As scientists continue to search high and low for effective COVID-19 treatments, a new model study suggests that randomization, early patient enrollment, and treatment initiation in clinical trials may be keys to identifying effective antiviral drugs.
Researchers led by Shingo Iwami, Associate Investigator at the Kyoto University Institute for the Advanced Study of Human Biology (ASHBi), and Keisuke Ejima, Assistant Research Scientist at Indiana University Bloomington, reported their findings in PLOS medicine.
“Almost all of the antiviral clinical studies have not observed any significant effects against SARS-CoV-2, so we wanted to show why and what is important for an optimal study design,” said first author Shoya Iwanami, assistant professor at Nagoya University.
Given the conflicting results of past studies, Iwanami and colleagues used a mathematical model to first analyze longitudinal data from clinical research patients. By simulating the amount of virus in the upper respiratory tract samples, the team found that virus-producing cells died at different rates and classified the patients into those with fast, moderate, or slow virus decay.
Doctors use observational studies to assess whether and when patients should receive antiviral treatment based on their symptoms, as opposed to randomization, which blindly divides patients into treatment and control groups. Since slow decay can be linked to more severe disease, observational studies may have been limited to certain patients because they fail to capture the spectrum of virus dynamics and skew the results.
“We found that randomization is important for successful clinical trials because [differences in virus decay rates] can affect the effectiveness of antiviral drugs, ”explains Iwanami.
Aside from randomization, the researchers also found that timing could affect the effectiveness of potential drug candidates. Regardless of the virus disintegration group, their simulations showed that initiating treatment five days after symptoms began masked the drug’s effectiveness. Meanwhile, antiviral drug administration within the first day of onset of symptoms improved results across the board.
To mimic randomized controlled trials, which are considered the gold standard for evaluating interventions, the researchers incorporated hypothetical drugs with high rates of SARS-CoV-2 inhibition into their model. Because patients were often recruited without considering the timing of treatment in previous studies, the team’s model indicated that these clinical studies would have required more than 10,000 participants per group to provide statistically significant data on drug efficacy – a practical challenge in terms of drug efficacy Patient recruitment and resource availability.
In contrast, the team found that if patients were recruited and treated early within one day of the onset of symptoms, the sample size required for an antiviral agent with 95% inhibition was reduced to only 584 participants per group and 458 participants per group for 99% inhibition would sink. Ultimately, their results underline the importance of randomization as well as timely patient recruitment and the start of treatment in the evaluation of COVID-19 drug candidates.
“We could apply this process to other clinical trials or diseases. This model of clinical design can accelerate drug repositioning or the development of new drugs, ”says Iwanami, adding that studies are currently being conducted based on these recommendations.
Edited by Gary Cramer