1. The antiviral agent baloxavir (baloxavir marboxil) decreased duration of influenza symptoms significantly more than in patients treated with either placebo or oseltamivir.
2. Baloxavir reduced viral load significantly more 1 day after initiation of treatment than placebo or oseltamivir.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Emergence of viral strains resistant to traditional influenza antiviral agents has made development of novel agents a public health need. The agent baloxavir functions as a prodrug to a small molecule inhibitor of the influenza viral replication process. Animal studies using baloxavir have showed its efficacy in reducing both influenza viral load and associated mortality. This phase 2 and 3 study evaluated baloxavir in patients with acute uncomplicated influenza infection and showed the primary endpoint of time to alleviation of influenza symptoms was reduced in baloxavir patients relative to patients treated with placebo or oseltamivir. Viral load after 1 day of treatment was also found to be significantly reduced in the baloxavir group relative to the placebo or oseltamivir groups. Adverse events related to treatment were found at a higher rate in the oseltamivir compared to the baloxavir or placebo groups.
Strengths of this study include inclusion of patients from multiple countries, the randomized design of the phase 3 study, and the thorough profile of adverse events. Limitations include study of only generally healthy patients and study of patients without complicated or severe influenza cases.
Click to read the study in NEJM
Relevant Reading: Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil
In-Depth [randomized controlled trial]: These associated phase 2 and phase 3 trials enrolled patients between 2015 and 2017. Eligible patients had a fever, one or more respiratory symptoms, and symptoms lasting less than 48 hours. Patients were excluded if they had underlying conditions or were hospitalized for their illness. Symptoms were assessed on a standard scale and samples for influenza viral load were taken at standard time points. The primary outcome was time to alleviation of symptoms. For the phase 2 trial 400 patients were enrolled and 389 completed the study. Baloxavir was studied at doses of 10, 20, and 40mg and all doses lowered duration of symptoms compared to placebo (54.2, 51.0, 49.5, and 77.7 hours, respectively; P<0.05 for all baloxavir doses compared to placebo). Adverse events were reported in 23.0 to 27.0% of patients in the baloxavir dose groups and 29.0% of patients in the placebo group. The phase 3 trial had 1366 patients complete the trial and 1064 (n=456, 231, and 377 for baloxavir, placebo, and oseltamivir groups, respectively) were included in the intention-to-treat analysis as they were confirmed influenza positive. Influenza A(H3N2) infection was present in over 80% of patients in all trial groups. Median time to alleviation of symptoms was lower in baloxavir patients compared to placebo with both confirmed influenza infection (53.7 hours vs. 80.2 hours, P<0.001) and the general study population (65.4 hours vs. 88.6 hours, P<0.001). Both adolescents and adults experienced faster symptom alleviation with baloxavir. Baloxavir significantly reduced viral load 1 day after treatment initiation compared to both oseltamivir and placebo treated patients. Adverse events were found in 20.7, 24.6, and 24.8% of patients in the baloxavir, oseltamivir, and placebo groups, respectively.
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