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Antiviral favipiravir was associated with significant reductions in influenza viral titers and median time to cessation of virus detection, but results for time to influenza illness alleviation were mixed, two international phase III trials found.

The US316 trial found that favipiravir was tied to a significant 14.4-hour reduction in median time to illness alleviation versus placebo (median 84.2 vs 98.6 hours, respectively, P=0.004), while the US317 trial found there was no significant difference between the drug and placebo (median 77.8 vs 83.9 hours), reported Frederick Hayden, MD, of the University of Virginia Health System in Charlottesville, and colleagues, writing in the .

Both trials randomized otherwise healthy adults ages 18-80 with at least two moderate to severe influenza-like symptoms and fever, and a positive test for or unknown exposure to influenza. US316 was conducted in 14 countries in the U.S., Africa, Europe, Asia, Australia, and New Zealand from January 2014 to March 2015. US317 was conducted in 10 countries and territories in the Americas from December 2013 to February 2015.

Patients were randomized 1:1 in US316 and 3:1 in US317 to receive either oral favipiravir or placebo.

In US316, the intention-to-treat population included 301 favipiravir and 322 placebo patients. Patients were a mean age of 41, 59% were women, and 78% were white. Notably, 78% were unvaccinated for the current influenza season. In US317, the intention-to-treat population included 526 favipiravir and 169 placebo patients.

There was no significant difference in time to return to normal activity between the two groups in both trials. Both trials found a significant median time to cessation of infectious virus detection in the favipiravir group compared with placebo. Mean viral titers also decreased more rapidly for those in the favipiravir group, the authors noted.

Regarding safety, a higher proportion of patients in the favipiravir group in both trials experienced treatment-emergent adverse events (AEs) -- 30.7% vs 25.9%, respectively, in US316 and 28.0% vs 25.1% in US317. Diarrhea, nausea, and urinary tract infection were the most common AEs, and they were typically mild or moderate, the authors said.

They added that in US316, five placebo patients and one favipiravir patient developed pneumonia. Serious treatment-emergent AEs included breast cancer and malignant melanoma in the placebo group and pneumonia in the favipiravir group in US316. In US317, treatment-emergent AEs in the favipiravir group included thyroid cancer, asthma exacerbation, pneumonia, colitis, and staphylococcal bacteremia. None of these AEs were judged to be related to the study drug, the authors said.

Mean uric acid levels increased in the favipiravir group versus baseline in the favipiravir group, but the authors noted that this "improved or resolved" by day 15, and there were no episodes of acute gout.

Hayden and colleagues pointed out that recipients who weighed at least 80 kg had a more "modest reduction" in time to illness alleviation -- meaning that a higher dose may be required "in some recipients to reliably obtain inhibitory concentrations," the team wrote.

"The optimal dose regimens for favipiravir need further study, particularly in heavier patients and in serious influenza," the researchers added.

Other limitations, they said, included the lack of a direct comparison to a proven influenza antiviral and that the trial did not assess participants for "emergence of influenza variants with reduced favipiravir susceptibility."

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