A Study of Intravenous Zanamivir Versus Oral Oseltamivir in Adults and Adolescents Hospitalized With Influenza

Influenza, Human Clinical Trial

— ZORO  

Official title:

A Phase III International, Randomized, Double-blind, Double-dummy Study to Evaluate the Efficacy and Safety of 300 mg or 600 mg of Intravenous Zanamivir Twice Daily Compared to 75 mg of Oral Oseltamivir Twice Daily in the Treatment of Hospitalized Adults and Adolescents With Influenza

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01231620
• Other study ID #: 114373
• Status: Completed
• Phase: Phase 3
• Start date: January 15, 2011
• Est. completion date: March 18, 2015

Study information

• Verified date: March 2018
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to test the safety and efficacy of zanamivir given intravenously and how well it works at two different doses in hospitalized adolescents and adults with flu. Zanamivir will be compared with oseltamivir, which is used for treating flu.

Description:

The recent influenza pandemic has highlighted the need for alternative formulations for anti-influenza therapies. This will be an international Phase III, double-blind, double-dummy, 3-arm study to evaluate the efficacy, antiviral activity and safety of IV zanamivir 600 mg twice daily compared to oral oseltamivir 75 mg twice daily, and 600 mg IV zanamivir twice daily compared to 300 mg IV zanamivir for 5 days in hospitalized subjects with laboratory confirmed or suspected influenza infection. For a given subject, the initial 5-day treatment course may be extended for up to 5 additional days if clinical symptoms or patient characteristics as assessed by the investigator warrant further treatment. Alternatively, if the investigator considers that a subject is failing to improve clinically on their randomized treatment, the investigator can choose to initiate the switch/rescue option (600 mg IV zanamivir twice daily) on any day from Day 6 through Day 10 for up to an additional 5 days of treatment. On switching treatments, subjects complete a maximum of 14 days of treatment and are followed-up to Post-Treatment +28 Days.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 626
• Est. completion date: March 18, 2015
• Est. primary completion date: March 18, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

• Male or female aged 16 years; a female is eligible to enter and participate in the study if she is:

1. of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post- menopausal); or,

2. of child-bearing potential, has a negative pregnancy test at Baseline, and agrees to use protocol specified methods of birth control while on study.

• Vital signs criteria defined as 3 or more of the following at Baseline:

1. Presence of fever [oral temperature of 38°C or equivalent] at Baseline. However, this requirement is waived if the subject has a history of fever within in the 24 hours prior to Baseline; or, if the subject reported symptoms of feverishness at some time during the 48 hours prior to Baseline.

AND at least 2 out of the following 4:

2. Oxygen saturation <95% on room air by trans-cutaneous method or need for any supplemental oxygenation or ventilatory support, or increase in oxygen supplementation requirement of =2 litres for subjects with chronic oxygen dependency. For those subjects with a history of chronic hypoxia (without supplemental oxygen), an oxygen saturation of at least 3% below the patient's historical baseline oxygen saturation will satisfy this criterion.

3. Respiration rate >24 breaths per minute. For those subjects who require ventilatory support or oxygen supplementation, this requirement is waived.

4. Heart rate >100 beats per minute.

5. Systolic blood pressure <90 mmHg.

• Onset of influenza symptoms within 6 days prior to study enrolment. Symptoms may include cough, dyspnea, sore throat, feverishness, myalgias, headache, nasal symptoms (rhinorrhea, congestion), fatigue, diarrhea, anorexia, nausea and vomiting.

• Clinical symptoms of influenza with positive influenza diagnostic test result or strong suspicion of influenza illness based on clinical symptoms and local surveillance information.

• Subjects willing and able to give written informed consent to participate in the study and to adhere to the procedures stated in the protocol, or legally acceptable representative willing and able to give written informed consent on behalf of the subject for minors, unconscious adults and those incapable of consenting themselves due to their medical condition, or included as permitted by local regulatory authorities, IRB/IECs or local laws.

• Severity of any medical illness that, in the Investigator's judgement, justifies hospitalization of the subject for treatment and supportive care

• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria:

• Subjects who have taken more than a total of 3 days (6 doses) of approved anti-influenza therapy in the period from onset of symptoms and prior to enrolment.

