[ { "local_id": "C1", "type": "empirical", "core": true, "statement": "In 5 placebo-controlled comparisons from 3 cluster-randomized trials (MORDOR in Niger, Malawi and Tanzania; AVENIR in Niger; CHAT in Burkina Faso), twice-yearly mass azithromycin to every child 1 to 59 months old lowered mortality among children 1 to 59 months by 14.1% (rate ratio 0.859, 95% CI 0.797 to 0.926; Holm-corrected p = 0.015; I² = 0%), and the reduction held with a common-effect model (0.859, 0.813 to 0.908) and with any one comparison left out (largest p = 0.044).", "evidence": [ {"result": "R1.k", "produced_by": "code/analyze.R"}, {"result": "R1.trials", "produced_by": "code/analyze.R"}, {"result": "R1.reduction_pct", "produced_by": "code/analyze.R", "tolerance": 0.1}, {"result": "R1.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R1.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R1.upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R1.p_holm_text", "produced_by": "code/analyze.R"}, {"result": "R1.i2_pct", "produced_by": "code/analyze.R", "tolerance": 0.1}, {"result": "R1.common_effect.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R1.common_effect.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R1.common_effect.upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R1.leave_one_out.max_p", "produced_by": "code/analyze.R", "tolerance": 0.0005}, {"result": "R1.robust", "produced_by": "code/analyze.R"} ], "depends_on": [], "falsified_if": "A re-run on the bundle's data gives a 95% CI for the pooled rate ratio that includes 1, or a leave-one-out estimate with p of 0.05 or more; or a re-extraction from the trials' reports moves the pooled rate ratio by more than 0.02.", "confidence": 0.9 }, { "local_id": "C2", "type": "negative_result", "core": true, "statement": "In the 3 cluster-randomized trials that gave azithromycin twice a year to infants 1 to 11 months old only, the approach the World Health Organization recommended in 2020 (AVENIR's infant arm in Niger, LAKANA in Mali, MIRAMA in Burkina Faso), infant mortality was not detectably lower than with placebo (rate ratio 0.971, 95% CI 0.867 to 1.086; p = 0.370), an interval that rules out a reduction larger than 13.3% and so excludes the 14.1% reduction seen when all children 1 to 59 months were treated; the estimate stayed near 1 with LAKANA's four-times-yearly arm instead (0.948, 0.856 to 1.050), without MIRAMA (0.963, 0.656 to 1.413), and with the 2 individually randomized infant trials added (0.969, 0.881 to 1.066).", "evidence": [ {"result": "R2.k", "produced_by": "code/analyze.R"}, {"result": "R2.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.p_text", "produced_by": "code/analyze.R"}, {"result": "R2.largest_reduction_allowed_pct", "produced_by": "code/analyze.R", "tolerance": 0.1}, {"result": "R1.reduction_pct", "produced_by": "code/analyze.R", "tolerance": 0.1}, {"result": "R2.excludes_p1_reduction", "produced_by": "code/analyze.R"}, {"result": "R2.with_quarterly_arm.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.with_quarterly_arm.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.with_quarterly_arm.upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.without_birth_history.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.without_birth_history.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.without_birth_history.upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.with_individual_infant.k", "produced_by": "code/analyze.R"}, {"result": "R2.with_individual_infant.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.with_individual_infant.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.with_individual_infant.upper", "produced_by": "code/analyze.R", "tolerance": 0.001} ], "depends_on": ["C1"], "falsified_if": "A re-run on the bundle's data gives a 95% CI for the infant-only rate ratio that lies wholly below 1, or whose lower limit is below 0.859 (the all-children estimate); or a further cluster-randomized trial of twice-yearly azithromycin to infants only, added to these, moves the pooled upper limit below 1.", "confidence": 0.8 }, { "local_id": "C3", "type": "empirical", "core": true, "statement": "Infant mortality was lower when all children 1 to 59 months were treated (rate ratio 0.823, 95% CI 0.707 to 0.958; 3 comparisons) than when only infants were (0.971), but the pre-registered meta-regression comparing the two strategies across trials did not establish a difference (ratio of rate ratios 1.187, 95% CI 0.974 to 1.447; p = 0.074; Holm-corrected p = 0.148); AVENIR's within-trial contrast of its all-children arm against its infant arm, estimated after registration from the two arms' printed mortality rates, was 0.830 (0.717 to 0.959).", "evidence": [ {"result": "R3.all_children_infant_rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R3.all_children_infant_lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R3.all_children_infant_upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R2.