Randomized trial of amoxicillin vs. placebo for pneumonia in Pakistan: A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP)

BACKGROUND: World Health Organization (WHO) recommends oral amoxicillin in fast breathing pneumonia while recent trial evidence indicates that non-treatment might be non-inferior. METHODS: A double blind randomized parallel placebo-controlled non-inferiority trial was conducted in slums of Karachi, Pakistan. Children 2-59 months at primary health care centres fulfilling WHO criteria for fast-breathing pneumonia without danger signs were randomized to three days of placebo (test treatment) or amoxicillin using WHO weight bands. Primary outcome was cumulative treatment failure from randomization to completion of 3 days of treatment. A priori non-inferiority margin was set based on treatment failure of 3.5% in amoxicillin and 1.75% in placebo arm (NI margin of 1.75%). RESULTS: Between November 9 2014 and November 30 2017, 4002 children were randomized; placebo (n=1999) and amoxicillin (n=2,003). Per protocol failure rates for placebo group were 4.9 % (995/ 1927) and amoxicillin group were 2.6 %( 51/1929); difference 2.23 %( Upper bound of 95 % CI 3.24; P Value <0.001), also similar by intention to treat analysis. Fever, anaemia and wheeze predicted treatment failure. Number-Needed-to-Treat to prevent each failure was 44 (95 % CI 31-80). Mortality rates were 0.05% with one death per group. Relapse rates were 2.2 % and 3.1 % in the placebo and standard arms respectively. CONCLUSIONS: Non-inferiority was not established for placebo over amoxicillin in fast breathing pneumonia as difference in treatment failure was 2.3%, above the pre-specified margin of 1.75%. Low failure rates in placebo and high number needed to treat suggests that implications may be context specific. Trial Registration Number: ClinicalTrials.gov number NCT02372461