Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND Influenza can cause significant morbidity and mortality in subjects at high risk for complications, including the elderly (age >or=65 years) and those with chronic respiratory, cardiovascular, or metabolic conditions. Effective prophylaxis can significantly reduce the disease burden in this population. Previous studies conducted primarily in non-high-risk subjects have reported the efficacy of inhaled zanamivir in preventing influenza. OBJECTIVE This study investigated the efficacy and safety of zanamivir in preventing influenza in community-dwelling adult and adolescent subjects at high risk for complications of influenza. METHODS This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in community-dwelling subjects aged >or=12 years who were at high risk for developing complications of influenza, were able to use the Diskhaler device (Glaxo Group Limited, Research Triangle Park, North Carolina), and were able to take the first dose of study medication within 5 days of laboratory-confirmed local influenza activity. Eligible subjects were randomized to receive inhaled zanamivir 10 mg or placebo once daily for 28 days. The primary end point was the proportion of randomized subjects who developed symptomatic influenza during prophylaxis, as confirmed by culture and/or serology. All adverse events (AEs) occurring after the first dose of study medication were recorded. RESULTS The study enrolled 3363 subjects, of whom 58% were female and 93% were white; the mean age of participants was 60.4 years (range, 12-94 years), and 4% were adolescents. Significantly fewer zanamivir-treated subjects developed symptomatic, laboratory- confirmed influenza during prophylaxis compared with placebo recipients (4/1678 vs 23/1685, respectively), representing a relative risk (RR) of 0.17 (95% CI, 0.07-0.44; P < 0.001) and a protective efficacy of 83%. The incidence of complications was reduced in zanamivir-treated subjects compared with placebo recipients (1/1678 and 8/1685), representing an RR of 0.12 (95% CI, 0.02-0.73; P = 0.042) and a protective efficacy of 88%. The numbers of zanamivir recipients (151/1678 [9%]) and placebo recipients (169/1685 [ 10 % ] ) who developed symptomatic influenza-like illness regardless of laboratory confirmation did not differ significantly (RR = 0.86; 95% CI, 0.70-1.06), indicating that zanamivir was not effective in preventing influenza-like illness that was not caused by influenza infection. Similarly, there was no significant difference in the numbers of zanamivir and placebo recipients who developed laboratory-confirmed infection regardless of symptoms (39/1678 [2%] and 52/1685 [3%], respectively; RR = 0.76; 95% CI, 0.50-1.15). Of these, 64 subjects (35 and 29) were asymptomatic; seroconversion occurred in all but 1 subject, indicating that zanamivir prophylaxis did not prevent asymptomatic seroconversion. During prophylaxis, 51% of subjects in both treatment groups reported at least 1 AE. There were no major differences in the frequency or nature of AEs between groups. The most commonly reported AEs (>or=3% of subjects in each treatment group) were consistent with upper respiratory viral infection (headache: 17% zanamivir, 18% placebo; cough: 14% and 15%, respectively; throat and tonsil discomfort/pain: 13% and 14%). There were no differences between groups in the overall incidence of viral respiratory infections (5% in both groups) or ear, nose, and throat infections (2% in both groups). None of the analyzed isolates from confirmed cases of influenza exhibited reduced susceptibility to zanamivir or genotypic evidence of resistance. CONCLUSIONS Zanamivir, administered once daily for 28 days, was efficacious in preventing infection with the predominant circulating strains in the 2000- 2001 influenza season in the Northern Hemisphere (influenza A/New Calendonia/20/99-1ike and influenza B/ Sichuan/379/99-like) in these high-risk community- dwelling subjects aged >or=12 years. Zanamivir was well tolerated, with a safety profile comparable to that of placebo. No emergence of resistant virus was detected.