Intravenous zanamivir or oral oseltamivir for hospitalised
patients with influenza: an international, randomised,
double-blind, double-dummy, phase 3 trial

J 2017

Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial

MARTY, Francisco M., Joan VIDAL-PUIGSERVER, Carol CLARK, Sandeep K. GUPTA, Esperanza MERINO et. al.

Basic information

Original name

Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial

Authors

MARTY, Francisco M. (840 United States of America), Joan VIDAL-PUIGSERVER (724 Spain), Carol CLARK (840 United States of America), Sandeep K. GUPTA (356 India), Esperanza MERINO (724 Spain), Denis GAROT (250 France), Marianne J. CHAPMAN (36 Australia), Frédérique J. JACOBS (56 Belgium), Eduardo RODRIGUEZ-NORIEGA (56 Belgium), Petr HUSA (203 Czech Republic, guarantor, belonging to the institution), Denise SHORTINO (840 United States of America), Helen A. WATSON (826 United Kingdom of Great Britain and Northern Ireland), Phillip J. YATES (826 United Kingdom of Great Britain and Northern Ireland) and Amanda F. PEPPERCORN (840 United States of America)

Edition

LANCET RESPIRATORY MEDICINE, OXFORD, ELSEVIER SCI LTD, 2017, 2213-2600

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30218 General and internal medicine

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 21.466

RIV identification code

RIV/00216224:14110/17:00096393

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/S2213-2600(16)30435-0

UT WoS

000396349100025

Keywords in English

zanamivir; oseltamivir; influenza

Abstract

V originále

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.

Citovat

MARTY, Francisco M., Joan VIDAL-PUIGSERVER, Carol CLARK, Sandeep K. GUPTA, Esperanza MERINO, Denis GAROT, Marianne J. CHAPMAN, Frédérique J. JACOBS, Eduardo RODRIGUEZ-NORIEGA, Petr HUSA, Denise SHORTINO, Helen A. WATSON, Phillip J. YATES and Amanda F. PEPPERCORN. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. LANCET RESPIRATORY MEDICINE. OXFORD: ELSEVIER SCI LTD, 2017, vol. 5, No 2, p. 135-146. ISSN 2213-2600. Available from: https://dx.doi.org/10.1016/S2213-2600(16)30435-0.

@article{1376993,
   author = {Marty, Francisco M. and VidalandPuigserver, Joan and Clark, Carol and Gupta, Sandeep K. and Merino, Esperanza and Garot, Denis and Chapman, Marianne J. and Jacobs, Frédérique J. and RodriguezandNoriega, Eduardo and Husa, Petr and Shortino, Denise and Watson, Helen A. and Yates, Phillip J. and Peppercorn, Amanda F.},
   article_location = {OXFORD},
   article_number = {2},
   doi = {http://dx.doi.org/10.1016/S2213-2600(16)30435-0},
   keywords = {zanamivir; oseltamivir; influenza},
   language = {eng},
   issn = {2213-2600},
   journal = {LANCET RESPIRATORY MEDICINE},
   title = {Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial},
   volume = {5},
   year = {2017}
}

TY  - JOUR
ID  - 1376993
AU  - Marty, Francisco M. - Vidal-Puigserver, Joan - Clark, Carol - Gupta, Sandeep K. - Merino, Esperanza - Garot, Denis - Chapman, Marianne J. - Jacobs, Frédérique J. - Rodriguez-Noriega, Eduardo - Husa, Petr - Shortino, Denise - Watson, Helen A. - Yates, Phillip J. - Peppercorn, Amanda F.
PY  - 2017
TI  - Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial
JF  - LANCET RESPIRATORY MEDICINE
VL  - 5
IS  - 2
SP  - 135-146
EP  - 135-146
PB  - ELSEVIER SCI LTD
SN  - 22132600
KW  - zanamivir
KW  - oseltamivir
KW  - influenza
N2  - 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.
ER  -

MARTY, Francisco M., Joan VIDAL-PUIGSERVER, Carol CLARK, Sandeep K. GUPTA, Esperanza MERINO, Denis GAROT, Marianne J. CHAPMAN, Frédérique J. JACOBS, Eduardo RODRIGUEZ-NORIEGA, Petr HUSA, Denise SHORTINO, Helen A. WATSON, Phillip J. YATES and Amanda F. PEPPERCORN. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. \textit{LANCET RESPIRATORY MEDICINE}. OXFORD: ELSEVIER SCI LTD, 2017, vol.~5, No~2, p.~135-146. ISSN~2213-2600. Available from: https://dx.doi.org/10.1016/S2213-2600(16)30435-0.

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