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Clinical Trial Results:
NAI114373: 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

Summary
EudraCT number	2010-021621-12
Trial protocol	SK DE FR GB HU NL CZ NO DK GR BE PL ES Outside EU/EEA
Global end of trial date	18 Mar 2015

Results information
Results version number	v2(current)
This version publication date	26 Feb 2017
First version publication date	10 Jul 2016
Other versions	v1
Version creation reason	Correction of full data set Minor changes required.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NAI114373

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, +1 8664357343,

Scientific contact

GSK Response Center, GlaxoSmithKline, +1 8664357343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Feb 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Mar 2015

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of treatment with 600 mg of intravenous (IV) zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily, and 600 mg IV zanamivir compared to 300 mg IV zanamivir twice daily on time to clinical response (TTCR).

Protection of trial subjects

N/A

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Jan 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Korea, Republic of: 18

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

Norway: 11

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

Slovakia: 1

Country: Number of subjects enrolled

Spain: 146

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

Belgium: 24

Country: Number of subjects enrolled

Czech Republic: 13

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

France: 42

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Greece: 19

Country: Number of subjects enrolled

Hungary: 8

Country: Number of subjects enrolled

Hong Kong: 3

Country: Number of subjects enrolled

India: 44

Country: Number of subjects enrolled

Brazil: 2

Country: Number of subjects enrolled

Russian Federation: 15

Country: Number of subjects enrolled

Mexico: 19

Country: Number of subjects enrolled

New Zealand: 13

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

Australia: 22

Country: Number of subjects enrolled

China: 18

Country: Number of subjects enrolled

United States: 151

Country: Number of subjects enrolled

South Africa: 13

Worldwide total number of subjects

626

EEA total number of subjects

285

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

400

From 65 to 84 years

189

85 years and over

Subject disposition

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Recruitment details

Screening details

Male and female adult and adolescent participants >=16 years of age hospitalized with documented influenza or suspected influenza were eligible for enrollment. A total of 626 participants were randomized, and 615 participants were included in the Intent-to-Treat Exposed (ITT-E) Population.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

IV zanamivir 300 mg

Arm description

Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.

Arm type

Experimental

Investigational medicinal product name

zanamivir

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

300 mg twice daily, adjusted for renal function

IV zanamivir 600 mg

Arm description

Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.

Arm type

Experimental

Investigational medicinal product name

zanamivir

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

600 mg twice daily, adjusted for renal function

Oral oseltamivir 75 mg

Arm description

Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.

Arm type

Active comparator

Investigational medicinal product name

oseltamivir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

75 mg twice daily, frequency adjusted for renal function

Number of subjects in period 1 ^[1]	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Started	201	209	205
Completed	175	178	166
Not completed	26	31	39
Adverse event, serious fatal	12	14	11
Physician decision	3	5	10
Consent withdrawn by subject	6	6	8
Adverse event, non-fatal	2	2	1
Lost to follow-up	3	4	9

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Male and female adult and adolescent participants >=16 years of age hospitalized with documented influenza or suspected influenza were eligible for enrollment. A total of 626 participants were randomized, and 615 participants were included in the Intent-to-Treat Exposed (ITT-E) Population.

Baseline characteristics

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Reporting group title

IV zanamivir 300 mg

Reporting group description

Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.

Reporting group title

IV zanamivir 600 mg

Reporting group description

Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.

Reporting group title

Oral oseltamivir 75 mg

Reporting group description

Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.

Reporting group values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg	Total
Number of subjects	201	209	205	615
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	55.2 ( 18.88 )	57.3 ( 17.39 )	55.9 ( 18.7 )	-
Gender categorical
Units: Subjects
Female	82	86	117	285
Male	119	123	88	330
Race
Units: Subjects
African American/African Heritage	12	4	10	26
American Indian or Alaskan Native	3	2	4	9
Asian - Central/South Asian Heritage	10	15	13	38
Asian - East Asian Heritage	12	18	13	43
Asian - South East Asian Heritage	6	4	7	17
Native Hawaiian or Other Pacific Islander	2	1	0	3
White - Arabic/North African Heritage	4	3	3	10
White -White/Caucasian/European Heritage	150	162	154	466
Unknown	1	0	1	2
Mixed Race	1	0	0	1

End points

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Reporting group title

IV zanamivir 300 mg

Reporting group description

Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.

Reporting group title

IV zanamivir 600 mg

Reporting group description

Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.

Reporting group title

Oral oseltamivir 75 mg

Reporting group description

Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.

