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

NCT ID: NCT03889743

Last Updated: 2025-06-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 280 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-08
• Study Completion Date: 2028-05-31

Brief Summary

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

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.

Conditions

Asthma; Inflammation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Dexamethasone

Group Type: EXPERIMENTAL

Dexamethasone treatment during 3 days

Intervention Type: DRUG

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.

controls

Group Type: PLACEBO_COMPARATOR

placebo treatment during 3 days

Intervention Type: DRUG

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.

Interventions

Dexamethasone treatment during 3 days

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.

Intervention Type: DRUG

placebo treatment during 3 days

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.

Intervention Type: DRUG

Other Intervention Names

lactose

Eligibility Criteria

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)
• evidence of rhinovirus infection by PCR-test in nasopharyngeal secretions
• 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.

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 non-invasive methods (high flow nasal cannula ventilation, CPAP or BiPAP),
• 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 related disease.

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 23 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Turku University Hospital

OTHER_GOV

Sponsor Role: collaborator

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

Haukeland University Hospital

OTHER

Sponsor Role: collaborator

University Hospital, Akershus

OTHER

Sponsor Role: collaborator

Helse Stavanger HF

OTHER_GOV

Sponsor Role: collaborator

University Hospital of North Norway

OTHER

Sponsor Role: collaborator

Ullevaal University Hospital

OTHER

Sponsor Role: collaborator

St. Olavs Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Geir Bråthen

Role: STUDY_DIRECTOR

St. Olavs Hospital

Locations

Turku University Hospital

Turku, , Finland

Site Status: RECRUITING

Haukeland University Hospital

Bergen, , Norway

Site Status: RECRUITING

Akershus University Hospital

Oslo, , Norway

Site Status: RECRUITING

Ullevål University Hospital

Oslo, , Norway

Site Status: RECRUITING

Stavanger University Hospital

Stavanger, , Norway

Site Status: RECRUITING

University Hospital of North Norway

Tromsø, , Norway

Site Status: RECRUITING

St Olavs Hospital

Trondheim, , Norway

Site Status: RECRUITING

Karolinska Universitetssjukhuset

Stockholm, , Sweden

Site Status: RECRUITING

Countries

Finland; Norway; Sweden

Central Contacts

Henrik Døllner, md phd

Role: CONTACT

henrik.dollner@ntnu.no

0047 73559531

Facility Contacts

Tuomas Jartti, md phd

Role: primary

Marit Vollsaether, md phd

Role: primary

Chris Inchley, md phd

Role: primary

Håvard Skjerven

Role: primary

Knut Øymar, md phd

Role: primary

Claus Klingenberg, md phd

Role: primary

Henrik Døllner, md phd

Role: primary

henrik.dollner@ntnu.no

Jon Konradsen, md phd

Role: primary

References

Elvebakk T, Dollner H, Partty A, Jartti H, Vuorinen T, Oymar K, Nerheim S, Moe N, Nordbo SA, Follestad T, Koski J, Vollsaeter M, Hofstad A, Klingenberg C, Leknessund CB, Skjerven HO, Risnes K, Soderhall C, Sissener E, Inchley CS, Konradsen JR, Jartti T. INnovative Steroid Treatment to reduce Asthma development in children after first-time Rhinovirus-induced wheezing (INSTAR): protocol for a randomised placebo-controlled trial. BMJ Open. 2025 Jul 30;15(7):e103530. doi: 10.1136/bmjopen-2025-103530.

Reference Type: DERIVED

PMID: 40738645 (View on PubMed)

Other Identifiers

2024-515350-25-01

Identifier Type: CTIS

Identifier Source: secondary_id

2018/1495

Identifier Type: -

Identifier Source: org_study_id