Preschool Wheeze: Inflammation/Infection Guided Management
Condition: Asthma
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a single-centre, randomised-controlled trial, comparing management of preschool
      wheeze. It specifically aims to compare management of preschool wheeze using current clinical
      guidelines to management determined by eosinophilic inflammation and infection. Participants
      will be children aged 1-5 years who have recurrent wheezing and will be allocated to one of
      two treatment groups, either current clinical care or pathological phenotype based
      management. They will be asked to make 2 study visits to the Royal Brompton Hospital over the
      course of 4 months.
    

Detailed description: 
      This study will determine the efficacy of treating preschool wheeze based on objective
      biomarkers of inflammation and presence of bacterial infection, and compare this to current
      clinical guidelines based management. Subjects will be recruited from out-patient clinics and
      attend for a screening/research visit during which assessments of pathological phenotype
      (bacterial infection and inflammation) will be made from induced sputum and blood. Their
      clinical phenotype will be determined by the Consultant. Subsequently, patients will be
      randomised to one of two arms:

      i) current clinical care ( as directed by their Consultant) ii) pathological phenotype based
      management- presence of eosinophilia in blood (_> 2%) or induced sputum (>2.4%) - will
      receive twice daily inhaled steroids ( beclometasone 200mcg bd) for 4 months, presence of
      bacterial infection in induced sputum or oropharyngeal swab- will receive 4 weeks of
      antibiotics targeted to the isolate, IF BOTH eosinophilic inflammation AND infection are
      present, then inflammation alone will be treated for 4 months.

      All patients will continue on as required bronchodilator therapy, and any other
      anti-inflammatory therapy ( other than inhaled steroids) e.g. montelukast.

      All participants will undergo an initial research/screening visit which will involve the
      following tests:

      Full blood count Total serum immunoglobulin E and radioallergosorbent test to house dust
      mite, grass pollen, tree pollen, cat, dog, aspergillus, milk, egg, peanut Assessment of lung
      function by incentive spirometry and lung clearance index (LCI) using the multiple breath
      washout technique Exhaled nitric oxide- using the offline tidal breathing technique Sputum
      induction using nebulised hypertonic saline Oro- pharyngeal swab Symptom questionnaire Health
      related quality of life questionnaire

      Management in the pathological phenotype arm:

        1. Eosinophilic inflammation, no bacterial infection:

           Children with sputum eosinophils >2.4% or blood eosinophils equal to and above 2% will
           be defined as eosinophilic and management will be as follows:

           i) Regular inhaled steroids ( beclometasone 200mcg bd) for 4 months in those previously
           not on any regular therapy.

           ii) Of children who have already been prescribed inhaled steroid therapy, those with an
           eosinophilic phenotype will continue for a further 4 months.

           iii) Children who have already been prescribed a regular leukotriene receptor antagonist
           will continue this and regular inhaled steroids (beclometasone 200mcg bd) will be added
           to their maintenance therapy for 4 months.

           iv) Use of as required bronchodilator therapy will continue

        2. Non- eosinophilic, no inflammation, no infection:

           Children with either sputum eosinophils _<2.4% or blood eosinophils <2% will be defined
           as non- eosinophilic and management will be as follows:

           i) Use of as required bronchodilators for acute symptoms ii) Non- eosinophilic children
           that have already been prescribed regular inhaled steroids will be asked to stop them
           for 4 months Children with no bacterial growth from oropharyngeal swab or induced
           sputum, and without eosinophilic inflammation will continue management according to the
           non-eosinophilic, no inflammation, no infection profile.

        3. Bacterial infection, no eosinophilic inflammation:

           Children with a positive bacterial culture result from oropharyngeal swab or induced
           sputum will be treated with a 4 week course of antibiotics. Four weeks of antibiotic
           therapy will be used as this has been shown to be beneficial in a previous study of
           severe preschool wheeze. If these children have already been prescribed regular inhaled
           steroids, they will be stopped for 4 months.