Primary: Median time to clinical response (TTCR) in participants with confirmed influenza

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End point title

Median time to clinical response (TTCR) in participants with confirmed influenza

End point description

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. The ITT-E Population is comprised of all randomized participants who received at least one dose of investigational product. The Influenza Positive Population (IPP) is comprised of all participants in the ITT-E Population with proven influenza infection. "-99999, 99999" indicates that full range data are not available.

End point type

Primary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[1]	162 ^[2]	163 ^[3]
Units: Days to success
median (full range (min-max))
Influenza positive sub-group	5.87 (-99999 to 99999)	5.14 (-99999 to 99999)	5.63 (-99999 to 99999)
Symptom Onset <=4 days sub-group	5.63 (-99999 to 99999)	4.8 (-99999 to 99999)	4.8 (-99999 to 99999)
ICU/ Mechanical ventilation sub-group	11.26 (-99999 to 99999)	12.79 (-99999 to 99999)	14.58 (-99999 to 99999)

Notes
[1] - IPP population
[2] - IPP population
[3] - IPP population

Statistical Analysis 1

Statistical analysis description

Influenza Positive Subgroup

Comparison groups

IV zanamivir 300 mg v IV zanamivir 600 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.2496 ^[5]

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

-0.73

Confidence interval

level

95%

sides

2-sided

lower limit

-1.79

upper limit

0.75

Notes
[4] - Wilcoxon rank-sum 2-sided test stratified by randomization strata
[5] - To control type 1 error, a fallback procedure with pre-specified order of hypothesis tests was used for each pair-wise comparison in the Influenza positive pop and two subgroups (ICU/Mech Vent, symptom onset <4 days).

Statistical Analysis 2

Statistical analysis description

Influenza Positive Subgroup

Comparison groups

IV zanamivir 600 mg v Oral oseltamivir 75 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.3912 ^[7]

Method

Wilcoxon rank-sum

Parameter type

Median difference (final values)

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-2.11

upper limit

0.97

Notes
[6] - Wilcoxon rank-sum 2-sided test stratified by randomization strata
[7] - To control type 1 error, a fallback procedure with pre-specified order of hypothesis tests was used for each pair-wise comparison in the Influenza positive pop and two subgroups (ICU/Mech Vent, symptom onset <4 days).

Statistical Analysis 3

Statistical analysis description

Symptom Onset <=4 Days Subgroup

Comparison groups

IV zanamivir 600 mg v IV zanamivir 300 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0923 ^[8]

Method

Wilcoxon rank-sum 2-sided test

Parameter type

Median difference (final values)

Point estimate

-0.83

Confidence interval

level

95%

sides

2-sided

lower limit

-1.98

upper limit

0.56

Notes
[8] - To control type 1 error, a fallback procedure with pre-specified order of hypothesis tests was used for each pair-wise comparison in the Influenza positive pop and two subgroups (ICU/Mech Vent, symptom onset <4 days).

Statistical Analysis 4

Statistical analysis description

Symptom Onset <=4 Days Subgroup

Comparison groups

IV zanamivir 600 mg v Oral oseltamivir 75 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8232 ^[9]

Method

Wilcoxon rank-sum 2 sided test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.05

upper limit

0.97

Notes
[9] - To control type 1 error, a fallback procedure with pre-specified order of hypothesis tests was used for each pair-wise comparison in the Influenza positive pop and two subgroups (ICU/Mech Vent, symptom onset <4 days).

Statistical Analysis 5

Statistical analysis description

ICU/Mechanic Ventilation Subgroup

Comparison groups

IV zanamivir 300 mg v IV zanamivir 600 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8711 ^[10]

Method

Wilcoxon rank-sum 2-sided test

Parameter type

Median difference (final values)

Point estimate

1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-4.29

upper limit

8.34

Notes
[10] - To control type 1 error, a fallback procedure with pre-specified order of hypothesis tests was used for each pair-wise comparison in the Influenza positive pop and two subgroups (ICU/Mech Vent, symptom onset <4 days).

Statistical Analysis 6

Statistical analysis description

ICU/Mechanic Ventilation Subgroup

Comparison groups

IV zanamivir 600 mg v Oral oseltamivir 75 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.512 ^[11]

Method

Wilcoxon rank-sum 2-sided test

Parameter type

Median difference (final values)

Point estimate

-1.79

Confidence interval

level

95%

sides

2-sided

lower limit

-11.1

upper limit

6.92

Notes
[11] - To control type 1 error, a fallback procedure with pre-specified order of hypothesis tests was used for each pair-wise comparison in the Influenza positive pop and two subgroups (ICU/Mech Vent, symptom onset <4 days).

