Small Trials of COVID-19 Treatments Need to Be Considered with Caution
Two small studies come to opposite conclusions about hydroxychloroquine for eliminating detectable COVID-19 coronavirus.
Two small trials, one in France and one in China, reported opposite results of testing hydroxychloroquine in patients with COVID-19. The report on the French trial results showed that 19 out of 26 patients in the treatment group had no detectable virus after treatment with either hydroxychloroquine or hydroxychloroquine and azithromycin. However, even in the treatment group 4 patients got worse with one dying, and another had to stop because the drug caused nausea. The French trial was an open-label, non-random design. This trial and the published report have been criticized for multiple flaws in data presentation and analysis (see PubPeer links below).
The report of the results was premature without information about the patient outcomes. But in the current pandemic situation, information such as that provided about detectable virus seems useful in deciding to test with a larger set of patients and consider for an additional clinical trials. Additionally, the work appears consistent with a summary of a Chinese trial with ~100 patients of a similar treatment, and the work was guided by reports (Yao et al. and Wang et al.) showing the effectiveness of chloroquine or hydroxychloroquine in reducing infection of cultured cells. Science writers, myself included, featured the results of the study as promising or encouraging.
Data from a Chinese trial with a random design for hydroxychloroquine treatment have now also been reported. Like the French trial with 36 patients, this is also a very small trial of only 30 patients: 15 in the control group and 15 in the treatment group. Both groups included patients of similar age, disease duration, and clinical presentation of COVID-19. Both groups included some patients with hypertension (5 in treatment and 3 in control), and each had a single patient with diabetes. The control group also included a patient with chronic obstructive pulmonary disease. Like the French study, one of the primary endpoints measured was the presence of the virus in the throat over the course of 7 days. Different than the French study, the Chinese study also reported patient outcomes at 14 days.
A confounding factor in the Chinese trial is that the patients received additional treatments. All patients received interferon alpha, 12 in the hydroxychloroquine treatment group received umifenovir (brand name Arbidol), 10 in the control group received umifenovir and 2 received the combination treatment lopinavir / ritonavir. Thus, hydroxychloroquine was not the only treatment variable in this study.
By 7 days, 14 patients in the treatment group and 13 in the control group were negative for detectable virus in a throat swab. By 14 days, all patients tested negative for the virus in a throat swab. All patients survived to 14 days. Both groups had patients with serious adverse effects, which were deemed not related to the hydroxychloroquine.
Both reports acknowledged that larger sample sizes were needed for statistically meaningful results. The Chinese trial report indicated at least 784 subjects were needed, the French trial reported that at least 48 subjects were needed. Neither trial has sufficient subjects for statistical validation of the results. Thus, as Dr. Fauci stated, they can be considered “anecdotal.”
Related Reading and Information
J. Chen, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J. Zhejiang Univ. (Med. Sci.) 49 (2020) DOI: 10.3785/j.issn.1008–9292.2020.03.03 {translated with Google translate}
X. Yao, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases ciaa237, DOI: 10.1093/cid/ciaa237
M. Wang, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30, 269–271 (2020). DOI: 10.1038/s41422–020–0282–0
J. Gao, et al. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 14, 72–73 (2020). DOI:10.5582/bst.2020.01047
Clinical Trials for “coronavirus” and “hydroxychloroquine” at clinicaltrials.gov
