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

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.

Keywords: Anti-inflammatory; Antimicrobial; Atypical pneumonia; Azithromycin; Carriage; Colonization; Diagnosis; Resistance; Respiratory tract infection; Stewardship.

Fig. 1

Study flow. ASC antibody-secreting cell, CAP community-acquired pneumonia, ED emergency department, ELISpot enzyme-linked immunospot, Ig immunoglobulin, LFA lateral flow assay, NPS nasopharyngeal swab, PCR polymerase chain reaction

Fig. 2

Sensitivity of the sample size for the co-primary endpoint duration to normalization of vital signs with regard to the non-inferiority margin, ${\delta }_{\text{HR}}$, expecting no difference between treatments (hazard ratio [HR] = 1)

Fig. 3

Sensitivity of the sample size for the co-primary endpoint CAP-related change in patient care status with regard to the non-inferiority margin, ${\delta }_{\text{ARD}}$, expecting no difference between placebo and azithromycin (absolute risk difference = 0), assuming a probability for a change in patient care status of 0.05