Primary: Percentage of participants with confirmed influenza acheiving a clinical response

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End point title

Percentage of participants with confirmed influenza acheiving a clinical response ^[12]

End point description

End point type

Primary

End point timeframe

Up to 42 days

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report.

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[13]	162 ^[14]	163 ^[15]
Units: Percentage of participants
number (not applicable)	85	87	77

Notes
[13] - IPP Population
[14] - IPP Population
[15] - IPP Population

No statistical analyses for this end point

Secondary: Percent of participants with respiratory improvement

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End point title

Percent of participants with respiratory improvement

End point description

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 acheiving respiratory improvement. This analysis utilizes the Wei-Johanson method.

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[16]	162 ^[17]	163 ^[18]
Units: Percentage of participants
number (not applicable)	77	78	74

Notes
[16] - IPP Population
[17] - IPP Population
[18] - IPP Population

Statistical Analysis 1

Comparison groups

IV zanamivir 600 mg v IV zanamivir 300 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.506

Method

Wei-Johnson method

Confidence interval

Statistical Analysis 2

Comparison groups

IV zanamivir 600 mg v Oral oseltamivir 75 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.41

Method

Wei-Johnson method

Confidence interval

Secondary: Number of participants with all cause and attributable mortality at Day 14, at Day 28, and at the End of Study Visit

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End point title

Number of participants with all cause and attributable mortality at Day 14, at Day 28, and at the End of Study Visit

End point description

The number of participants who died on or before Day 14, Day 28, and the End of Study Visit are summarized.

End point type

Secondary

End point timeframe

On or before Day 14, Day 28, End of Study Visit (assessed up to 42 days)

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[19]	162 ^[20]	163 ^[21]
Units: Participants
number (not applicable)
Died on or before Study Day 14: all cause	5	8	5
Died on or before Study Day 28: all cause	8	9	9
Died while on-study: all cause	10	12	10
Died on or before Study Day 14: attributable	3	4	4
Died on or before Study Day 28: attributable	5	5	5
Died while on-study: attributable	5	6	6

Notes
[19] - IPP Population
[20] - IPP Population
[21] - IPP Population

No statistical analyses for this end point

Secondary: Change from Baseline in the Katz Activities of Daily Living (ADL) score and each ADL activity score

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End point title

Change from Baseline in the Katz Activities of Daily Living (ADL) score and each ADL activity score

