For K1, the estimated sample size in both study groups was 588, based on assumptions that the risk of infection with SARS-CoV-2 would be 5% for the placebo group and 2% for the vaccine group. Considering a 10% dropout rate and 5% baseline seropositivity or RT-PCR positivity, it was calculated that 680 subjects would be screened in both groups of K1. Total sample sizes were calculated as 7545 for the vaccine group and 3773 for the placebo group in order to be able to detect a minimum clinically significant difference of 1% (with estimated incidence rates of 1% for the vaccine group and 2% for the placebo group) in a two-sided hypothesis testing design with 95% CIs. With the addition of a 10% dropout rate and 5% seropositivity or RT-PCR positivity at baseline, the total sample size was determined to be 13 000 participants, of whom 1360 would be in K1 and 11 640 in K2.

The initial study protocol indicated that if the efficacy of the vaccine could be demonstrated with an interim analysis done with 40 confirmed cases of COVID-19, masking would be removed and participants in the placebo group would be offered CoronaVac. Because the study was initiated with health-care workers at high risk, it was estimated that 5% of the placebo group (29 participants) and 2% of the vaccine group (11 participants) would have to be infected to demonstrate a clinical efficacy of 60%. If those rates could not be obtained in K1, enrolment would begin for K2. The enrolment rate remained very low for K1 and, after an interim safety analysis on Nov 18, 2020, the data and safety monitoring board decided to start enrolment into K2. Although the prespecified number of COVID-19 cases for the interim efficacy analysis was 40, as the incidence throughout Turkey increased rapidly, the Ministry of Health asked for a preliminary analysis to be able to grant an emergency use authorisation for CoronaVac. Therefore, a non-predefined interim analysis was done on Dec 24, 2020, with 29 cases, which showed an efficacy above 60%. Afterwards, as community vaccination commenced, study participants were unmasked starting with K1 in blocks. The masked follow-up of those participants continued until their code was unmasked, and 41 COVID-19 cases were attained by the time all of the codes were unmasked and the prespecified interim analyses for efficacy and safety were done. Therefore, the cutoff date for inclusion in the analyses of the primary efficacy outcome and the secondary efficacy outcomes was the unmasking date of each participant in both groups. The follow-up period was defined as the period (days) from the randomisation date to the unmasking date. The data lock date was March 16, 2021. Safety data in the CoronaVac intention-to-treat group were gathered in an unmasked manner after the unmasking date, and an extended safety analysis until the data lock date is also presented.

All analyses were done using SPSS for Windows (version 25.0). Descriptive analyses were presented using mean and SD for continuous variables and frequency and percentage for categorical variables. 95% CI was presented for efficacy, calculated as events per COVID-19-free person-years (ie, the sum of RT-PCR-confirmed COVID-19 cases divided by the sum of time from vaccine protection to diagnosis or unmasking).

Time to diagnosis of COVID-19 from the time of anticipated vaccine protection in both groups was presented with Kaplan-Meier survival curves. Safety analyses were done in the intention-to-treat population. Because the study product is an inactivated vaccine, a single dose was not expected to be as efficacious as two doses, and the primary efficacy analysis was therefore done in the per protocol population (defined as participants who received two doses of vaccine or placebo in accordance with group allocation. To compare adverse events between the study groups, the χ2 test was used when the χ2 condition was met; otherwise, Fisher's exact test was used. A Mantel-Haenszel test of trend was used in the analysis of the positive anti-RBD antibody results among age groups within both sexes. A log-rank test was used for the comparison of follow-up duration between the treatment groups. The independent data and safety monitoring board monitored the quality of evidence, adverse events, revisions in line with the current literature, individual privacy, and data reliability from the planning stage to the end of the study.

This study is registered with ClinicalTrials.gov (NCT04582344).

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