• Subjects who, in the opinion of the investigator, are not likely to survive beyond 48 hours from Baseline.

• Subjects who are considered to require concurrent therapy with another influenza antiviral medication.

• Subjects who are known or suspected to be hypersensitive to any component of the study medications.

• Subjects with creatinine clearance =10 mL/min who are not being treated with continuous renal replacement therapy (CRRT).

• Subjects who require Extra Corporeal Membrane Oxygenation (ECMO) at Baseline

• Subjects who require routine/intermittent hemodialysis or continuous peritoneal dialysis (due to inability to provide appropriate dosing schedule for oseltamivir) at Baseline. CRRT modalities are allowed.

• Liver toxicity criteria based on local laboratory results obtained within 24 hours of Baseline:

1. ALT or AST 3xULN and bilirubin 2xULN

2. ALT 5xULN

• Underlying chronic liver disease with evidence of severe liver impairment.

• History of severe cardiac disease or clinically significant arrhythmia (either on ECG or by history) which, in the opinion of the Investigator, will interfere with the safety of the individual subject.

• Females who are pregnant or are breastfeeding.

• Treatment with investigational parenteral anti-influenza drugs (IV peramivir, IV zanamivir or IV oseltamivir) in the 4 weeks prior to Baseline.

• French and Korean subjects: the French or Korean subject has participated in any study using an investigational drug during the previous 30 days.

Related Conditions & MeSH terms

• Influenza, Human

Intervention

Drug:
• Zanamivir
Zanamivir aqueous solution, 10 mg/mL, will be provided as a single use, sterile clear, colorless preparation in 20 mL clear glass vials.
• Placebo to match zanamivir
Placebo to match IV zanamivir will be provided as a normal saline solution of a matched volume.
• Oseltamivir
Oseltamivir will be provided as over-encapsulated 75 mg capsules.
• Placebo to match oseltamivir
Placebo to match oral oseltamivir will be provided as capsules with a common excipient of appropriate quality.

