Indiaclen Short Course Amoxycillin Therapy for Pneumonia With Wheeze
Condition: Non-Severe Pneumonia With Wheeze
MeSH terms: Pneumonia
Study type: Interventional
Phase: Phase 3

Summary: 
      Background: The current Integrated management of childhood infections (IMCI) algorithm
      prescribes that children with wheeze and fast breathing presenting to first level health
      facilities are given antibiotics if they continue to have fast breathing after two doses of
      bronchodilator. The primary purpose of the algorithm is to prevent mortality due to bacterial
      pneumonia. However, an unknown proportion of children managed in this fashion will have a
      viral related wheezing illness or asthma rather than pneumonia. Although it is unlikely that
      wheezing syndromes are a significant cause of mortality for children in developing countries,
      these algorithms are likely to result in unnecessary administration of antibiotics as well as
      inadequate treatment of recurrent wheezing illness. We do not have clear evidence about
      whether antibiotics can be withheld in some categories of children with wheeze. It is clear
      that wheeze can occur in bacterial infection and in addition co-infection with virus and
      bacteria has been well demonstrated in several studies of pneumonia etiology in children.
      Although some studies have found that children with more severe disease or who are blood
      culture positive are more likely to be febrile at presentation, this sign is not sufficiently
      sensitive or specific to determine whether antibiotics should be administeredSetting: The
      study will be conducted in eight medical colleges situated in Lucknow, Nagpur, New Delhi,
      Mumbai, Chennai, Trivandrum, Vellore, and Chandigarh. Design: This will be a multicentric,
      randomized, double blind efficacy trial. . Hypothesis: The primary hypothesis is that the use
      of oral amoxycillin for three days would be as effective, in terms of clinical cure on day 4
      as compared to use of oral placeboMain objective: To compare the proportion of children aged
      2 to 59 months presenting with non-severe pneumonia with wheeze whose respiratory rate does
      not fall below the age specific cut-off after three doses of nebulized salbutamol, that
      achieve clinical cure on day 4 on 3 day of treatment with oral amoxycillin versus
      placebo.Inclusion criteria: Children aged 2-59 months with non-severe pneumonia based on WHO
      criteria of respiratory rate above the age specific cut-off, audible / ausculatory wheeze.
      Exclusion criteria: Children with severe disease, received any documented antibiotic
      treatment in the past 48 hours, diagnosed asthmatic on maintenance therapy, complicating
      acute non-pulmonary or chronic illness, known drug allergy, hospitalization in the past 2
      weeks, history of measles within the last month, known immunodeficiency disorder, prior
      enrollment in the study, residing in areas not accessible for follow-up or whose guardian
      refuses to consent for the study. Sample size: Has been calculated to test the null
      hypothesis. There will be 950 children in each arm. Thus each site is required to recruit a
      minimum of 225 cases over 18 months.
    

