Innovative Steroid Treatment to Reduce Asthma Development in Children After First-time Rhinovirus Induced Wheezing

Study Overview
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Brief Summary
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The overall objective of the study is to determine the efficacy of corticosteroids in preventing recurrent wheezing and asthma in high-risk, first-time severe wheezing children with rhinovirus infection, stratified by rhinovirus genome load. The secondary objectives are to determine duration and severity of each acute episode with acute expiratory breathing difficulty, the number of episodes with acute expiratory breathing difficulty, degree of pulmonary hyperreactivity and quality of life within 24 months after study entry.

Detailed Description
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Asthma is a major and growing public health problem in Norway and beyond. The reason for the increased occurrence of asthma is still poorly understood. However, the disease is a result of a complex interplay between genetic and environmental factors. The current view of asthma pathogenesis is that an abnormal immune response to environmental agents, such as allergens or respiratory viruses, is responsible for initiation and perpetuation of chronic inflammation in genetically susceptible individuals. It is also increasingly evident that asthma originates early in life. However, intervention measures introduced before birth and during the first year of life that reduced or eliminated exposure to house dust, pets, and tobacco smoke together with encouragement of breast-feeding and delayed introduction of solid foods, only had minor effects in preventing asthma development. Thus, there is an urgent need to develop new approaches to asthma prevention in young children. Recent evidence suggests that rhinovirus infection is a main and independent trigger of acute wheezing and asthma exacerbations in children. Rhinovirus may cause 20-40% of acute wheezing episodes (bronchiolitis) in children during the first 2 years of life, and up to 90% of asthma exacerbations in older children. Rhinovirus etiology of early wheezing is particularly interesting because it has been strongly associated with recurrent wheezing and doctor-diagnosed asthma up to 13 years of age. The strength of this effect has been reported with odds ratios ranging from 3 to 10 during early life. Previously, personal objective markers for increased asthma risk have mainly been related to the presence of atopy development, but atopic disease with eczema generally manifests later, at age 2-3 years. This understanding of early-life rhinovirus associated wheezing as an early marker for asthma has opened a novel opportunity for effective secondary prevention of asthma by identifying children with increased risk of asthma. Recognizing the role of rhinovirus as an early risk factor for asthma development, has made it essential to control viral effects. Unfortunately, no feasible rhinovirus antivirals are available for children yet. Rhinovirus infection may lead to broken epithelial barriers facilitating development of inflammation, and asthma is a chronic inflammatory disease of the airways. It is becoming increasingly clear that control of early virus induced inflammation that may develop into chronic inflammation is crucial to intervene with the asthma disease development. Most cases with bronchiolitis are caused by respiratory syncytial virus (RSV) and rhinovirus. Recent data have shown that RSV is associated with a more severe short-term outcome than rhinovirus, whereas rhinovirus more often than RSV is associated with a more severe long-term outcome related to atopic predisposition and with increased risk of developing asthma. In line with this, several randomized clinical trials (RCT) have failed to show any corticosteroid effect in preventing asthma after early-life infection with RSV. In contrast, and as a major finding that in fact have led to this project, researchers in Turku, Finland have previously reported a post hoc analysis of RCT data showing that a short treatment with oral prednisolone during the first wheezing episode caused by rhinovirus, reduced the risk of recurrent wheezing over the next 1 - 7 years. Moreover, in a prospective single-center RCT, the same researchers confirmed that children with high rhinovirus genome load did benefit from systemic corticosteroids by having fewer recurrences during a 12-month follow-up period and 25% less asthma diagnoses during a 1- and 4-year follow-up.16;17 Hence, asthma after RSV may not be prevented by corticosteroids because RSV infected children less often are atopic and less often develop chronic inflammation, whereas early rhinovirus induced wheezing often occur in genetic predisposed and/or atopic children, and therefore asthma development may be prevented by early corticosteroid intervention. These highly clinically relevant findings must be confirmed in an adequately powered multicenter RCT to fully address the clinical significance of corticosteroid intervention. We expect that this trial will be a landmark in demonstrating long-term disease modifying effects of recurrent wheezing and asthma inception.