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Adelaide	South Australia
Australia	GSK Investigational Site	Bedford Park	South Australia
Australia	GSK Investigational Site	Clayton	Victoria
Australia	GSK Investigational Site	Heidelberg	Victoria
Australia	GSK Investigational Site	Herston	Queensland
Australia	GSK Investigational Site	Melbourne	Victoria
Australia	GSK Investigational Site	Melbourne	Victoria
Australia	GSK Investigational Site	Perth	Western Australia
Australia	GSK Investigational Site	Westmead	New South Wales
Belgium	GSK Investigational Site	Brussel
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Leuven
Belgium	GSK Investigational Site	Liege
Brazil	GSK Investigational Site	Rio de Janeiro
Brazil	GSK Investigational Site	São Paulo
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Chicoutimi	Quebec
Canada	GSK Investigational Site	Halifax	Nova Scotia
Canada	GSK Investigational Site	Hamilton	Ontario
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Trois-Rivières	Quebec
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Changchun	Jilin
China	GSK Investigational Site	Changsha	Hunan
China	GSK Investigational Site	Chengdu
China	GSK Investigational Site	Chongqing
China	GSK Investigational Site	Guangzhou
China	GSK Investigational Site	Haikou	Hainan
China	GSK Investigational Site	Hangzhou
China	GSK Investigational Site	Hangzhou	Zhejiang
China	GSK Investigational Site	Nanchang	Jiangxi
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Tianjin
China	GSK Investigational Site	Xian	Shaanxi
Colombia	GSK Investigational Site	Bogotá
Czechia	GSK Investigational Site	Brno
Czechia	GSK Investigational Site	Brno - Bohunice
Czechia	GSK Investigational Site	Hradec Kralove
Czechia	GSK Investigational Site	Praha 8
Denmark	GSK Investigational Site	Aarhus N
Denmark	GSK Investigational Site	Hvidovre
Denmark	GSK Investigational Site	Odense C
France	GSK Investigational Site	Dijon Cedex
France	GSK Investigational Site	Limoges cedex
France	GSK Investigational Site	Nîmes cedex 9
France	GSK Investigational Site	Orléans cedex 2
France	GSK Investigational Site	Poitiers Cedex
France	GSK Investigational Site	Tours cedex 9
Germany	GSK Investigational Site	Erlangen	Bayern
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Homburg	Saarland
Germany	GSK Investigational Site	Regensburg	Bayern
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Greece	GSK Investigational Site	Chaidari
Greece	GSK Investigational Site	Goudi, Athens
Hong Kong	GSK Investigational Site	Kwun Tong
Hong Kong	GSK Investigational Site	Shatin
Hong Kong	GSK Investigational Site	Tuen Mun
Hungary	GSK Investigational Site	Debrecen
Hungary	GSK Investigational Site	Kaposvár
Hungary	GSK Investigational Site	Miskolc
Hungary	GSK Investigational Site	Székesfehérvár
Hungary	GSK Investigational Site	Szombathely
India	GSK Investigational Site	Bangalore
India	GSK Investigational Site	Civil Lines
India	GSK Investigational Site	Lucknow
India	GSK Investigational Site	Lucknow
India	GSK Investigational Site	Pune
India	GSK Investigational Site	Pune
India	GSK Investigational Site	Trivandrum
Korea, Republic of	GSK Investigational Site	Guro Gu
Korea, Republic of	GSK Investigational Site	Gyeonggi
Korea, Republic of	GSK Investigational Site	Kangwon-do
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Mexico	GSK Investigational Site	Aguascalientes
Mexico	GSK Investigational Site	Chihuahua
Mexico	GSK Investigational Site	Cuautitlán, Estado De México	Estado De México
Mexico	GSK Investigational Site	Guadalajara	Jalisco
Mexico	GSK Investigational Site	San Nicolas de los Garza	Nuevo León
Netherlands	GSK Investigational Site	Nijmegen
New Zealand	GSK Investigational Site	Auckland
New Zealand	GSK Investigational Site	Auckland
New Zealand	GSK Investigational Site	Auckland
New Zealand	GSK Investigational Site	Christchurch
New Zealand	GSK Investigational Site	Hamilton
New Zealand	GSK Investigational Site	Hastings
New Zealand	GSK Investigational Site	Newtown
Norway	GSK Investigational Site	Bergen
Norway	GSK Investigational Site	Trondheim
Poland	GSK Investigational Site	Chorzow
Poland	GSK Investigational Site	Debica
Poland	GSK Investigational Site	Trzebnica
Poland	GSK Investigational Site	Warszawa
Russian Federation	GSK Investigational Site	Barnaul
Russian Federation	GSK Investigational Site	Barnaul
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Sankt-Peterburg
Russian Federation	GSK Investigational Site	Smolensk
Slovakia	GSK Investigational Site	Bratislava
Slovakia	GSK Investigational Site	Martin
South Africa	GSK Investigational Site	Bellville
South Africa	GSK Investigational Site	Die Wilgers
South Africa	GSK Investigational Site	Les Marais
South Africa	GSK Investigational Site	Middelburg	Mpumalanga
South Africa	GSK Investigational Site	Panorama
South Africa	GSK Investigational Site	Worcester
Spain	GSK Investigational Site	Alicante
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Granada
Spain	GSK Investigational Site	Granada
Spain	GSK Investigational Site	L'Hospitalet de Llobregat
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Murcia
Spain	GSK Investigational Site	Oviedo
Spain	GSK Investigational Site	Pama de Mallorca
