Canadian researchers drew similar conclusions from the extensive use of oseltamivir during the 2009 H1N1 pandemic. In a commentary in the Canadian Medical Association Journal, Matthew Cheng, MDCM, of McGill University Health Centre in Montreal, Canada, and colleagues wrote, “Even now, because there has been no RCT, it is not definitely known whether oseltamivir is efficacious…”
The Canadian authors conclude, “There is a strong ethical and clinical argument for replacing such ‘random’ care with randomized care.”
Many of the larger studies are collaborative, multinational trials linking study initiators in the United States, Canada, China, and France with clinical researchers in Southeast Asia, Australasia, and a dozen European countries.
China is currently running more randomized treatment trials than any other country, closely followed by the United States. So far, most countries hit hard by COVID-19 are hosting at least one randomized study, with the exception of Spain and Iran. This will likely change over time — the World Health Organization (WHO) is working on a randomized, multicenter adaptive trial that will cover “multiple sites,” so far unspecified.
WHO has identified a list of “promising candidates” for COVID-19 treatment. These include remdesivir (an investigational agent); lopinavir-ritonavir (approved for use in HIV) with or without interferon; investigational immunotherapies such as monoclonal and polyclonal antibodies; and convalescent sera.
In its January 27 statement, WHO did not support the antimalarial chloroquine (or hydroxychloroquine), ribavirin (used for hepatitis), or corticosteroids/steroids for COVID-19 clinical studies.
WHO is encouraging adaptive trial designs that test candidate drugs in sequence and can be launched quickly.
Four Multinational Trials Underway
Four COVID-19 multinational adaptive trials are already underway, one starting with the investigational agent remdesivir, and two with the HIV drug combination of lopinavir-ritonavir. The fourth has four therapy groups from the outset: remdesivir, lopinavir-ritonavir with or without interferon, and hydroxychloroquine.
Remdesivir is the first agent investigated in the NIH-sponsored trial ACTT, headed by Kalil at the University of Nebraska.
A broad-spectrum antiviral agent, remdesivir (GS-5734, Gilead Sciences Inc) has been studied as a potential treatment for Ebola, Marburg, MERS, and SARS without success. Kalil said remdesivir was chosen as the kick-off drug candidate for the NIH COVID-19 study on the basis of data from cell culture and two animal models.