Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial

Duval, Xavier; van der Werf, Sylvie; Blanchon, Thierry; Mosnier, Anne; Bouscambert-Duchamp, Maude; Tibi, Annick; Enouf, Vincent; Charlois-Ou, Cécile; Vincent, Corine; Andreoletti, Laurent; Tubach, Florence; Lina, Bruno; Mentré, France; Leport, Catherine

At enrolment (day 0), a nasal swab for virological analysis was performed using a standard operating procedure (sample kit plus instructional video). Patients were allocated to treatment by a randomization list, with an arm ratio of 1:1:1, balanced by practitioner. A computer random number generator was used to select random permuted blocks of size 3. This randomisation code was given to the central hospital pharmacy that prepared blinded treatment units in conformity with good manufacturing practices (GMP). Each general practitioner received six treatment units and was told to distribute them by order of inclusion of his patients in the trial. Allocation was concealed through the similarity of all the containers and the impossibility for the GP to identify the treatment arm when opening the container. The three treatments were (1) oseltamivir capsule for oral use plus inhaled zanamivir, (2) oseltamivir plus inhaled placebo, (3) zanamivir plus oral placebo. Oseltamivir dosage was 75 mg orally twice daily; zanamivir dosage was 10 mg by oral inhalation using the commercialized GlaxoSmithKline Diskhaler, twice daily. Active drugs and placebo were kindly provided by Roche and Glaxo-SmithKline laboratories. A visiting nurse performed a nasal swab for virological analysis on day 2. Patients returned to their general practitioner at day 7 for a follow-up examination, and were contacted by phone on day 14. Patients, general practitioners assigning the patients, and outcome assessors (practitioners, virologists, patients), were blinded to treatment assignment throughout the study and statisticians until the end of the analysis.