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- Title
Phase 2b Study of Pimodivir (JNJ-63623872) as Monotherapy or in Combination With Oseltamivir for Treatment of Acute Uncomplicated Seasonal Influenza A: TOPAZ Trial.
- Authors
Finberg, Robert W; Lanno, Riin; Anderson, David; Fleischhackl, Roman; van Duijnhoven, Wilbert; Kauffman, Robert S; Kosoglou, Teddy; Vingerhoets, Johan; Leopold, Lorant
- Abstract
<bold>Background: </bold>Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A.<bold>Methods: </bold>In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated.<bold>Results: </bold>Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea.<bold>Conclusions: </bold>Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development.<bold>Clinical Trials Registration: </bold>NCT02342249, 2014-004068-39, and CR107745.
- Subjects
ANTIVIRAL agents; COMBINATION drug therapy; COMPARATIVE studies; DIARRHEA; DRUG resistance in microorganisms; HETEROCYCLIC compounds; INFLUENZA; RESEARCH methodology; MEDICAL cooperation; PROTEINS; PYRIDINE; RESEARCH; TIME; VIRAL physiology; VIRAL load; EVALUATION research; INFLUENZA A virus; RANDOMIZED controlled trials; BLIND experiment; ACUTE diseases; OSELTAMIVIR
- Publication
Journal of Infectious Diseases, 2019, Vol 219, Issue 6, p1026
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiy547