

      Finally, there is little data on quality of life in children and parents during and after a
      pneumonic episode. It is important to measure the impact of such a common disease on both
      parent and patient as well as to assess the impact of medical management on QOL so as to have
      a more holistic approach to medicine. Two previous studies have looked at QOL. One was a
      study comparing all acute diseases to chronic diseases[8]. The other looked at CAP but
      without the use of structured questionnaires[9]

      Methodology

      Randomized, Double Blind, Placebo Controlled Trial Children aged 3 months till <5 years old
      Admitted to University Malaya Medical Centre (UMMC) hospital with a severe community acquired
      pneumonia Eligibility Ages Eligible for Study: 3 Months to 59 Months Genders Eligible for
      Study: Both

      Inclusion Criteria:

      Children admitted with severe pneumonia as defined by the presence of all the following as
      defined as below:

        -  3 months to 59 months old

        -  History of cough and/or shortness of breath Unwell for <= 7 days

        -  Increased respiratory rate ( ≥ 50/min if ≤12 months old, ≥ 40/min)

        -  Any of the following signs/symptoms are present at examination that would necessitate
           admission: chest retractions, cyanosis, saturation< 92% on air, poor feeding or lethargy

        -  Documented fever (axillary /central temp ≥ 38/38.5°C) within 24 hrs of admission

        -  Abnormal chest radio graph(CXR) with presence of alveolar infiltrates

        -  Responds to IV antibiotics by the first 72 hrs and able to go home with oral antibiotics
           i.e. no more hypoxia and afebrile and reduced respiratory symptoms

      Exclusion Criteria:

      Children who (a) are transferred from another hospital (b) refuse blood taking (c) have a
      doctor diagnosis of asthma or recurrent wheezing illness (d) have a diagnosis of
      bronchiolitis i.e. wheezing in a child with a CXR with no consolidation (e) do not have an
      acute illness ( ie >7 days) (f) are unable to come for follow-up (g) do not have community
      acquired pneumonia e.g. aspiration pneumonia (h)have a complicated pneumonia with effusion,
      pneumothorax, clinical suspicion of necrotizing pneumonia (i)require paediatric intensive
      care unit (PICU) admission or use of non-invasive ventilation (j)significant comorbidities
      that can increase the risk of having a complicated pneumonia- (k) need other antibiotics like
      anti-staph or macrolides (l)have an extra-pulmonary infection e.g. meningitis (m)are allergic
      to penicillin (n) are unable to tolerate oral antibiotics and (o)have underlying illness that
      can predispose to recurrent pneumonia

      Randomized, Double Blind, Placebo Controlled Trial Children aged 3 months till <5 years old
      Admitted to UMMC hospital with a severe community acquired pneumonia Informed signed consent
      will be obtained from parents first. All children will have full blood count and CXR taken

      Additional blood and urine as detailed below will also be taken:

      a. Blood for PCR -streptococcus pneumoniae, staphylococcus aureus, Haemophilus influenzae,
      Mycoplasma pnuemoniae, Chlamydia pneumoniae will be taken.

      NPS for respiratory bacteria and viruses (by culture and PCT-similar as above) All these
      samples will be tested in our hospital laboratory. If samples cannot be processed
      immediately, they will be stored in a -80 deg C freezer except for the NPS for bacterial
      culture.

      All data will be collected at enrollment and at each follow-up visit on a standardized data
      sheet. Baseline demographic data( age, gender, address, ethnicity, household size, income,
      parent education, caregivers, household appliances) and medical information( birth history,
      breastfeeding and weaning, growth, immunization, smoke exposure, co-morbidity, daily
      hospitalization information) will be obtained from parents and medical charts. CXRs and
      routine blood test results will also be recorded.