End point description

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. Only those participants available at the specified time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1) and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[22]	162 ^[23]	163 ^[24]
Units: Scores on the scale
arithmetic mean (standard deviation)
Total Score Day 5/6, n=149, 150, 139	1.07 ( 1.959 )	0.93 ( 1.782 )	0.78 ( 1.837 )
Total Score Day 10/11, n=16, 6, 12,	0.88 ( 1.746 )	0.5 ( 0.837 )	-0.08 ( 3.029 )
Total Score Last Day of S/R, n=5, 2, 8	0.2 ( 2.49 )	-3 ( 4.243 )	0.75 ( 1.165 )
Total Score PT+28 Day, n=138, 134, 120	2.13 ( 2.234 )	1.72 ( 2.342 )	1.98 ( 2.142 )
Bathing: DAY 5/6, n=149, 150, 139	0.24 ( 0.488 )	0.19 ( 0.429 )	0.18 ( 0.438 )
Bathing: DAY 10/11, n=16, 6, 12	0.19 ( 0.403 )	0 ( 0 )	0 ( 0.426 )
Bathing: Last Day of S/R, n=5, 2, 8	0.2 ( 0.447 )	-0.5 ( 0.707 )	0 ( 0 )
Bathing: PT + 28 DAYS, n=138, 134, 120	0.43 ( 0.498 )	0.34 ( 0.505 )	0.39 ( 0.507 )
Dressing DAY 5/6, n=149, 150, 139	0.23 ( 0.481 )	0.21 ( 0.438 )	0.14 ( 0.427 )
Dressing: Day 10/11, n=16, 6, 12	0.13 ( 0.342 )	0 ( 0 )	-0.08 ( 0.515 )
Dressing: Last Day of S/R, n=5, 2, 8	0.2 ( 0.447 )	-0.5 ( 0.707 )	0.13 ( 0.354 )
Dressing:PT+28 Day, n=138, 134, 120	0.42 ( 0.495 )	0.37 ( 0.515 )	0.41 ( 0.494 )
Toileting: DAY 5/6, n=149, 150, 139	0.19 ( 0.456 )	0.19 ( 0.439 )	0.14 ( 0.409 )
Toileting: Day 10/11, n=16, 6, 12	0.13 ( 0.342 )	0.33 ( 0.516 )	0.08 ( 0.515 )
Toileting: Last Day of S/R, n=5, 2, 8	0.2 ( 0.447 )	-0.5 ( 0.707 )	0 ( 0.535 )
Toileting: PT+28 Day, n=138, 134, 120	0.4 ( 0.491 )	0.32 ( 0.514 )	0.37 ( 0.484 )
Transferring: DAY 5/6, n=149, 150, 139	0.28 ( 0.505 )	0.23 ( 0.451 )	0.17 ( 0.41 )
Transferring: Day 10/11, n=16, 6, 12	0.19 ( 0.403 )	0.17 ( 0.408 )	0.08 ( 0.515 )
Transferring: Last Day of S/R, n=5, 2, 8	0 ( 0.707 )	-0.5 ( 0.707 )	0.25 ( 0.463 )
Transferring: PT+28 Day, n=138, 134, 120	0.45 ( 0.499 )	0.36 ( 0.526 )	0.4 ( 0.492 )
Continence: DAY 5/6, n=149, 150, 139	0.07 ( 0.322 )	0.05 ( 0.314 )	0.07 ( 0.374 )
Continence: Day 10/11, n=16, 6, 12	0.13 ( 0.342 )	0 ( 0 )	-0.08 ( 0.669 )
Continence: Last Day of S/R, n=5, 2, 8	-0.2 ( 0.447 )	-0.5 ( 0.707 )	0.13 ( 0.354 )
Continence: PT+28 Day, n=138, 134, 120	0.22 ( 0.431 )	0.16 ( 0.422 )	0.23 ( 0.439 )
Feeding: Day 5/6, n=149, 150, 139	0.07 ( 0.331 )	0.07 ( 0.309 )	0.08 ( 0.382 )
Feeding: Day 10/11, n=16, 6, 12	0.13 ( 0.342 )	0 ( 0 )	-0.08 ( 0.669 )
Feeding: Last Day of S/R, n=5, 2, 8	-0.2 ( 0.447 )	-0.5 ( 0.707 )	0.25 ( 0.463 )
Feeding: PT+28 Day, n=138, 134, 120	0.21 ( 0.409 )	0.17 ( 0.416 )	0.19 ( 0.395 )

Notes
[22] - IPP Population
[23] - IPP Population
[24] - IPP Population

No statistical analyses for this end point

Secondary: Median time to return to pre-morbid functional status as measured by the Katz ADL score and each ADL activity score

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End point title

Median time to return to pre-morbid functional status as measured by the Katz ADL score and each ADL activity score

End point description

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. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles)

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[25]	162 ^[26]	163 ^[27]
Units: Days
median (full range (min-max))
Total score; n=139, 138, 130	2 (2 to 38)	2 (2 to 37)	2.5 (2 to 57)
Bathing; n=135, 133, 126:	2 (2 to 38)	2 (2 to 37)	2 (2 to 57)
Dressing; n=138, 135, 126	2 (2 to 38)	2 (2 to 40)	2 (2 to 57)
Toileting; n=139, 136, 130	2 (2 to 38)	2 (2 to 31)	2 (2 to 40)
Transferring; n=140, 140, 133	2 (2 to 38)	2 (2 to 31)	2 (2 to 40)
Continence; n= 142, 143, 139	2 (2 to 35)	2 (2 to 33)	2 (2 to 31)
Feeding; n= 145, 148, 144	2 (2 to 29)	2 (2 to 32)	2 (2 to 36)

Notes
[25] - IPP Population
[26] - IPP Population
[27] - IPP Population

No statistical analyses for this end point

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

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End point title

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

End point description

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

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[28]	162 ^[29]	163 ^[30]
Units: Participants
number (not applicable)
Total	139	138	130
Bathing	135	133	126
Dressing	138	135	126
Toileting	139	136	130
Transferring:	140	140	133
Continence	142	143	139
Feeding	145	148	144

Notes
[28] - IPP Population
[29] - IPP Population
[30] - IPP Population

No statistical analyses for this end point

Secondary: Median time to return to the pre-morbid level of activity as measured by the 3-point scale

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End point title

Median time to return to the pre-morbid level of activity as measured by the 3-point scale

End point description

Median time to return to pre-morbid level of activity was assessed during the study i.e 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). Participants successed in pre-morbid functional status were analyzed.