        4. Eosinophilic inflammation AND bacterial infection:

      Children with raised eosinophils in induced sputum or blood AND positive bacterial culture
      will be managed according to the eosinophilic inflammation alone guideline. They will only be
      given inhaled steroids for 4 months, and no antibiotics. This is to assess only one
      intervention at a time. However, the investigators do not anticipate many children will be in
      this group as our previous data shows those with positive bacterial cultures are very
      unlikely to have eosinophilia.

      Management in the clinical guidelines arm:

      The children will be treated as directed by their Consultant Paediatrician. The prescription
      for the drugs to be used will be dispensed from the pharmacy department at the Royal Brompton
      Hospital- as directed by the clinician. Usually only 2 weeks of medication is prescribed by
      the pharmacy, but for this trial 4 months' supply will be given.

      Concomitant treatment

      The following medication will be allowed to continue during the intervention period in both
      study arms:

        1. Use of rescue medication with bronchodilators for acute symptoms- salbutamol and/or
           ipratropium bromide

        2. Use of leukotriene receptor antagonist- montelukast- can continue regardless of whether
           it is being taken regularly or as required for acute symptoms

      Monitoring:

      The trial will be monitored according to the monitoring plan agreed and written by the
      Sponsor, based on internal risk assessment procedure. Where appropriate the CI will be asked
      to complete a copy of the Sponsor's self-monitoring template. It is the responsibility of the
      CI to ensure this is completed and submitted to the research organisation on request. It is
      the responsibility of the research organisation to determine the monitoring risk assessment
      and explain the rationale.

      The study may be subject to inspection and audit by Imperial College London under their remit
      as Sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to
      good clinical practice.

      Statistics and Data analysis:

      Categorical data will be presented as number and percentage and comparisons between groups
      done using the chi squared or Fishers exact test. All numerical data will be tested for
      normality and normally distributed data will be presented as mean standard deviation and
      comparisons between groups done using the 2 sample independent t test. For the data that are
      not normally distributed the median (IQR) will be presented and comparisons between groups
      done using the Mann-Whitney test. Poisson regression will be done to determine the factors
      that affect the primary endpoint, the number of unplanned hospital visits.

      There will be data checks to compare data entered into the registry, against predefined rules
      for range using the INFORM database.

      Type of subjects to be recruited:

      All subjects will be aged between 1 and 5 years old. All subjects will have moderate to
      severe preschool wheeze, defined as _>2 oral steroid bursts for acute wheeze in the last 12
      months, with at least one oral steroid burst in the last 6 months.

      Number of subjects:

      Based on published data for children with moderate preschool wheeze it is apparent that
      approximately five healthcare attendances occur per child per year. In the current study, the
      investigators wish to reduce the proportion of healthcare contacts by at least one-third per
      year. In order to achieve this with 80% power, and accepting statistical significance at the
      5% level, the investigators require a minimum of 36 evaluable patients with moderate wheeze
      per group. Evaluable patients are those from whom at least a blood sample to assess
      inflammation and an oropharyngeal swab to determine infection can be obtained prior to
      randomisation. A total of at least 72 children will therefore be recruited. However, this is
      the minimum number, and the investigators aim to recruit 100 children (50 per group) if
      possible.

      The number of subjects is not based on a precise power calculation as this is a proof of
      concept study to determine the feasibility of this approach, and to inform a future power
      calculation for a large multi-centre trial addressing the same question.
    

Intervention name(s): Beclometasone; Co-amoxiclav; Azithromycin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Beclometasone dipropionate 200mcg bd for 4 months; Co-amoxiclav 0.3ml/kg bd for 4 weeks; Azithromycin 10mg/kg od for 4 weeks
Other intervention name(s): Clenil; Augmentin Duo; Zithromax
Intervention MeSH terms: Azithromycin; Amoxicillin-Potassium Clavulanate Combination; Beclomethasone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Preschool; Wheeze; Moderate; Severe