      Quality of life, stress level, severity of illness , of parents and children with pneumonia,
      will be assessed at these time points too: during their admission (average of 3-5 days) and
      during follow-ups( average at, 4 weeks, 3 months(phone call only with no questionnaire
      administered), 6 months, 1 year post their pneumonic episode) using the following
      questionnaires-Paediatric proxy cough quality of life-8 (PCQOL-8), Canadian Acute Respiratory
      Illness and Flu Scale (CARIFS) (in hospital only), cough diary( at home, daily for 1
      month),Depression Anxiety Stress Scale 21( DASS21).

      The PCQOL-8 and DASS21 have been translated and validated in Bahasa Melayu. The CARIFS and
      the cough diary was recently translated in Bahasa Melayu and piloted for the purpose of this
      study.

      Treatments will be administered only after at least 48-72 hrs of intravenous(IV) antibiotics
      ( penicillin/ampicillin/ amoxicillin-clavulanate acid/cefuroxime) and the patients are ready
      for discharge : afebrile, improved respiratory symptoms and signs, saturation > 92% in air
      and ready to be converted to oral antibiotics.

      Arm 1: Twice a day oral amoxicillin-clavulanate (22.5mg/kg/dose) for 10 days Arm 2: Twice a
      day oral amoxicillin-clavulanate (22.5mg/kg/dose) for 3 days followed by oral placebo for 7
      days The random treatments will be allocated via computer generated number sequence and will
      be supervised by a statistician.

      All medications will be prepared and dispensed by the pharmacy department in suspension form.
      The appearance of the placebo will be similar to the active medication. Investigators and
      subjects will be blinded.

      At discharge, parents will be asked to fill up a daily cough diary at home. Treatment
      failure/exit criteria will be fulfilled if any of the following occur: death, recrudescence
      of fever ≥38 °C (axilla) with respiratory signs of pneumonia, hypoxaemia < 92% on air), need
      for antibiotic treatment, new CXR changes.

      On discharge, children will be followed up at regular intervals of 4 weeks, 3 moths(phone
      call), 6 months and 1 year, to ensure they are well and also to detect residual or recurring
      respiratory symptoms i.e. presence of cough/breathlessness/fever, recrudescence of pneumonia
      and other respiratory illness, fever and upper respiratory tract infection(URTI), growth,
      need for unscheduled healthcare visits for respiratory symptoms, need for antibiotic
      treatments for respiratory/upper airway symptoms, abnormal physical findings, over a period
      of 1 year post-discharge from hospital. Adverse effects of antibiotics e.g. vomiting,
      diarrhoea, rash and adherence (returned empty bottles) to medication will be recorded.

      CXR will be repeated at 4 weeks and at 1 year(if clinically indicated). These will be scored
      by a radiologist who will be masked to allotted treatment.

      At 12 months, if the age allows it, children will be asked to perform lung function tests.

      During these follow-ups they will be given questionnaires: PCQOL-8, DASS21. At the 4 week
      discharge, CXR as well as blood and NPS will be collected for testing for bacterial and viral
      organisms. At 4 weeks, daily cough diaries will be collected back and reviewed.

      Sample size calculation is based on the primary aim. We expect a 20% superiority difference
      in the extended antibiotic regime and assuming a 20% drop-out, sample size should be 204
      children (102 in each arm).