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	138 ^[31]	137 ^[32]	135 ^[33]
Units: Days
median (full range (min-max))	5 (2 to 34)	4 (2 to 31)	4 (1 to 57)

Notes
[31] - IPP Population
[32] - IPP Population
[33] - IPP Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated clinical symptoms of influenza

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End point title

Number of participants with the indicated clinical symptoms of influenza

End point description

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

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[34]	162 ^[35]	163 ^[36]
Units: Participants
number (not applicable)
Anorexia	102	112	123
Cough	151	150	157
Diarrhea	64	57	66
Dyspnea	143	145	152
Fatigue	144	144	148
Feverishness	138	145	136
Headache	104	102	103
Myalgias	115	117	114
Nasal symptoms (rhinorrhea, congestion)	118	123	122
Nausea	57	51	77
Sore throat	94	115	97
Vomiting	27	23	45

Notes
[34] - IPP Population
[35] - IPP Population
[36] - IPP Population

No statistical analyses for this end point

Secondary: Median duration of clinical symptoms of influenza

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End point title

Median duration of clinical symptoms of influenza

End point description

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[37]	162 ^[38]	163 ^[39]
Units: Days
median (full range (min-max))
Anorexia; n=102, 112, 123	5 (1 to 39)	3 (1 to 46)	5 (1 to 55)
Cough; n= 151, 150, 157	14 (1 to 39)	13 (1 to 46)	15 (1 to 56)
Diarrhea; n=64, 57, 66	3 (1 to 29)	2 (1 to 28)	3 (1 to 23)
Dyspnea; n=143, 145, 152	7 (1 to 40)	6 (1 to 43)	8 (1 to 56)
Fatigue; n= 144, 144, 148	11 (1 to 41)	11 (1 to 44)	12 (1 to 56)
Feverishness; n=138, 145, 136	2 (1 to 28)	2 (1 to 29)	2.5 (1 to 56)
Headache; n=104, 102, 103	3 (1 to 33)	3 (1 to 33)	4 (1 to 56)
Myalgias; n=115, 117, 114	4 (1 to 39)	3 (1 to 34)	4 (1 to 56)
Nasal symptoms; n=118, 123, 122	6 (1 to 34)	4 (1 to 43)	5.5 (1 to 35)
Nausea; n=57, 51, 77	3 (1 to 34)	2 (1 to 24)	2 (1 to 28)
Sore throat; n=94, 115, 97	3 (1 to 28)	2 (1 to 36)	3 (1 to 35)
Vomiting; n=27, 23, 45	2 (1 to 19)	1 (1 to 11)	1 (1 to 20)

Notes
[37] - IPP Population
[38] - IPP Population
[39] - IPP Population

No statistical analyses for this end point

Secondary: Number of participants with complications of influenza and associated antibiotic use

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End point title

Number of participants with complications of influenza and associated antibiotic use

End point description

The number of participants with complications of influenza and associated antibiotic use is summarized

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[40]	162 ^[41]	163 ^[42]
Units: Participants
number (not applicable)
Associated use of any antibiotic	22	16	29
Any complication of influenza	34	33	41

Notes
[40] - IPP Population
[41] - IPP Population
[42] - IPP Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated ventilation status: modality of invasive and non-invasive ventilator support and oxygen supplementation

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End point title

Number of participants with the indicated ventilation status: modality of invasive and non-invasive ventilator support and oxygen supplementation

End point description

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.

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[43]	162 ^[44]	163 ^[45]
Units: Participants
number (not applicable)
Day 1, Machine-Assisted: ECMO	0	0	0
Day 1, Machine-Assisted: Endotracheal	28	25	27
Day 1, SOD	96	103	87
Day 1, No supplemental O2 or ventilation support	32	29	37
Day 1, Respiratory Support	34	29	39
AT on Study, Machine-Assisted: ECMO	2	0	1
AT on Study, Machine-Assisted: Endotracheal	36	31	37
AT on Study, SOD	137	137	128
AT on Study, No supplemental O2 or ventilation sup	138	135	131
AT on Study, Respiratory Support	46	37	50

Notes
[43] - IPP Population
[44] - IPP Population
[45] - IPP Population

No statistical analyses for this end point

Secondary: Median time duration of invasive and non-invasive ventilator support and oxygen supplementation

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End point title

Median time duration of invasive and non-invasive ventilator support and oxygen supplementation

End point description

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. Only those participants available with the indicated ventilator support or oxygen supplementation were analyzed (represented by n=X, X, X in the category titles).