Taiwan	GSK Investigational Site	Taipei
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Bangkok
United Kingdom	GSK Investigational Site	Bristol
United Kingdom	GSK Investigational Site	Cardiff
United Kingdom	GSK Investigational Site	Liverpool
United Kingdom	GSK Investigational Site	Manchester
United States	GSK Investigational Site	Asheville	North Carolina
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Augusta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Bethlehem	Pennsylvania
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Bismarck	North Dakota
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Chula Vista	California
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Council Bluffs	Iowa
United States	GSK Investigational Site	Escondido	California
United States	GSK Investigational Site	Fullerton	California
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Idaho Falls	Idaho
United States	GSK Investigational Site	La Jolla	California
United States	GSK Investigational Site	La Mesa	California
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Louisville	Kentucky
United States	GSK Investigational Site	Marshfield	Wisconsin
United States	GSK Investigational Site	Missoula	Montana
United States	GSK Investigational Site	Oak Park	Illinois
United States	GSK Investigational Site	Oceanside	California
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Peoria	Illinois
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Roanoke	Virginia
United States	GSK Investigational Site	Royal Oak	Michigan
United States	GSK Investigational Site	Saint Louis	Missouri
United States	GSK Investigational Site	Sarasota	Florida
United States	GSK Investigational Site	Stamford	Connecticut
United States	GSK Investigational Site	Sunrise	Florida
United States	GSK Investigational Site	Toledo	Ohio
United States	GSK Investigational Site	Topeka	Kansas
United States	GSK Investigational Site	Troy	Michigan
United States	GSK Investigational Site	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  China,  Colombia,  Czechia,  Denmark,  France,  Germany,  Greece,  Hong Kong,  Hungary,  India,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Norway,  Poland,  Russian Federation,  Slovakia,  South Africa,  Spain,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Clinical Response (TTCR) in Participants With Confirmed Influenza	Clinical response is defined as the resolution of at least 4 of the 5 vital signs (temperature, oxygen saturation, respiratory status, heart rate, systolic blood pressure) within the respective resolution criteria, maintained for at least 24 hours, or hospital discharge, whichever occurred first. This analysis was performed for Influenza positive population, for those with symptom onset less than or equal to (<=) 4 days, and for those on mechanical (mech) ventilation or in intensive care unit (ICU). 99 days is censored time for the participants who did not achieve TTCR.	Up to 42 days
Secondary	Percentage of Participants With Respiratory Improvement	Respiratory Status (RS) is a component of TTCR. Response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), a need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate of =<24 breaths/minute (without supplemental oxygen). Data are presented as the percentage of participants achieving respiratory improvement.	Up to 42 days
Secondary	Number of Participants With All Cause and Attributable Mortality at Day 14, at Day 28, and at the End of Study Visit	The number of participants who died on or before Day 14, Day 28, and the End of Study Visit were summarized.	On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days)
Secondary	Change From Baseline in the Katz Activities of Daily Living (ADL) Score and Each ADL Activity Score	The Katz ADL scores were collected for bathing, dressing, toileting, transferring, continence, and feeding activities and were assessed once daily during the treatment period/hospitalization and once at each post-treatment Clinic Visit. For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent. Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline is defined as the difference at each time point (Day 5/6, and Day 10/11, and last day S/R if treatment was extended beyond 5 days) and the end of the study (post-treatment [PT] +28 Days) compared to Baseline.	Baseline (Day 1) and up to 42 days
Secondary	Median Time to Return to Pre-morbid Functional Status as Measured by the Katz ADL Score and Each ADL Activity Score	Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. Median time to return to pre-morbid functional status was assessed via the Katz ADL score (bathing, dressing, toileting, transferring, continence, and feeding activities). For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. The total score is generated by adding the scores of all six activities. A total score of 6 indicates that the participant was independent; a total score of 0 indicates that the participant was very dependent.	Up to 42 days
