KIDS-STEP_Betamethasone Therapy in Hospitalised Children With CAP

Study Overview
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Brief Summary
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The purpose of this study is to concurrently evaluate whether adjunct treatment with corticosteroids in children hospitalized with CAP is more effective in terms of the proportion of children reaching clinical stability and whether such adjunct treatment is no worse in terms of CAP relapse.

Detailed Description
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The incidence of community-acquired pneumonia (CAP) in young children remains high (20- 30/1000 child-years) even in high-income settings with routine pneumococcal vaccination, and is associated with a high rate of hospitalisation (around 10/1000 child-years). In low-and middle-income settings, pneumonia is the leading infectious cause of death in children less than 5 years of age. In high-income settings, working mothers of children hospitalised with CAP have been reported to loose on average 4.2 workdays compared with 1.7 workdays for children with CAP managed in primary care. In addition to this economic burden, there is a substantial impact on quality of life for the affected child and the family. Children who are admitted with CAP experience on average 13 nonroutine days with slightly shorter periods of decreased appetite (8.5 days), disordered sleep (4.5 days) and absence from routine out-of-home childcare (7.5 days). Any intervention that ensures rapid clinical stabilization allowing for early hospital discharge without negative impacts on the overall recovery in children hospitalised with CAP would therefore carry substantial socioeconomic benefits. Only few small trials have addressed the potential impact of oral steroid treatment in CAP during childhood. Nagy et al reported a significant reduction in fever duration and length of stay in children with severe CAP receiving methylprednisolone for 5 days compared with children receiving placebo in a randomised trial with 59 participants. A randomised trial comparing adjunct dexamethasone or methylprednisolone against standard of care (no placebo) planning to enroll 40 participants was being set up but has been withdrawn prior to recruitment (NCT01631916). A placebo-controlled randomised trial of adjunct corticosteroids in CAP complicated by pleural effusion and/or empyema with 56 participants has been completed (NCT01261546), but has not yet reported on its findings. An observational analysis using propensity scores found that adjunct corticosteroids were associated with a shorter hospital stay only in children also receiving beta-agonist therapy, concluding that any benefit might only be seen in children with acute wheezing. All in all, there is a lack of pragmatic randomized controlled trials ( RCT) with sufficient power and high external validity to provide a definitive answer to the question of the effect of adjunct steroids in children hospitalised with CAP. Infection-related unwanted effects of adjunct steroids are potentially relevant in the context of childhood CAP. A higher proportion of children hospitalised with CAP reaching early clinical stability would only be desirable if this were shown not to be offset by a higher rate of clinically relevant CAP recurrence. A rebound phenomenon after corticosteroid discontinuation has been postulated to explain a higher rate of infection recurrence (19% compared with 9% in placebo group) among adults. Data from a recent individual patient data metaanalysis, however, indicate that an increased risk of CAP recurrence may be rather associated with longer duration of adjunct steroids in adults with CAP. To our knowledge, the question about the effect of adjunct steroid treatment in childhood CAP in relation to a postulated rebound phenomenon measured clinically as CAP recurrence has not been formally addressed in a trial. CAP-specific readmission rates for children are low at around 5%. In bronchiolitis, another acute lower respiratory tract infection for which oral corticosteroid treatment has been investigated, an increased risk of hospital revisits associated with steroid treatment could not be identified in a Cochrane metaanalysis.

Official Title
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A Randomised Placebo-controlled Multi-centre Effectiveness Trial of Adjunct Betamethasone Therapy in Hospitalised Children With Community Acquired Pneumonia (CAP)

Conditions
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Community-acquired Pneumonia

Intervention / Treatment
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* Drug: Celestamine®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body weight between 5 kg and 45 kg Admission to hospital (i.e. assignment of an inpatient case number) Clinical diagnosis of CAP (according to predefined criteria) Parent and/or child (as age-appropriate) willing to accept all possible randomised allocations and to be contacted by telephone weekly up to and including at 4 weeks after randomisation Informed consent form for trial participation signed by parent Exclusion Criteria: Presence of local chest complications Chronic underlying disease associated with an increased risk of very severe CAP or CAP of unusual aetiology Bilateral wheezing without focal chest signs AND clinical indication for primary administration of steroids (most likely to represent respiratory tract infection affecting the medium airways, i.e. not pneumonia) Admission to hospital with a primary clinical diagnosis of bronchiolitis Inability to tolerate oral medication Documented allergy or any other known contraindication to any trial medication Subacute or chronic conditions requiring higher betamethasone equivalent or known primary or secondary adrenal insufficiency Known diabetes mellitus (type 1) Hospitalisation within the last two weeks preceding current admission with the possibility that pneumonia could be hospital-acquired or healthcare-associated Completion of a course of systemic corticosteroids within 2 weeks from enrolment for courses of >5 days Transfer for any reason to a non-participating hospital directly from the paediatric emergency department Parent are unlikely to be able to reliably participate in telephone follow-up because of significant language barriers Participation in another study with investigational drug within the 30 days preceding and during the present study Previous enrolment into the current study Enrolment of the investigator, his/her family members, and other dependent persons.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 14 Years

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: KIDS-STEP is a phase III strategic investigator-initiated, randomised, placebo-controlled, fully blinded multicentre superiority trial with two parallel groups
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Celestamine® N 0.5<br>oral betamethasone solution, once daily for two consecutive days at 0.1-0.2 mg/kg | Drug: Celestamine®<br>* Children in KIDS-STEP will be receiving either oral betamethasone (Celestamine®) or oral placebo dosed once daily for two consecutive days. Celestamine® N 0.5 liquidum is a betamethasone solution and will be used in the active comparator arm. Study medication will be administered orally once a day on two consecutive days. A standard dose of 0.1-0.2 mg/kg will be used. All doses used in KIDS-STEP fall into the range of recommended doses according to the Summary of Medical Product Characteristics.<br>|
| Placebo Comparator: Placebo<br>oral placebo matched to the product described above | Drug: Celestamine®<br>* Children in KIDS-STEP will be receiving either oral betamethasone (Celestamine®) or oral placebo dosed once daily for two consecutive days. Celestamine® N 0.5 liquidum is a betamethasone solution and will be used in the active comparator arm. Study medication will be administered orally once a day on two consecutive days. A standard dose of 0.1-0.2 mg/kg will be used. All doses used in KIDS-STEP fall into the range of recommended doses according to the Summary of Medical Product Characteristics.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to clinical stability | (i) The proportion of children clinically stable at 48 hours after randomization in the active treated group (oral betamethasone for 2 days) as compared to the control group (placebo) will be one primary outcome. | from randomization until hour 48 | 
| CAP-related re-admission measured by number of childs re-admitted to hospital due to CAP | (ii) The proportion of children with CAP-related readmission within 28 days after randomization comparing oral betamethasone and placebo will be the co-primary outcome. | from randomization until day 28 |