Official Title
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Innovative Steroid Treatment to Reduce Asthma Development in Children After First-time Rhinovirus Induced Wheezing - the INSTAR Study

Conditions
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Asthma, Inflammation

Intervention / Treatment
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* Drug: Dexamethasone treatment during 3 days
* Drug: placebo treatment during 3 days


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: admitted to pediatric acute wards in the participating hospitals in Norway, Finland, Sweden. referred for first severe wheezing episode, defined as first-time acute breathing difficulty with wheezing ever, appearing less than 7 days from onset of symptoms one or more of the following:(a) fever, (b) hypoxia (SAT O2 <= 92%), (c) retractions (inter-, subcostal), (d) prolonged expiration (on auscultation), (e) expiratory rhonchi (on auscultation) rhinovirus positive PCR test in nasopharyngeal secrete signed informed consent and expected cooperation of the patients for the treatment and follow-up must be obtained and documented according to ICH GCP, and national/local regulations. COVID-19 negative and/or SARS-CoV-2 negative PCR test in nasopharyngeal secrete during the current infection Exclusion Criteria: previous episodes with wheezing, defined as a history of acute breathing difficulty with wheezing in need of treatment at a general practitioner or at hospital, or parental information about similar breathing difficulties gestational age <37 weeks chronic illness other than atopy (eczema), previous systemic or inhaled corticosteroid treatment, participation to another trial, varicella infection or contact during the last 2-3 weeks, need for intensive care unit treatment during the present infection, except for respiratory support with high flow nasal cannula ventilation, any reason why, in the opinion of the investigator, the patient should not participate (e.g. not able to comply with study procedures). COVID-19 and/or SARS-CoV-2 positive PCR test in nasopharyngeal secretions during the current infection

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 24 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In Sweden and Finland children who are rhinovirus negative but otherwise fulfill the inclusion criteria, will be included for comparison. They will not be randomized and participate in the intervention but receive follow-up as rhinovirus positive participants.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone<br> | Drug: Dexamethasone treatment during 3 days<br>* Dexamethasone 1,0 mg oral tablets. The exact daily dose of dexamethasone will be 0.3 mg/kg (maximum 6.0 mg). The recommended administration of all tablets is to crush the tablets to a smooth powder and then mix with jelly or yogurt. The dissolved dexamethasone is given by mouth and it is recommended to give it in relation to a meal/breastfeeding. If a child vomits within 30 min, the same dose will be given one more time after a break.<br>|
| Placebo Comparator: controls<br> | Drug: placebo treatment during 3 days<br>* 1,0 mg oral tablets. The exact daily dose of lactose (instead of dexamethasone) will be 0.3 mg/kg (maximum 6.0 mg). The recommended administration of all tablets is to crush the tablets to a smooth powder and then mix with jelly or yogurt. The dissolved dexamethasone is given by mouth and it is recommended to give it in relation to a meal/breastfeeding. If a child vomits within 30 min, the same dose will be given one more time after a break.<br>* Other names: lactose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to a new physician-confirmed wheezy episode within 24 months after study entry |  | 24 months | 
| time to need for a regular controller medication for asthma within 24 months after study entry |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| duration of respiratory symptoms | as determined at the first episode of acute breathing difficulty within 24 months of study entry | 24 months | 
| severity of respiratory symptoms | as determined at the first episode of acute breathing difficulty within 24 months of study entry | 24 months | 
| the number of episodes with acute breathing difficulty since start of study medication | as determined at scheduled follow-up visit within 24 months of study entry | 24 months | 
| the duration of episodes with acute breathing difficulty since start of study medication | as determined at scheduled follow-up visit within 24 months of study entry | 24 months | 
| the degree of pulmonary hyperreactivity | as determined at scheduled follow-up visit within 24 months of study entry | 24 months | 
| quality of life: Infant Toddler Quality of Life© (ITQOL©) questionnaire | as determined at scheduled follow-up visit within 24 months of study entry | 24 months | 
| body height |  | 24 months | 
| body weight |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory Sounds, Steroids, Rhinovirus