Background
Objectives
Primary
Secondary
Tertiary
Subgroup
Methods
Study design and setting
Study population
Inclusion criteria
Exclusion criteria
Study interventions
Study endpoints
Primary outcome
Secondary outcomes
Study procedures
Screening, enrolment, and randomization
Follow up
Unblinding
Laboratory testing
Microbiology testing
Other testing
Data handling
Safety and adverse events
Statistical analysis
Sample size
Analysis
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 |