Statistical analysis
The primary endpoint was the need for patient transfer to ICU within 14 days of hospital admission as judged by the attending physicians. Based on available data from the literature at the time of study planning in the first half of 2020, we assumed that up to 25% of patients admitted to hospital with COVID-19 would require ICU care within 14 days of admission [Initially, we planned a 2:1 (SoC+Doxy:SoC) randomization and interim analyses, allowing the possibility of stopping for both success and futility once the status of 50% and 75% of participants were known. In addition, we allowed for a futility-only interim once the status of 25% of participants was known. Loss to follow up was assumed to be ≤5%. The trial required 80% power to detect a reduction in the risk of needing admission to ICU from 25% to 12.5% using a one-sided significance level of 2.5%. These criteria gave a sample size of 347 in total, 231 in the doxycycline + SoC arm and 116 in the SoC arm. Due to an error during the implementation of the randomisation, the app used a 1:1 allocation ratio. It should be noted that, for any given sample size, the power of a study using a 1:1 allocation ratio is greater than that of a study that uses any other allocation ratio. For full details of the initial and revised sample size calculations, see the supplemental appendix (