Detailed description: 
      Background: The World Health Organizations acute lower respiratory infections (ALRI)
      management algorithms depend primarily on two key clinical signs: elevated respiratory rate
      and chest indrawing. The current Integrated management of childhood infections (IMCI)
      algorithm prescribes that children with wheeze and fast breathing presenting to first level
      health facilities are given antibiotics if they continue to have fast breathing after two
      doses of bronchodilator. The primary purpose of the algorithm is to prevent mortality due to
      bacterial pneumonia. However, an unknown proportion of children managed in this fashion will
      have a viral related wheezing illness or asthma rather than pneumonia. Although it is
      unlikely that wheezing syndromes are a significant cause of mortality for children in
      developing countries, these algorithms are likely to result in unnecessary administration of
      antibiotics as well as inadequate treatment of recurrent wheezing illness. In both developed
      and developing countries respiratory syncytial virus is the predominant etiological agent
      responsible for bronchiolitis and wheezing illness in the first two years of life. Moreover
      data from several studies demonstrates that respiratory syncitial virus (RSV) infection and
      the bronchiolitis syndrome are a major component of the total ALRI in children living in
      developing countries. The relevant literature on therapy includes studies in which children
      were labelled as bronchiolitis and others in which children were classified as wheezing
      illness.We do not have clear evidence about whether antibiotics can be withheld in some
      categories of children with wheeze. It is clear that wheeze can occur in bacterial infection
      and in addition co-infection with virus and bacteria has been well demonstrated in several
      studies of pneumonia etiology in children. Although some studies have found that children
      with more severe disease or who are blood culture positive are more likely to be febrile at
      presentation, this sign is not sufficiently sensitive or specific to determine whether
      antibiotics should be administered.There has been extensive debate about whether infants and
      young children in the first year of life respond to bronchodilator therapy. Proposed reasons
      for a lack of response have included: immaturity of bronchiolar smooth muscle, increased
      dynamic airway closure and relatively larger degrees of mucosal edema. A literature search
      between 1980 and 2000 reveals five randomized placebo controlled trials of beta agonist
      administered to acutely wheezing infants in which clinical outcomes were determined. Overall
      these studies support the hypothesis that children aged less than 12 to 18 months are less
      responsive to bronchodilator therapy than older children. However, they also demonstrate that
      use of inhaled short acting bronchodilators for the acute treatment of wheeze offers some
      benefits for clinical outcomes even in this young age group. The benefits of beta agonists
      may be restricted to children with recurrent wheezing and at most provide a very small
      clinical benefitSetting: The study will be conducted in eight medical colleges situated in
      New Delhi, Chandigarh, Lucknow, Mumbai, Nagpur, Chennai, Vellore and Trivandrum. Design: This
      will be a multicentric, randomized, double blind efficacy trial. Block randomization will be
      done in Dept. of Pharmacology, KGMU, Lucknow, which is not the coordinating center for the
      trial. Blocks will be generated in mixed batches. The medicines will be then placed in by the
      pharmacy according to the intervention type determined by the pharmacy. Two hundred and
      twenty five random numbers will be generated in blocks of varying lengths for each of the
      nine sites.OutcomesPrimary: Clinical Cure: Respiratory rate below agerate below ages specific
      cut-off (<50 bpm in infants <1 year and <40 bpm in ages 12 - 59 months) and absence of
      auscultatory as well as audible wheeze.Secondary: Response to nebulization: Respiratory rate
      below age specific cut-off (<50 bpm in infants <1 year and <40 bpm in ages 12 - 59 months)
      after a maximum of three doses of nebuliaztion with salbutamol, auscultaroy wheeze may or may
      not be present. But there is no audible wheeze.Clinical failure of therapy: Any signs of
      severe pneumonia or severe disease; chest in drawing, convulsions, drowsiness or inability to
      drink at any time; Respiratory rate above age specific cut-off on day 4 or after that (with
      or without wheeze);Oxygen saturation on pulse oximetry <90% on day 4 or after that;
      Documented axillary temperature > 101 degrees Fahrenheit. In addition, children who die
      within the follow-up period of 14 days or are lost to follow-up on day 4 will also be
      considered as failed.Clinical relapse at day 7- 15: Signs of severe pneumonia or very severe
      disease among cases who were clinically cured on day 4 follow-up.Hypothesis: The primary
      hypothesis is that the use of oral amoxycillin for three days would be as effective, in terms
      of clinical cure on day 4 as compared to use of oral placebo. Intervention: Amoxycillin
      tablets (125 mg) or placebo They will be used after dissolving in 5 ml of clean water. The
      medicines will be given according to the weight of the child as follows:q 4 - 6 KG ½ tablet
      thrice a dayq 7 - 10 KG 1 tablet thrice a dayq 11 - 15 KG 1 ½ tablet thrice a dayq 16 - 20 KG
      2 tablets thrice a dayMain objective: To compare the proportion of children aged 2 to 59
      months presenting with non-severe pneumonia with wheeze whose respiratory rate does not fall
      below the age specific cut-off after three doses of nebulized salbutamol, that achieve
      clinical cure on day 4 on 3 day of treatment with oral amoxycillin versus placeboSecondary
      objectives: Among all cases of non-severe pneumonia with wheeze1. To assess the proportion of
      children aged 2 to 59 months presenting with non-severe pneumonia with wheezing audible
      wheeze2. To assess the proportion of children aged 2 to 59 months presenting with non-severe
      pneumonia with wheezing who respond to up to three doses of nebulization with
      salbutamol.Among cases of non-severe pneumonia with wheeze aged 2 to 59 months who respond to
      three doses of salbutamol3. To assess the proportion of who fail therapy at day 4 of the
      initial successful bronchodilator therapy with inhaled salbutamol.4. To assess the proportion
      relapse at day 11- 14 of the initial successful bronchodilator therapy with inhaled
      salbutamol.5.To compare the cost of treatment of clinical failures and relapses among those
      treated with oral salbutamol.6 .To assess the association of bronchodilator response with
      age, season, number of previous wheezing episodes, audible versus auscultatory wheeze and
      family history of asthma.7.To assess the association of relapse in children who showed
      improvement after being treated with inhaled salbutamol, with age, respiratory syncytial
      virus (RSV) isolation, season, number of previous wheezing episodes, audible versus
      auscultatory wheeze and family history of asthma.Among cases of non-severe pneumonia with
      wheeze aged 2 to 59 months who do not respond to three doses of salbutamol8.To compare the
      proportion of children who are judged to be clinically cured after 3 days of treatment but
      who relapse within the next 11-14 days observation on 3-day treatment with oral amoxycillin
      versus placebo.9.To compare the cost of treatment of clinical failures and relapses among
      those treated with oral amoxycillin or placebo.10. To assess the association of clinical
      failure on day 4 with age, respiratory syncytial virus (RSV) isolation, season, number of
      previous wheezing episodes, audible versus auscultatory wheeze, family history of asthma and
      randomization to amoxycillin therapy.Inclusion criteria: Children aged 2-59 months with
      non-severe pneumonia based on WHO criteria of respiratory rate above the age specific
      cut-off, audible / ausculatory wheeze, accessible to follow up, whose guardians give written
      informed consent.Exclusion criteria: Children with severe disease, received any documented
      antibiotic treatment in the past 48 hours, diagnosed asthmatic on maintenance therapy,
      complicating acute non-pulmonary or chronic illness, known drug allergy, hospitalization in
      the past 2 weeks, measles or history of measles within the last month, known immunodeficiency
      disorder, prior enrollment in the study, residing in areas not accessible for follow-up or
      whose guardian refuses to consent for the study. Radiological Pneumonia on X-Ray.Sample size:
      Two modes of therapies will be assumed to be equal if the failure rate in new regimen is not
      more than 17%. So each site will be required to recruit and follow up 225 cases in each arm
      over 18 months. Thus there will be 950 children in each arm.Policy relevance: The present
      study plans to evaluate the role of antibiotic in children with non-severe pneumonia
      presenting with wheeze. It will define the patient and disease characteristics associated
      with clinical failure and the need for antibiotics. The results of the study will formulate
      policy to use antibiotics in children with non-severe pneumonia and wheeze.
    

Intervention name(s): Amoxycillin
Intervention type(s): Drug
Intervention MeSH terms: Amoxicillin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Pneumonia; Wheezing; Treatment; Children; India