The coronavirus disease 2019 (COVID-19) pandemic that has been ongoing since 2019 is still ongoing and how to control it is one of the international issues to be addressed. Antiviral drugs that reduce the viral load in terms of reducing the risk of secondary infection are important. For the general control of emerging infectious diseases, establishing an efficient method to evaluate candidate therapeutic agents will lead to a rapid response. We evaluated clinical trial designs for viral entry inhibitors that have the potential to be effective pre-exposure prophylactic drugs in addition to reducing viral load after infection. We used a previously developed simulation of clinical trials based on a mathematical model of within-host viral infection dynamics to evaluate sample sizes in clinical trials of viral entry inhibitors against COVID-19. We assumed four measures as outcomes, namely change in log10-transformed viral load from symptom onset, PCR positive ratio, log10-transformed viral load, and cumulative viral load, and then sample sizes were calculated for drugs with 99 % and 95 % antiviral efficacy. Consistent with previous results, we found that sample sizes could be dramatically reduced for all outcomes used in an analysis by adopting inclusion/exclusion criteria such that only patients in the early post-infection period would be included in a clinical trial. A comparison of sample sizes across outcomes demonstrated an optimal measurement schedule associated with the nature of the outcome measured for the evaluation of drug efficacy. In particular, the sample sizes calculated from the change in viral load and from viral load tended to be small when measurements were taken at earlier time points after treatment initiation. For the cumulative viral load, the sample size was lower than that from the other outcomes when the stricter inclusion/exclusion criteria to include patients whose time since onset is earlier than 2 days was used. We concluded that the design of efficient clinical trials should consider the inclusion/exclusion criteria and measurement schedules, as well as outcome selection based on sample size, personnel and budget needed to conduct the trial, and the importance of the outcome regarding the medical and societal requirements. This study provides insights into clinical trial design for a variety of situations, especially addressing infectious disease prevalence and feasible trial sizes. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".