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

• ClinicalTrials.gov Identifier: NCT03889743
• Recruitment Status: Recruiting
• First Posted: March 26, 2019
• Last Update Posted: May 10, 2023
• Sponsor: St. Olavs Hospital
• Collaborators: Turku University Hospital; Karolinska University Hospital; Haukeland University Hospital; University Hospital, Akershus; Helse Stavanger HF; University Hospital of North Norway; Ullevaal University Hospital
• Information provided by (Responsible Party): St. Olavs Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Asthma; Inflammation	Drug: Dexamethasone treatment during 3 days; Drug: placebo treatment during 3 days	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 280 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Innovative Steroid Treatment to Reduce Asthma Development in Children After First-time Rhinovirus Induced Wheezing - the INSTAR Study
• Actual Study Start Date: May 1, 2019
• Estimated Primary Completion Date: May 2025
• Estimated Study Completion Date: May 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dexamethasone	Drug: 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.
Placebo Comparator: controls	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.; Other Name: lactose

Outcome Measures

Primary Outcome Measures :

1. time to a new physician-confirmed wheezy episode within 24 months after study entry [ Time Frame: 24 months ]
2. time to need for a regular controller medication for asthma within 24 months after study entry [ Time Frame: 24 months ]

Secondary Outcome Measures :

1. duration of respiratory symptoms [ Time Frame: 24 months ]
   as determined at the first episode of acute breathing difficulty within 24 months of study entry
2. severity of respiratory symptoms [ Time Frame: 24 months ]
   as determined at the first episode of acute breathing difficulty within 24 months of study entry
3. the number of episodes with acute breathing difficulty since start of study medication [ Time Frame: 24 months ]
   as determined at scheduled follow-up visit within 24 months of study entry
4. the duration of episodes with acute breathing difficulty since start of study medication [ Time Frame: 24 months ]
   as determined at scheduled follow-up visit within 24 months of study entry
5. the degree of pulmonary hyperreactivity [ Time Frame: 24 months ]
   as determined at scheduled follow-up visit within 24 months of study entry
6. quality of life: Infant Toddler Quality of Life© (ITQOL©) questionnaire [ Time Frame: 24 months ]
   as determined at scheduled follow-up visit within 24 months of study entry
7. body height [ Time Frame: 24 months ]
8. body weight [ Time Frame: 24 months ]

Eligibility Criteria

• Ages Eligible for Study: 3 Months to 24 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)
• 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

Contacts and Locations

Contacts

Contact: Henrik Døllner, md phd; 0047 73559531; henrik.dollner@ntnu.no

Locations

Finland

Turku University Hospital; Recruiting

Turku, Finland

Contact: Tuomas Jartti, md phd

Norway

Haukeland University Hospital; Recruiting

Bergen, Norway

Contact: Marit Vollsaether, md phd

Akershus University Hospital; Recruiting

Oslo, Norway

Contact: Chris Inchley, md phd

Ullevål University Hospital; Recruiting

Oslo, Norway

Contact: Håvard Skjerven

Stavanger University Hospital; Recruiting

Stavanger, Norway

Contact: Knut Øymar, md phd

University Hospital of North Norway; Recruiting

Tromsø, Norway

Contact: Claus Klingenberg, md phd

St Olavs Hospital; Recruiting

Trondheim, Norway

Contact: Henrik Døllner, md phd henrik.dollner@ntnu.no

Sweden

Karolinska Universitetssjukhuset; Recruiting

Stockholm, Sweden

Contact: Jon Konradsen, md phd

Sponsors and Collaborators

St. Olavs Hospital

Turku University Hospital

Karolinska University Hospital

Haukeland University Hospital

University Hospital, Akershus

Helse Stavanger HF

University Hospital of North Norway

Ullevaal University Hospital

Investigators

• Study Director: Elisabeth Selvaag; St. Olavs Hospital

More Information

• Responsible Party: St. Olavs Hospital
• ClinicalTrials.gov Identifier: NCT03889743
• Other Study ID Numbers: 2018/1495; 2015-001077-40 ( EudraCT Number )
• First Posted: March 26, 2019
• Last Update Posted: May 10, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Olavs Hospital:

Respiratory Sounds; Steroids; Rhinovirus

Additional relevant MeSH terms:

Asthma; Inflammation; Respiratory Sounds; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Pathologic Processes; Signs and Symptoms, Respiratory; Dexamethasone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents