Preschool Wheeze: Inflammation/Infection Guided Management (PrIGMa)

Use of Pathological Phenotype to Determine Optimal Management for Moderate to Severe Preschool Wheeze

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Beclometasone; Drug: Co-amoxiclav; Drug: Azithromycin

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Reported recurrent wheeze, needing at least 2 courses of oral steroids in the last 12 months, at least one course of oral steroids in the last 6 months
• Past wheeze confirmed by a clinician

Exclusion Criteria:

• Any known cardiac disease
• Any chronic respiratory condition (other than preschool wheeze) diagnosed by a physician
• Any chronic condition that increases susceptibility to respiratory tract infections such as severe developmental delay and feeding difficulty/unsafe swallow Prematurity <34 weeks, or requirement of ventilation in the newborn period History of neonatal chronic lung disease Family not contactable by telephone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pathological phenotype; Regular inhaled steroids- Beclometasone dipropionate 200mcg bd for 4 months OR antibiotic therapy- Co- amoxiclav (0.3ml/kg bd) or Azithromycin (10mg/kg od) for 4 weeks	Drug: Beclometasone; Beclometasone dipropionate 200mcg bd for 4 months; Other Names: Clenil; Drug: Co-amoxiclav; Co-amoxiclav 0.3ml/kg bd for 4 weeks; Other Names: Augmentin Duo; Drug: Azithromycin; Azithromycin 10mg/kg od for 4 weeks; Other Names: Zithromax
Active Comparator: Clinical guidelines; The children will be treated as directed by their Consultant Paediatrician. The treatment may include- regular inhaled steroids- beclometasone dipropionate 200mcg bd for 4 months OR antibiotic therapy- Co-amoxiclav (0.3ml/kg bd) or Azithromycin (10mg/kg od) for 4 weeks	Drug: Beclometasone; Beclometasone dipropionate 200mcg bd for 4 months; Other Names: Clenil; Drug: Co-amoxiclav; Co-amoxiclav 0.3ml/kg bd for 4 weeks; Other Names: Augmentin Duo; Drug: Azithromycin; Azithromycin 10mg/kg od for 4 weeks; Other Names: Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Unscheduled Healthcare Visits (UHCV)	Actual number of unscheduled healthcare visits (UHCV) includes GP, A&E or hospital admission. This is median number of visits in 4 months - with range.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health Related Quality of Life	Quality of life assessed using the Paediatric Caregivers Asthma Quality of Life Questionnaire (PACQLQ). The scores are from 1.0-7.0, higher value is a better outcome. We calculated the actual score at baseline and at 4 months. A change in score of 0.5 is considered clinically significant. We recorded actual value at baseline and actual value at 4 months.	4 months
Symptom Days	Number of days with symptoms during 4 months	4 months
Number of Courses of Oral Steroids	Number of steroid courses needed during 4 months for any acute symptoms.	4 months and up to 1 year later

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: National Institute for Health Research, United Kingdom
• Investigators: Principal Investigator: Sejal Saglani, Imperial College London

Publications and helpful links

General Publications

• Undela K, Goldsmith L, Kew KM, Ferrara G. Macrolides versus placebo for chronic asthma. Cochrane Database Syst Rev. 2021 Nov 22;11(11):CD002997. doi: 10.1002/14651858.CD002997.pub5.

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2015
• Primary Completion (Actual): August 17, 2018
• Study Completion (Actual): August 17, 2018

Study Registration Dates

• First Submitted: August 4, 2015
• First Submitted That Met QC Criteria: August 5, 2015
• First Posted (Estimate): August 6, 2015

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Severe; Preschool; Moderate; Wheeze
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Anti-Asthmatic Agents; Respiratory System Agents; beta-Lactamase Inhibitors; Beclomethasone; Azithromycin; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: 165460