Abstract
Background
Researchers around the world are urgently conducting clinical trials to develop new treatments for reducing mortality and morbidity related to COVID-19. However, due to unknown features of the disease and complexity of the patient population, traditional trial designs may not be optimal in such patients. We propose two independent clinical trials designs based on careful grouping of the expected characteristics of patient population. This could serve as a useful guide for researchers designing COVID-19 related Phase II/III trials.
Methods
Using the commonly utilized World Health Organization ordinal scale on patient status, we classify patients into three risk groups. In this approach, patients in Stages 3, 4 and 5 are categorized as the intermediate-risk group while patients in Stages 6 and 7 are categorized as the high-risk group. To ensure that an intervention, if deemed efficacious, is promptly made available to vulnerable patients, we propose a group sequential design with two interim analyses along with a final analysis and a toxicity monitoring rule for the intermediate-risk group. For the high-risk group, we propose a group sequential design with two interim analyses without toxicity monitoring.
Results
Based on different response rates, effect sizes, and power, required sample size and toxicity boundaries are calculated for each scenario. Sample size requirements for the designs with interim analyses are only marginally greater than the ones without. In addition, for both the intermediate-risk group and the high-risk group, conducting two interim analyses have identical required sample size compared with just one interim analysis. Additional issues that could potentially impact the trial are discussed.
Conclusions
We recommend using composite endpoints, with binary outcome for those in Stages 3, 4 and 5 with a power of 90% to detect an improvement of 20% in response rate, and 30 days mortality rate outcome for those in Stages 6 and 7 with a power of 90% to detect 15% (effect size) reduced mortality rate, in the COVID-19 trial design. For the intermediate-risk group, two interim analyses for efficacy evaluation along with toxicity monitoring are encouraged. For the high-risk group, two interim analyses without toxicity monitoring is advised.
Clinical Design for Phase II/III Clinical Trials for Testing Therapeutic Interventions in COVID-19 Patients