Statistical Analysis
Since this was a pilot study, no sample size or power calculations were used; We aimed to recruit 100 patients as a pragmatic approach to evaluate efficacy signals that could promote larger studies of nebulised UFH for the treatment of hospitalised patients with COVID-19. As this pilot study was not powered for definitive efficacy analysis, significance tests were 1-sided with a 10% significance level, an approach used in early phase clinical trials[14].
Treatment effects on survival rate were analysed by Fisher‘s exact text, while length of stay was analysed by Wilcoxon signed ranked test. In case of death during the study, a value of 29 days was assigned for the number of days of hospitalization. The time to hospital discharge was estimated by use of the Kaplan-Meier method and Hazard Ratio risk estimates by Cox model proportional risk analysis. The change in MOCS was analysed by Mann-Whitney. The number of days that each subject was both oxygen free and alive up to day 29 was determined. Fisher‘s exact text was used to assess the effect of UFH on the requirement for mechanical ventilation.
Both primary and secondary outcomes were measured using 3 datasets, with the ITT and mITT being the primary populations of interest:
ITT (Intention-to-treat), corresponding to all subjects who were randomised and, for those in the active treatment group, received at least one dose of nebulised UFH, and participated in at least one post-baseline assessment.
A modified ITT (mITT) population which excluded (from both arms of the ITT population) subjects admitted to ITU within 24 hrs of randomisation and subjects who died within 24 hrs of randomisation. Patients randomised to active treatment were required to have received at least 4 administrations of nebulised UFH, corresponding to 24 hours after randomisation.
PP (Per protocol), corresponding to all subjects who adhered to the major criteria in the protocol (e.g. all subjects who completed efficacy analyses, whose study drug compliance was between 75% and 125%), and all subjects who did not substantially deviate from the protocol. In addition, a post hoc analysis of the sub-group of PP patients who received at least 6 administrations of UFH was analysed; this group was called PP6.