A randomized controlled non-inferiority trial of placebo versus macrolide antibiotics for Mycoplasma pneumoniae infection in children with community-acquired pneumonia: trial protocol for the MYTHIC Study
Patrick M. Meyer Sauteur,
Michelle Seiler,
Romy Tilen,
Ester Osuna,
Margarete von Wantoch,
Semjon Sidorov,
Christoph Aebi,
Philipp Agyeman,
Florence Barbey,
Julia A. Bielicki,
Ludivine Coulon,
Beate Deubzer,
Alex Donas,
Ulrich Heininger,
Kristina Keitel,
Henrik Köhler,
Lisa Kottanattu,
Roger Lauener,
Anita Niederer-Loher,
Klara M. Posfay-Barbe,
Maren Tomaske,
Noémie Wagner,
Petra Zimmermann,
Franziska Zucol,
Stefanie von Felten,
Christoph Berger
Affiliations
Patrick M. Meyer Sauteur
Division of Infectious Diseases and Hospital Epidemiology, Children’s Research Center, University Children’s Hospital Zurich, University of Zurich
Michelle Seiler
Emergency Department, Children’s Research Center, University Children’s Hospital Zurich, University of Zurich
Romy Tilen
Division of Infectious Diseases and Hospital Epidemiology, Children’s Research Center, University Children’s Hospital Zurich, University of Zurich
Ester Osuna
Division of Infectious Diseases and Hospital Epidemiology, Children’s Research Center, University Children’s Hospital Zurich, University of Zurich
Margarete von Wantoch
Children’s Research Center, University Children’s Hospital Zurich, University of Zurich
Semjon Sidorov
Division of Infectious Diseases and Hospital Epidemiology, Children’s Research Center, University Children’s Hospital Zurich, University of Zurich
Christoph Aebi
Division of Pediatric Infectious Disease, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern
Philipp Agyeman
Division of Pediatric Infectious Disease, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern
Florence Barbey
Children’s Hospital Aarau
Julia A. Bielicki
Department of Infectious Diseases and Vaccinology, University of Basel Children’s Hospital (UKBB)
Ludivine Coulon
Department of Pediatrics, Department Mother-Woman-Child, Lausanne University Hospital
Beate Deubzer
Department of Pediatrics, Cantonal Hospital Graubuenden
Alex Donas
Emergency Department, Children’s Hospital of Central Switzerland
Ulrich Heininger
Department of Infectious Diseases and Vaccinology, University of Basel Children’s Hospital (UKBB)
Kristina Keitel
Division of Pediatric Emergency Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern
Henrik Köhler
Children’s Hospital Aarau
Lisa Kottanattu
Institute of Pediatrics of Southern Switzerland, EOC
Roger Lauener
Children’s Hospital of Eastern Switzerland St. Gallen
Anita Niederer-Loher
Children’s Hospital of Eastern Switzerland St. Gallen
Klara M. Posfay-Barbe
Children’s Hospital of Geneva, Geneva University Hospitals
Maren Tomaske
Department of Pediatrics, Triemli Hospital Zurich
Noémie Wagner
Children’s Hospital of Geneva, Geneva University Hospitals
Petra Zimmermann
Department of Pediatrics, University of Fribourg and Fribourg Hospital
Franziska Zucol
Department of Pediatrics, Cantonal Hospital Winterthur
Stefanie von Felten
Department of Biostatistics at Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich
Christoph Berger
Division of Infectious Diseases and Hospital Epidemiology, Children’s Research Center, University Children’s Hospital Zurich, University of Zurich
Abstract Background Mycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) in school-aged children. Macrolides are the first-line treatment for this infection. However, it is unclear whether macrolides are effective in treating M. pneumoniae CAP, mainly due to limitations in microbiological diagnosis of previous studies. The extensive global use of macrolides has led to increasing antimicrobial resistance. The overall objective of this trial is to produce efficacy data for macrolide treatment in children with M. pneumoniae CAP. Methods The MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3–17 years with clinically diagnosed CAP will be screened with a sensitive and commercially available M. pneumoniae-specific IgM lateral flow assay from capillary blood. Mycoplasma pneumoniae infection in screened patients will be verified retrospectively by respiratory PCR (reference test) and IgM antibody-secreting cell enzyme-linked immunospot (ELISpot) assay (confirmatory test for distinguishing between carriage and infection). Patients will be randomized 1:1 to receive a 5-day treatment of macrolides (azithromycin) or placebo. The co-primary endpoints are (1) time to normalization of all vital signs, including body temperature, respiratory rate, heart rate, and saturation of peripheral oxygen (efficacy), and (2) CAP-related change in patient care status (i.e., admission, re-admission, or intensive care unit transfer) within 28 days (safety). Secondary outcomes include adverse events (AEs), as well as antimicrobial and anti-inflammatory effects. For both co-primary endpoints, we aim to show non-inferiority of placebo compared to macrolide treatment. We expect no macrolide effect (hazard ratio of 1, absolute risk difference of 0) and set the corresponding non-inferiority margins to 0.7 and −7.5%. The “at least one” success criterion is used to handle multiplicity with the two co-primary endpoints. With a power of 80% to reject at least one null hypothesis at a one-sided significance level of 1.25%, 376 patients will be required. Discussion This trial will produce efficacy data for macrolide treatment in children with M. pneumoniae CAP that might help to reduce the prescription of antibiotics and therefore contribute to the global efforts toward reducing antimicrobial resistance. Trial registration ClinicalTrials.gov, NCT06325293. Registered on 24 April 2024
