Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial
Por:
Marty, F, Vidal-Puigserver, J, Clark, C, Gupta, S, Merino E, Garot, D, Chapman, M, Jacobs, F, Rodriguez-Noriega, E, Husa, P, Shortino, D, Watson, H, Yates, P and Peppercorn, A
Publicada:
1 feb 2017
Categoría:
Pulmonary and respiratory medicine
Resumen:
Background Neuraminidase inhibitors are effective for the treatment of
acute uncomplicated influenza. However, there is an unmet need for
intravenous treatment for patients admitted to hospital with severe
influenza. We studied whether intravenous zanamivir was a suitable
treatment in this setting.
Methods In this international, randomised, double-blind, double-dummy,
phase 3 trial, we recruited patients aged 16 years or older with severe
influenza admitted to 97 hospitals from 26 countries. We randomly
assigned patients (1:1:1 stratified by symptom onset <= 4 days or 5-6
days) to receive 300 mg or 600 mg intravenous zanamivir, or
standard-of-care (75 mg oral oseltamivir) twice a day for 5-10 days;
patients were followed up for 28 days. The randomisation schedule,
including stratification, was generated using GlaxoSmithKline's RandAll
software. Patients, site study staff, and sponsor were masked to study
treatment. The primary endpoint was time to clinical response-a
composite of vital sign stabilisation and hospital discharge-in the
influenza-positive population. The trial was powered to show an
improvement of 1.5 days or greater with 600 mg intravenous zanamivir.
Pharmacokinetic, safety, and virology endpoints were also assessed. This
trial is registered with ClinicalTrials.gov, number NCT01231620.
Findings Between Jan 15, 2011, and Feb 12, 2015, 626 patients were
randomly assigned to receive 300 mg intravenous zanamivir (n=201), 600
mg intravenous zanamivir (n=209), or 75 mg oral oseltamivir (n=205)
twice a day; 11 patients discontinued the study before receiving any
study treatment. 488 (78%) of 626 patients had laboratory-confirmed
influenza. Compared with a median time to clinical response of 5.14 days
in the 600 mg intravenous zanamivir group, the median time to clinical
response was 5.87 days (difference of -0.73 days, 95% CI -1.79 to 0.75;
p=0.25) in the 300 mg intravenous zanamivir group and 5.63 days
(difference of -0.48 days, 95% CI -2.11 to 0.97; p=0.39) in the
oseltamivir group. Four patients with influenza A/H1N1pdm09 in the
oseltamivir group developed H275Y resistance mutations. Adverse events
were reported in 373 (61%) of treated patients and were similar across
treatment groups; the most common adverse events (300 mg intravenous
zanamivir, 600 mg intravenous zanamivir, oseltamivir) were diarrhoea (10
[5%], 15 [7%], 14 [7%]), respiratory failure (11 [5%], 14 [7%], 11
[5%]), and constipation (7 [3%], 13 [6%], 10 [5%]). 41 (7%) treated
patients died during the study (15 [7%], 15 [7%], 11 [5%]); the most
common causes of death were respiratory failure and septic shock.
Interpretation Time to clinical response to intravenous zanamivir dosed
at 600 mg was not superior to oseltamivir or 300 mg intravenous
zanamivir. All treatments had a similar safety profile in hospitalised
patients with severe influenza.
Filiaciones:
Marty, F:
Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA
Vidal-Puigserver, J:
Hosp Univ Son Espases, Serv Urgencies, Palma De Mallorca, Illes Balears, Spain
Clark, C:
William Beaumont Hosp, Dept Emergency Med, Royal Oak, MI 48072 USA
Gupta, S:
MV Hosp & Res Ctr, Lucknow, Uttar Pradesh, India
Merino E:
Hosp Gen Univ Alicante, Alicante, Spain
Garot, D:
Hop Bretonneau, Serv Reanimat Polyvalente, Tours, France
Chapman, M:
Royal Adelaide Hosp, Adelaide, SA, Australia
Jacobs, F:
Univ Libre Bruxelles, CUB Erasme, Dept Infect Dis, Brussels, Belgium
Rodriguez-Noriega, E:
Hosp Civil Guadalajara Fray Antonio Alcalde, Infectol, Guadalajara, Jalisco, Mexico
UDG Guadalajara, Inst Patol Infecciosa & Expt, CUCS, Guadalajara, Jalisco, Mexico
Husa, P:
Masaryk Univ, Dept Infect Dis, Fac Med, Brno, Czech Republic
Univ Hosp Brno, Brno, Czech Republic
Shortino, D:
PAREXEL Int, Res Triangle Pk, NC USA
Watson, H:
GlaxoSmithKline, Stockley Pk, Middx, England
Yates, P:
GlaxoSmithKline, Stevenage, Herts, England
Peppercorn, A:
GlaxoSmithKline, Boston, MA USA
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