Clinical trial NCT03474991: KIDS-STEP_Betamethasone Therapy in Hospitalised Children With CAP
Official title: A Randomised Placebo-controlled Multi-centre Effectiveness Trial of Adjunct Betamethasone Therapy in Hospitalised Children With Community Acquired Pneumonia (CAP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Community-acquired Pneumonia
Lead sponsor: University Children's Hospital Basel
Sponsor class: OTHER
Collaborators: name: Swiss National Fund for Scientific Research
name: University Hospital, Basel, Switzerland
name: SwissPedNet
First posted: 2018-03-23
Enrollment: 510
Sex: ALL
Minimum age (years): 6
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: KIDS-STEP is a phase III strategic investigator-initiated, randomised, placebo-controlled, fully blinded multicentre superiority trial with two parallel groups
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: time to clinical stability
timeFrame: from randomization up to 2 days
measure: CAP-related re-admission measured by number of childs re-admitted to hospital due to CAP
timeFrame: from randomization until day 28
Secondary outcomes:
Other outcomes:
Locations:
city: Bochum
country: Germany
facility: Universitätsklinikum der Ruhr-Universität Bochum, Klinik für Kinder- und Jugendmedizin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf, Klinik für Allgemeine Pädiatrie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Zentrum für Kinder und Jugendmedizin Freiburg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Klinik für Kinder- und Jugendmedizin
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau, Klinik für Kinder u. Jugendliche
city: Basel
country: Switzerland
facility: University of Basel Children's Hospital (UKBB)
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Geneva
country: Switzerland
facility: Geneva University Hospital, Department of Pediatrics
city: Lausanne
country: Switzerland
facility: Centre hospitalier universitaire vaudois
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital, Kinderspital
city: Saint Gallen
country: Switzerland
facility: Ostschweizer Kinderspital
city: Villars-sur-Glâne
country: Switzerland
facility: Kantonsspital- Freiburger Spital (HFR)
city: Zürich
country: Switzerland
facility: University-Childrens Hospital Zürich
Study officials:
affiliation: University of Basel Children's Hospital (UKBB)
name: Johannes van der Anker, Prof MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kohns Vasconcelos M, Meyer Sauteur PM, Keitel K, Santoro R, Heininger U, van den Anker J, Bielicki JA. Strikingly Decreased Community-acquired Pneumonia Admissions in Children Despite Open Schools and Day-care Facilities in Switzerland. Pediatr Infect Dis J. 2021 Apr 1;40(4):e171-e172. doi: 10.1097/INF.0000000000003026. No abstract available.
citation: Kohns Vasconcelos M, Meyer Sauteur PM, Santoro R, Coslovsky M, Lura M, Keitel K, Wachinger T, Beglinger S, Heininger U, van den Anker J, Bielicki JA. Randomised placebo-controlled multicentre effectiveness trial of adjunct betamethasone therapy in hospitalised children with community-acquired pneumonia: a trial protocol for the KIDS-STEP trial. BMJ Open. 2020 Dec 29;10(12):e041937. doi: 10.1136/bmjopen-2020-041937.