      Data will be presented in accordance with the CONSORT guidelines on reporting on RCTs.
      Analysis will be done by Dr. Rafdzah, a statistician. An intention to treat approach will be
      used for all analyses. For the primary aim i.e. the clinical outcome of the different
      antibiotic durations, the main outcomes being looked at are (a) clinical cure-complete
      resolution of symptoms and signs at 4 weeks ,(b) proportion of children without chronic
      respiratory symptoms or signs at the 12 month follow-up , using odds ratio(95%CI) with
      logistic regression and linear regression. For continuous variables, t-tests and Mann-Whitney
      tests will be used depending on the normality of the data. A Kaplan-Meier curve will be
      constructed for each group for the time to next respiratory illness and hospitalization and
      proportions will be compared by regression models. For prevalence of respiratory pathogens,
      point prevalence will be reported on and multivariable logistic regression adjusting for
      baseline carriage and antibiotic resistance will examine the effects of treatment duration on
      the different organisms particularly Streptococcus pneumoniae and Haemophilus influenzae and
      Staph aureus.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Clinical cure
time frame: 30 days
description: Complete resolution of symptoms. No treatment failure or exit failure i.e. need for antibiotics or readmission into hospital for a respiratory condition
measure: Quality of life of child and parent
time frame: on admission, at discharge, at follow-ups( 4 weeks, 6 months and 1 year)
description: Severity of cough by using the translated and validated PCQOL-8 to assess impact of cough on the child and parent.
measure: Impact of pneumonia on the parent
time frame: on admission, at discharge, at follow-ups(average 1 week, 4 weeks, 6 months and 1 year)
description: Using the translated and validated DASS21 on parents
measure: Severity of pneumonia
time frame: during the admission which expected duration will be 5 days, daily twice a day to do the questionnaires
description: Using the translated and validated the Canadian Acute Respiratory Influenza Scale(CARIFS)
measure: Adverse effects
time frame: at 4 weeks follow-up
description: Treatment related adverse effects of antibiotics e.g. diarrhoea, vomiting
measure: Time to next hospitalisation or visit to healthcare unit
time frame: during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 year
description: Time to the next hospitalization or visit to the doctor for respiratory symptoms
measure: Number hospitalised for pneumonia or unscheduled healthcare visits
time frame: during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 year
description: proportion of children hospitalised for respiratory illness or need for unscheduled healthcare visits
measure: Bacterial isolates
time frame: at the 4 weeks appointment
description: Bacterial isolates: resistance pattern, resolution or persistence. Viral isolates: positive or negative These will be assessed at admission and 4 weeks post-discharge
measure: Radiological resolution
time frame: at the 4 weeks appointment
description: Radiological resolution and correlation with respiratory symptoms
measure: Prevalence of chronic respiratory symptoms and signs post pneumonia
time frame: during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 yea
description: Presence of respiratory symptoms and signs e.g. cough, failure to thrive, reduced effort tolerance, clubbing, persistent respiratory signs
measure: Severity of cough during 4 weeks post-discharge
time frame: at the 4 weeks appointment, cough diary which will be done by parents daily from discharge
description: Using the visual scale cough diary
measure: Cost effective analysis of long vs short course of antibiotics for pneumonia
time frame: at the 4 weeks appointment
description: To see if the extended antibiotic course is cost effective
arm group label: Amoxicillin-Potassium Clavulanate
arm group type: Experimental
description: Patient will be on amoxicillin-clavulanate 22.5mg/kg/dose bd for 10 days
arm group label: Placebo
arm group type: Active Comparator