Secondary	Number of Participants Who Returned to Their Pre-morbid Functional Status as Assessed Per the Katz ADL Score and Each ADL Activity Score at the End of the Study	Pre-morbid functional status is defined as the best functional status in the 4 weeks prior to enrolment. The number of participants who returned to their pre-morbid functional status at the end of the study assessed per the Katz ADL score (bathing, dressing, toileting, transferring, continence and feeding activities) is summarized.	Up to 42 days
Secondary	Median Time to Return to the Pre-morbid Level of Activity as Measured by the 3-point Scale	Median time to return to pre-morbid level of activity was assessed once daily during treatment/hospitalization and once at each post-treatment assessment and was measured using the 3- point scale (bed rest, limited ambulation, or unrestricted).	Up to 42 days
Secondary	Number of Participants With the Indicated Clinical Symptoms of Influenza	Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient hospitalization and once at each post-treatment assessment.	Up to 42 days
Secondary	Median Time of Duration of Clinical Symptoms of Influenza	Influenza clinical symptoms included nasal symptoms (rhinorrhea, congestion), feverishness, cough, myalgias, fatigue, diarrhea, anorexia, dyspnea, headache, sore throat, nausea, and vomiting. Influenza symptoms were assessed once daily during inpatient/hospitalization and once at each post-treatment assessment.	Up to 42 days
Secondary	Number of Participants With Complications of Influenza and Associated Antibiotic Use	The number of participants with complications of influenza and associated antibiotic use were summarized	Up to 42 days
Secondary	Number of Participants With the Indicated Ventilation Status: Modality of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation	Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit. The number of participants reported for machine-assisted: extracorporeal membrane oxygenation (ECMO), endotracheal mechanical ventilation, and supplemental oxygen delivery (SOD), no supplemental oxygen (O2) or ventilation support, Respiratory support at "any time (AT) on study" and at Baseline (Day 1) are summarized. Data for the "any time (AT) on study" time point was reported.	Up to 42 days
Secondary	Median Time of Duration of Invasive and Non-invasive Ventilator Support and Oxygen Supplementation	Ventilation status was assessed three times daily during the treatment period/hospitalization. Ventilation status was assessed once daily during inpatient/hospitalization and once at each post-treatment clinic visit.	Baseline (Day 1) and up to 42 days
Secondary	Median Time of Duration of Hospitalization and Intensive Care Unit (ICU) Stay	Hospital duration and ICU duration was assessed from the first day of dosing. Hospital duration was calculated as the discharge date minus the admission date + 1. Hospital duration while on study was the earlier of discharge, completion, or withdrawal minus the later of the admission date or the study start date + 1. ICU duration-Modified was calculated as the original ICU duration minus ICU days prior to Study Day 1.	Day 1 to the end of the study (assessed up to 42 days)
Secondary	Median Time to the Absence of Fever and Improved Respiratory Status, Oxygen Saturation, Heart Rate, and Systolic Blood Pressure	The absence of fever is defined as a non-axillary temperature recording <=36.6 degrees Celsius axillary, <= 37.2 degrees Celsius oral or <= 37.7 degrees Celsius core. Respiratory Status (RS) response criteria included the return to the pre-morbid oxygen requirement (participants with chronic oxygen use), or the need for supplemental oxygen (administered by any modality: ventilator, non-invasive ventilation, facemask, facetent, nasal canula, etc.) to no need for supplemental oxygen, or a respiratory rate =<24 breaths/minute (without supplemental oxygen). Oxygen saturation response criteria: >=95% (without supplemental oxygen). Heart rate response criteria: =<100 beats/minute. Systolic blood pressure response criteria: >=90 millimeters of mercury. Vital signs were assessed three times daily during the treatment period/hospitalization. Vital signs were assessed once daily during inpatient/hospitization and once at each post-treatment clinic visit.	Baseline (Day 1) and up to 42 days
Secondary	Median Time to Virologic Improvement	Virologic improvement is defined as a 2 log drop in viral load or sustained undetectable viral ribonucleic acid (RNA) (on two successive occasions) as measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal samples. Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Days 6, 8, 10 and on the last day of randomized treatment. For participants who utilized the Switch (S)/Rescue (R) option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Nasopharyngeal swabs were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16, and +28 day assessment.	Baseline (Day 1) and up to 42 days
