Statistical methods for primary and secondary outcomes {20a}
infections, febrile neutropenia, fever
ADVERSE EVENT, NEUTROPENIC FEVER, FEBRILE NEUTROPENIA, ADVERSE EVENT, EVENT, INFECTIONS, SECONDARY, REGRESSION
This phase 3 trial will compare the efficacy of fosfomycin with that of ciprofloxacin in preventing the occurrence of at least one episode of neutropenic fever of infectious origin in a randomized non-inferiority design.The primary endpoint is febrile neutropenia of infectious origin. This analysis will be performed in the intention-to-treat (ITT) and in the per-protocol population (PP). The ITT population is defined as all patients who are eligible and randomized. The PP population consists of all patients who do not have major protocol deviations, as determined by the study PI, and have received prophylactic drugs for at least of 24 h.The rate of febrile neutropenia will be compared between the 2 arms with a chi-square test with 2-sided alpha of 0.05. The difference in the proportion and the associated 95% CIs will be provided. If, within either patient arm, the data suggest a possible difference in baseline incidence between the randomization strata, we will consider Cochran-Mantel–Haenszel test to examine the association between the incidence of febrile neutropenia and the study treatment with adjustment for the randomization strata. Logistic regression models will be performed to evaluate the treatment effect on the incidence of febrile neutropenia adjusting for stratification and other baseline patient characteristics.The analysis of the secondary endpoints will be performed as follows:Rate and type of documented infections with 2-sided alpha of 0.05. Again, logistic regression models will be performed to evaluate the treatment effect on the incidence of each event adjusting for stratification and other baseline patient’s characteristics.Amount of concomitant antibiotic utilization. The analysis will be performed with a 2-sample Survival will be analyzed using the Kaplan–Meier estimate. The K-M survival curves and medians (if estimable) along with their 2-sided 95% CIs will be provided for each treatment arm. The log-rank test will be used to compare treatment arms. Differences in survival without fever will also be assessed with a log-rank test at the 5% significance level.Adverse events. This end point is included in the safety analysis and will be performed in the SP. AE will be categorized as severe and non-severe, as this classification determines the notification procedure. Intensity of AE will be evaluated according to the National Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.034.The microbiological safety assessments will be analyzed as specified in item 33.