description: Patient will be on amoxicillin-clavulanate 22.5mg/kg/bd for 3 days followed by another 7 days of placebo medication given at the same dose and frequency
intervention type: Drug
intervention name: Amoxicillin-Potassium Clavulanate Combination
description: Oral antibiotic for 10 days
arm group label: Amoxicillin-Potassium Clavulanate
arm group label: Placebo
other name: Augmentin
other name: Clomovid
other name: Co-amoxiclav
intervention type: Drug
intervention name: Placebo
description: Placebo made to look like the study drug-main ingredient sugar syrup made by the pharmacy department in the hospital In the placebo arm, patient will be given 3 days of antibiotic followed by 7 days of placebo
arm group label: Placebo
other name: Placebo arm
criteria: 
gender: All
minimum age: 3 Months
maximum age: 59 Months
healthy volunteers: No
facility: 
country: Malaysia
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PMID: 18545744
citation: Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O'Brien KL, Campbell H, Black RE. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013 Apr 20;381(9875):1405-1416. doi: 10.1016/S0140-6736(13)60222-6. Epub 2013 Apr 12.
PMID: 23582727
citation: Chang AB, Byrnes CA, Everard ML. Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis. Paediatr Respir Rev. 2011 Jun;12(2):97-103. doi: 10.1016/j.prrv.2010.10.008. Epub 2010 Dec 4.
PMID: 21458737
citation: Trenholme AA, Byrnes CA, McBride C, Lennon DR, Chan-Mow F, Vogel AM, Stewart JM, Percival T. Respiratory health outcomes 1 year after admission with severe lower respiratory tract infection. Pediatr Pulmonol. 2013 Aug;48(8):772-9. doi: 10.1002/ppul.22661. Epub 2012 Sep 19.
PMID: 22997178
citation: Gilani Z, Kwong YD, Levine OS, Deloria-Knoll M, Scott JA, O'Brien KL, Feikin DR. A literature review and survey of childhood pneumonia etiology studies: 2000-2010. Clin Infect Dis. 2012 Apr;54 Suppl 2(Suppl 2):S102-8. doi: 10.1093/cid/cir1053.
PMID: 22403223
citation: Yasin RM, Zin NM, Hussin A, Nawi SH, Hanapiah SM, Wahab ZA, Raj G, Shafie N, Peng NP, Chu KK, Aziz MN, Maning N, Mohamad JS, Benjamin A, Salleh MA, Zahari SS, Francis A, Ahmad N, Karunakaran R. Current trend of pneumococcal serotypes distribution and antibiotic susceptibility pattern in Malaysian hospitals. Vaccine. 2011 Aug 5;29(34):5688-93. doi: 10.1016/j.vaccine.2011.06.004. Epub 2011 Jun 30.
PMID: 21723357
citation: Chan PW, Goh AY, Chua KB, Kharullah NS, Hooi PS. Viral aetiology of lower respiratory tract infection in young Malaysian children. J Paediatr Child Health. 1999 Jun;35(3):287-90. doi: 10.1046/j.1440-1754.1999.00359.x.
PMID: 10404452
citation: Kulpeng W, Sornsrivichai V, Chongsuvivatwong V, Rattanavipapong W, Leelahavarong P, Cairns J, Lubell Y, Teerawattananon Y. Variation of health-related quality of life assessed by caregivers and patients affected by severe childhood infections. BMC Pediatr. 2013 Aug 13;13:122. doi: 10.1186/1471-2431-13-122.
PMID: 23941314
citation: Shoham Y, Dagan R, Givon-Lavi N, Liss Z, Shagan T, Zamir O, Greenberg D. Community-acquired pneumonia in children: quantifying the burden on patients and their families including decrease in quality of life. Pediatrics. 2005 May;115(5):1213-9. doi: 10.1542/peds.2004-1285.
PMID: 15867027
citation: Edmond K, Scott S, Korczak V, Ward C, Sanderson C, Theodoratou E, Clark A, Griffiths U, Rudan I, Campbell H. Long term sequelae from childhood pneumonia; systematic review and meta-analysis. PLoS One. 2012;7(2):e31239. doi: 10.1371/journal.pone.0031239. Epub 2012 Feb 22.
PMID: 22384005
citation: Jimenez Ortega AI, Lopez-Neyra A, Sanz Santiago V, Alvarez-Coca J, Villa Asensi JR. [Pulmonary function in children following community-acquired pneumonia contracted at pre-school age]. An Pediatr (Barc). 2011 Nov;75(5):314-9. doi: 10.1016/j.anpedi.2011.05.002. Epub 2011 Jul 31. Spanish.
PMID: 21684825
responsible party type: Principal Investigator
investigator affiliation: University of Malaya
investigator full name: Anna Marie Nathan
investigator title: Consultant and Associate Professor
mesh term: Pneumonia
mesh term: Amoxicillin
mesh term: Clavulanic Acid
mesh term: Clavulanic Acids
mesh term: Amoxicillin-Potassium Clavulanate Combination