Secondary	Change From Baseline in Quantitative Virus Culture From Nasopharyngeal Swabs Positive at Baseline	Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Day 6, Day 8, Day 10, Day 11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day1, S/R Day3, S/R Day5, or S/R Day6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the Post-Treatment +2, +5, +9, +16 and +28Day assessment. Viral load was measured by Quantitative Virus Culture, log10 50% Tissue Culture Infectious Dose (TCID50)/milliliter (mL). Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline was calculated as the post-Baseline value minus Baseline value .	Baseline (Day 1), Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable
Secondary	Change From Baseline Viral Load (Influenza A or B) by qPCR From Nasopharyngeal Swabs Positive at Baseline	Nasopharyngeal swabs were collected daily from Baseline through Day 5. If randomized treatment was continued beyond Day 5, samples were taken on Treatment Day 6, Day 8, Day 10, Day 11, and the last day of randomized treatment. For participants who utilized the S/R option, samples were taken on S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6, whichever was the last day of S/R treatment. Samples were taken if the participant was symptomatic and continued to be hospitalized on the post-treatment +2, +5, +9, +16 and +28 day assessment. Viral load as measured by PCR. Baseline is defined as the pre-dose value collected on Study Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline (Day 1), Day 3, Day 5, Day 8, Day 10, Day 11 and/or last day of randomized treatment, if randomized treatment was extended beyond 5 days, and S/R Day 5/6 (up to Day 14) if applicable
Secondary	Number of Participants With no Detectable Viral RNA and the Absence of Cultivable Virus in Lower Respiratory Samples (Bronchoalveolar Lavage Sample [BAL], Endotracheal Aspirate)	Lower respiratory samples included BAL and endotracheal aspirates. Endotracheal aspirates were requested in participants (par.) who were intubated. Upper (nasopharyngeal swabs) and lower (Endotracheal aspirates, bronchoalveolar lavage samples) respiratory samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment [trt]). Endotracheal aspirates were collected in participants who were intubated. If trt was continued beyond Day 5, additional samples were taken on Trt Day 6, Day 8, Day 10, and/or the day of the last dose of randomized trt, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R trt. If the par. was symptomatic and hospitalized, samples were taken on the Post-Trt +2, +5, +9, +16 assessment days, and at the Post-Trt [PT]+28 Day assessment. Assessment of samples was done by quantitative RT-PCR and viral culture.	Baseline (Day 1) and up to 42 days
Secondary	Median Time to no Detectable Viral RNA and the Absence of Cultivable Virus in Any Obtained Sample (Upper and Lower Respiratory Samples)	Upper (nasopharyngeal swabs) and lower (Endotracheal aspirates, bronchoalveolar lavage samples, where available) respiratory samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment). Endotracheal aspirates were collected in participants who were intubated. If treatment was continued beyond Day 5, additional samples were taken on Treatment Day 6, Day 8, Day 10, and/or the day of the last dose of randomized treatment, if applicable, and S/R Day 1, S/R Day 3, S/R Day 5, or S/R Day 6 if the last day of S/R treatment. If the participant was symptomatic and hospitalized, samples were taken on the Post-treatment+2, +5, +9, +16 assessment days, and at the Post-Treatment +28 Day. Assessment of samples was done by quantitative RT-PCR.	Baseline (Day 1) and up to 42 days
Secondary	Number of Participants With Resistance-associated Mutations Detected in the Neuraminidase (NA) and Hemagglutinin (HA) Gene of Influenza A and B Viruses in Nasopharyngeal Swabs and Endotracheal/BAL Samples	Nasopharyngeal swabs and endotracheal /BAL samples were collected for viral susceptibility analysis. Susceptibility analyses consisted of phenotyping and genotyping. Resistance mutations were detected by genotyping. Viral susceptibility to zanamivir and oral oseltamivir at Baseline and throughout treatment determined by NA and HA (gene of influenza A and B viruses) sequence analysis and NA enzyme inhibition. Number of participants with viral mutation events are summarized, this includes all resistance mutations (substitutions) i.e. those present at Baseline and those that emerged during treatment.	Baseline (Day 1) and up to 42 days
Secondary	Number of Participants With Any Adverse Event (AE) Considered to be Related to Study Treatment	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. All AEs were assessed by the Investigator as related or not related to the study treatment.	Up to 42 days
Secondary	Number of Participants With Any Severe or Grade 3/4 AE	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) table for grading the severity of AEs. Grade 3=severe; Grade 4=potentially life threatening.	Up to 42 days
Secondary	Number of Participants Who Permanently Discontinued the Study Treatment Due to an AE	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.	Up to 42 days
Secondary	Number of Participants Who Were Permanently Discontinued From the Study Due to an AE	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse.	Up to 42 days
