Variable/outcome | Hypothesis | Outcome measure | Methods of analysis |
---|---|---|---|
Primary | |||
Clinical cure (per-protocol) | Short-course (5-day) treatment with high-dose amoxicillin is non-inferior to long-course (10-day) treatment | At visit (day 14–21) composite of: 1. Defervesced on or before day 4 2. No more than 1 further fever spike until visit 3. No tachypnoea and decreased work of breathing 4. No additional antibacterials given Dichotomous | Logistic regression |
Secondary, between-group comparisons | |||
Absenteeism (caregiver, from work) | Short-course treatment is non-inferior to long-course treatment | Daily symptom diaries: self-reported number of caregiver-days absent from work (count) | Poisson regression |
Absenteeism (child, from daycare/school) | Short-course treatment is non-inferior to long-course treatment | Daily symptom diaries: reported number of child-days absent from daycare/school (count) | Poisson regression |
Mild drug adverse reactions | Fewer in short-course arm than in long-course arm | Daily symptom diaries: Reported number of child-days with diarrhoea, rash, abdominal pain, yeast infection (count) | Poisson regression |
Anaphylaxis and other severe drug adverse reactions | Fewer in short-course arm than in long-course arma | Daily symptom diaries, SAE reports. Dichotomous | Descriptive statistics |
Adherence to study medications | Better in short-course arm than in long-course arm | Daily symptom diaries, RA interview: “adherence” defined as > 80% amoxicillin doses given (<3 doses of initial 15 doses in short-course arm, < 6 doses in reference arm) Dichotomous | Logistic regression |
Recurrence of respiratory illness after primary outcome visit but before 30-day follow up | Short-course treatment is non-inferior to long-course treatment | RA interview. Dichotomous | Logistic regression |
Development of antibiotic-resistant organism (ARO) colonization | Less frequent in short-course arm than in long-course arm | Enteric swab testing: “new colonization”’ defined as 3–6 month swab ARO positivity in context of baseline swab ARO negativity. Dichotomous | Logistic regression |
Disruption of gut microbiome | Less marked in short-course arm than in long-course arm | Enteric swab testing: comparison of gut microbiome at 3–6 months to baseline gut microbiome. Continuous | Linear regression |
Tertiary, entire-cohort | |||
Distribution of salivary C-reactive protein in cohort | Mean will be greater than that observed in children with bronchiolitis but less than that observed in children with empyema | Salivary swab testing: continuous | Descriptive statistics expressed as mean (95% CI) |
Prevalence of high-level S. pneumoniae nasopharyngeal colonization | Majority of cohort will be positive | Nasopharnygeal swab (NPS) testing: Dichotomous | Percentage, with 95% CI |
Prevalence of Mycoplasma detection | Minority of cohort will be positive | NPS testing: Dichotomous | Percentage, with 95% CI |
Subgroup analyses | |||
Older (age 5–10 years) vs. younger (age <5 years) | Older age group will have higher salivary CRP values, lower rates of S. pneumoniae high-level colonization, more Mycoplasma positivity, and decreased rates of clinical cure | Clinical cure (as defined above) | Logistic regression with an interaction term between subgroup and treatment variables |
Higher vs. lower salivary CRP | Higher salivary CRP will be associated with decreased rates of clinical cure | Clinical cure | Logistic regression with an interaction term between subgroup and treatment variables |
Virus/Mycoplasma detected in baseline NPS vs. no virus detected (for primary outcome) | Detection of a virus or Mycoplasma will not affect observed rates of clinical cure | Clinical cure | Logistic regression with an interaction term between subgroup and treatment variables |
Sensitivity analyses – for primary outcome only | |||
Intention-to-treat | Results will remain robust | Clinical cure | Logistic regression |
Strict per-protocol (those with adherence >80% and radiologist-verified pneumonia) | Results will remain robust | Clinical cure | Logistic regression |