Merits, flaws in trials of drug for COVID-19

Scientists have recently reported mixed clinical results for the closely watched experimental COVID-19 drug remdesivir, with the Chinese trial finding no significant benefits while the preliminary data from the United States claimed patients receiving the drug had seen improvements.

Experts around the world said both studies have their merits and flaws. Nevertheless, current clinical evidence suggests remdesivir may not be the magic bullet it was assumed to be by some media outlets. More research into the drug's efficacy and side effects are necessary.

Due to the Chinese trial not reaching its target enrollment, and the US study not being peer-reviewed or published, their findings should be taken with a grain of salt, they said, adding the public should not rush to dismiss or endorse the drug.

On Thursday, the journal Lancet published peer-reviewed results of the drug's clinical trial in China, led by Cao Bin, vice-president of the China-Japan Friendship Hospital.

The study was based on 237 patients, far less than the intended sample size of 453 cases, and this deficiency was due to the steep decline in the total number of COVID-19 cases in China, the authors said.

The Chinese study was a double-blinded, randomized, controlled trial－the golden standard for clinical research. The study found that the median number of days to show clinical improvement in the remdesivir group was 21 days, not significantly different from that in the control group, which was 23.

The drug also did not significantly lower the mortality rate of patients. The test group had a morality rate of 14 percent, while that of the control group was 13 percent.

Meanwhile, both groups shared a similar ratio of patients who experienced adverse effects, with 66 percent and 64 percent in the testing and control groups respectively.

The most common adverse events in both groups were constipation, a low level of albumin in the blood, and a deficiency of red blood cells.

However, 18 patients in the test group dropped out of the study due to serious side effects such as respiratory failure, compared to four dropouts in the control group.

On Thursday, Cao said in his article on Breath-Circles, a Chinese media platform for respiratory medical professionals, that remdesivir did not reach the expected therapeutic results in his study, but at least the drug is proven to be generally safe.

But due to the study being underpowered, the Chinese authors cautioned against too much being read into their results. They suggested further research, especially with regard to exploring the drug's potency in early treatment or in conjunction with other antiviral treatments.

As for the US study, which is being conducted by the National Institute of Allergy and Infectious Diseases, preliminary results said patients who received remdesivir had a 31 percent faster recovery time than the control group, according to information released by the National Institutes of Health on Thursday.

The median recovery time was 11 days for treated patients compared with 15 days for those in the control group. The results also suggested a slight decrease in the mortality rate of 8 percent for the group receiving the drug versus 11.6 percent for the control group.

The US study, which began on Feb 21, was a double-blinded, randomized, controlled trial involving 1,063 patients. The NIH did not release information about the adverse effects or the dosage used in the experiment, but promised to release comprehensive and peer-reviewed data in a later report.

Cao told Chinese media that objectively speaking, the Chinese trial was more rigorously designed, but he admitted it was difficult to compare the two studies due to different experiment designs and endpoint criteria.

In the Chinese study, a patient could only be enrolled within 12 days of the onset of symptoms, so to avoid interference from other treatments and to ensure more accurate results. The US study did not have this requirement, according to the NIH.

In addition, the criteria for recovery were more lenient in the US study, Cao said. The US study defines the day of recovery as the first day on which the subject satisfies one of the following three categories: being hospitalized but not requiring supplemental oxygen, not being hospitalized but with limited activities, or not being hospitalized and with no limitations on activities.

The Chinese study had a six-point scale to describe a range of clinical status from discharged to hospitalized with ventilators to intensive care patients needing extracorporeal membrane oxygenation, a life support machine that pumps and oxygenates a patient's blood from outside the body.

Clinical improvement is documented if a patient's condition improves by two levels or more on the scale. "If remdesivir is really a wonder cure, then it should have shown an obvious therapeutic advantage compared with the control group," Cao told news outlet Caixin.

In a comment published in the Lancet, John Norrie, a professor of medical statistics and trial methodology at the University of Edinburgh in the United Kingdom, said that while the Chinese clinical trials were well designed, the results were inconclusive due to insufficient statistical power.

"However, a trial is not just its primary clinical outcome－there are important data on safety, viral load, and secondary outcomes," he said.

Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said the US study featured some encouraging results, but full assessment cannot be made without seeing the full publication of its outcomes.

"This is the first substantial evidence that remdesivir has genuine benefits, but they are certainly not dramatic," he said.