Secondary	Number of Participants With Any Severe or Grade 3/4 Treatment-related AE	An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. AEs that occurred during the study were evaluated by the Investigator and graded according to the DAIDS table for grading the severity of adult and pediatric AEs. Grade 3=severe; Grade 4=potentially life threatening. All AEs were assessed by the Investigator as related or not related to the study treatment.	Up to 42 days
Secondary	Number of Participants With the Indicated Chemistry Laboratory Values Shifts From Baseline (Day 1) and up to 42 Days	Samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), switch/rescue (S/R) Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Clinical chemistry parameters included albumin, alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino tranferase (AST), total bilirubin, calcium, creatine kinase, chloride, carbon dioxide content (CO2), creatinine, potassium, magnesium, sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening. The number of participants with values that were G1, G2, G3 and G4 relative to the normal range are summarized.	Baseline (Day 1) and up to 42 days
Secondary	Number of Participants With the Indicated Hematology Values Shifts From Baseline (Day 1) and up to 42 Days	Blood samples for laboratory assessments were collected at Baseline (Day 1), Day 3, Day 5/6, Day 8, Day 10/11 (or last day of randomized treatment), S/R Day 1, S/R Day 3, and S/R Day 5/6 (last day of S/R treatment for those participants who utilized this option), Post-Treatment +2 (if hospitalized), and Post-Treatment +5, +16, and +28 Days. Hematology parameters included hemoglobin, lymphocytes, total neutrophils, platelet count, and white blood cell (WBC) count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade (G) 1=mild, G2= moderate, G3=severe and G4=potentially life threatening. The number of participants with values that were G1, G2, G3 and G4 relative to the normal range for the indicated hematology parameters is summarized. Baseline is defined as the pre-dose value collected on Study Day 1.	Baseline (Day 1) and up to 42 days
Secondary	Number of Participants With the Indicated Treatment-emergent (TE) Grade (G) 3/4 Clinical Chemistry Toxicities	A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). Clinical chemistry parameters included albumin, ALP, ALT, AST, total bilirubin, calcium, creatine kinase, chloride, CO2/bicarbonate, creatinine, potassium, magnesium and sodium. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.	Baseline (Day 1) and up to 42 days
Secondary	Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Hematology Toxicities	A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of investigational product). The hematology parameters included hemoglobin, lymphocytes, total neutrophils, platelet count, and WBC count. Per the DAIDS table for grading the severity of adult and pediatric AEs, Grade 3=severe and Grade 4=potentially life threatening. Baseline is defined as the pre-dose value collected on Study Day 1.	Baseline (Day 1) and up to 42 days
Secondary	Median Quantity of Oxygen Delivery Measured at Baseline (Day 1) and During the Study	Oxygen delivery were assessed three times daily at Baseline (Day 1) and during the treatment period/hospitalization (ideally at least 6 hours apart) and once daily during inpatient/hospitalization and once at Post +5 days, +16 days, and +28 days clinic visits. The median quantity of oxygen delivery during the study was not summarized since the data was not collected in a way to accurately calculate values. Baseline is defined as the pre-dose value collected on Study Day 1.	Baseline (Day 1) and during the study
Secondary	Number of Participants Assessed as Normal/Abnormal (Clinically Significant [CS] and Not Clinically Significant [NCS]) for 12-lead Electrocardiogram (ECG) at Baseline (Day 1) and Day 4	On Baseline/Day 1, a 12-lead ECG was obtained within approximately 24 hours prior to dosing. The number of participants with an ECG status of normal and abnormal CS or NCS, as determined by the Investigator, is reported. Normal=all ECG parameters within the accepted normal ranges. Abnormal=ECG findings outside of normal ranges. CS=ECG with a CS abnormality that meets exclusion criteria. NCS=ECG with an abnormality that is not CS nor meets exclusion criteria, per Investigator, based on reasonable standards of clinical judgment. In the original protocol ECGs were also done on Day 4, however, amendment 2 removed this requirement and therefore not all participants had Day 4 ECGs.	Baseline (Day 1) and Day 4
Secondary	Serum Concentration of IV Zanamivir	Pharmacokinetic samples were collected at four time points to characterize peak concentration (end of infusion; C[EOI]) after the first dose on Day 1 and on Day 4 to characterize the pre-dose concentration (C[0]), the peak concentration C(EOI), and the trough concentration at 11-12 hours post-dose (C[12]) of zanamavir. Data was summarized by Creatinine clearance (CL) Category. The dose on Day 1 is the initial dose (unadjusted) and the dose on Day 4 is the maintenance dose.	Day 1 and Day 4

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