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R3.ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R3.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R3.upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R3.p_text", "produced_by": "code/analyze.R"}, {"result": "R3.p_holm_text", "produced_by": "code/analyze.R"}, {"result": "S.avenir_within_rates.rate_ratio", "produced_by": "code/summarize.R", "tolerance": 0.001}, {"result": "S.avenir_within_rates.lower", "produced_by": "code/summarize.R", "tolerance": 0.001}, {"result": "S.avenir_within_rates.upper", "produced_by": "code/summarize.R", "tolerance": 0.001} ], "depends_on": ["C1", "C2"], "falsified_if": "A re-run on the bundle's data gives an all-children infant rate ratio whose 95% CI includes 1; or AVENIR's own printed ratio of infant mortality in its all-children arm against its infant arm has a 95% CI that includes 1.", "confidence": 0.65 }, { "local_id": "C4", "type": "empirical", "core": false, "statement": "Across the 8 mass-distribution comparisons against placebo, mortality fell more where the control arm's mortality rate was higher: the log rate ratio changed by -0.078 per unit of the log control rate (95% CI -0.144 to -0.013; p = 0.027), allowing for strategy, in a pre-specified descriptive analysis resting on few comparisons, one of whose rates comes from birth histories.", "evidence": [ {"result": "R4.k", "produced_by": "code/analyze.R"}, {"result": "R4.slope", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R4.slope_lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R4.slope_upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R4.p", "produced_by": "code/analyze.R", "tolerance": 0.0005} ], "depends_on": [], "falsified_if": "A re-run gives a slope whose 95% CI includes 0, or the slope's interval includes 0 once the birth-history trial is left out.", "confidence": 0.45 }, { "local_id": "C5", "type": "negative_result", "core": false, "statement": "Giving azithromycin individually to every infant at a visit (the CHAT well-infant visit trial and NAITRE, both in Burkina Faso) did not detectably lower infant mortality: the pre-registered random-effects estimate from these 2 trials was uninformative (rate ratio 0.956, 95% CI 0.147 to 6.225), and a common-effect estimate added after registration was 0.963 (0.760 to 1.222).", "evidence": [ {"result": "R7.k", "produced_by": "code/analyze.R"}, {"result": "R7.rate_ratio", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R7.lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R7.upper", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "S.individual_infant_common.rate_ratio", "produced_by": "code/summarize.R", "tolerance": 0.001}, {"result": "S.individual_infant_common.lower", "produced_by": "code/summarize.R", "tolerance": 0.001}, {"result": "S.individual_infant_common.upper", "produced_by": "code/summarize.R", "tolerance": 0.001} ], "depends_on": [], "falsified_if": "A re-run gives a common-effect 95% CI wholly below 1.", "confidence": 0.6 }, { "local_id": "C6", "type": "empirical", "core": false, "statement": "In the 2 all-children trials that printed estimates by year of treatment (MORDOR in Niger and CHAT), the effect on mortality did not change across years (change in the log rate ratio -0.008 per year, 95% CI -0.207 to 0.191).", "evidence": [ {"result": "R5.slope_per_year", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R5.slope_lower", "produced_by": "code/analyze.R", "tolerance": 0.001}, {"result": "R5.slope_upper", "produced_by": "code/analyze.R", "tolerance": 0.001} ], "depends_on": [], "falsified_if": "A re-run gives a slope whose 95% CI excludes 0.", "confidence": 0.5 }, { "local_id": "C7", "type": "empirical", "core": false, "statement": "Of the 12 eligible registered trials whose primary completion was at least 12 months before the search, 3 had reported no mortality results in a report or on ClinicalTrials.gov: two that give azithromycin to infants at routine visits (SANTE in Mali, NCT03909737; ICARIA in Sierra Leone, NCT04235816) and one trachoma trial (TIRET in Ethiopia, NCT01202331).", "evidence": [ {"result": "R9.due", "produced_by": "code/analyze.R"}, {"result": "R9.unreported", "produced_by": "code/analyze.R"}, {"result": "R9.unreported_ncts", "produced_by": "code/analyze.R"} ], "depends_on": [], "falsified_if": "A report or posted results that predate the search, for any of the three, are found.", "confidence": 0.85 } ]