End point type

Secondary

End point timeframe

Baseline and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[46]	162 ^[47]	163 ^[48]
Units: Days
median (full range (min-max))
Ventilator Support, n=46, 37, 50	9 (0 to 38)	5.2 (0 to 36)	8.2 (0 to 36)
Oxygen Supplementation, n=137, 137, 128	4.4 (0 to 38)	4.2 (0 to 43)	3.7 (0 to 36)

Notes
[46] - IPP Population
[47] - IPP Population
[48] - IPP Population

No statistical analyses for this end point

Secondary: Median time of duration of hospitalization and Intensive Care Unit (ICU) stay

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End point title

Median time of duration of hospitalization and Intensive Care Unit (ICU) stay

End point description

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 calculatd as the original ICU duration minus ICU days prior to Study Day 1. Only those participants with the indicated hospitalization or ICU stay were analyzed (represented by n=X, X, X in the category titles)

End point type

Secondary

End point timeframe

Day 1 to the end of the study (assessed up to 42 days)

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[49]	162 ^[50]	163 ^[51]
Units: Days
median (full range (min-max))
Hospitalization; n=163, 162, 163	10 (1 to 108)	8 (2 to 64)	9 (1 to 58)
Hospitalization while on study; n=163, 162, 163	8 (1 to 39)	6 (1 to 43)	7 (1 to 39)
Hospitalization-ICU; n=72, 56, 71	8 (1 to 41)	7.5 (1 to 36)	8 (1 to 36)
ICU Duration Modified; n=70, 54, 69	7 (1 to 39)	6 (1 to 36)	7 (1 to 36)

Notes
[49] - IPP Population
[50] - IPP Population
[51] - IPP Population

No statistical analyses for this end point

Secondary: Median time to the absence of fever and improved respiratory status, oxygen saturation, heart rate, and systolic blood pressure

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End point title

Median time to the absence of fever and improved respiratory status, oxygen saturation, heart rate, and systolic blood pressure

End point description

The absence of fever is defined as a nonaxillary 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.

End point type

Secondary

End point timeframe

Baseline and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[52]	162 ^[53]	163 ^[54]
Units: Days
median (full range (min-max))
Fever	1.6 (0 to 34)	0.8 (0 to 14)	1.5 (0 to 31)
Oxygen Saturation; n=98, 108, 99	5.3 (0 to 30)	5.6 (0 to 32)	4.5 (0 to 25)
Respiratory status; n=126, 126, 121	3.5 (0 to 31)	3.6 (0 to 32)	2.8 (0 to 21)
Heart rate; n=156, 148, 155	0.4 (0 to 28)	0.4 (0 to 21)	0.5 (0 to 24)
Systolic blood pressure; n=156, 156, 154	0.3 (0 to 23)	0.3 (0 to 14)	0.3 (0 to 16)

Notes
[52] - IPP Population
[53] - IPP Population
[54] - IPP Population

No statistical analyses for this end point

Secondary: Median time to virologic improvement

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End point title

Median time to virologic improvement

End point description

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. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). Data presented is for subjects positive at Baseline.

End point type

Secondary

End point timeframe

Baseline and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[55]	162 ^[56]	163 ^[57]
Units: Days
median (full range (min-max))
Influenza A and B; n=116, 122, 129	3 (2 to 34)	3 (2 to 35)	3 (2 to 34)
Influenza A/H1N1; n=47, 42, 48	3 (2 to 13)	3 (2 to 34)	3 (2 to 34)
Influenza A/H3N2, n=55, 58, 61	3 (2 to 8)	3 (2 to 35)	3 (2 to 11)
Influenza B; n=15, 20, 21	5 (2 to 34)	3 (2 to 21)	3 (2 to 12)

Notes
[55] - IPP Population
[56] - IPP Population
[57] - IPP Population

No statistical analyses for this end point

Secondary: Change from Baseline in quantitative virus culture from nasopharyngeal swabs positive at Baseline

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End point title

Change from Baseline in quantitative virus culture from nasopharyngeal swabs positive at Baseline

End point description

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). Change from Baseline was calculated as the post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). "99999": data are not available/analysis was not performed. Data presented is for participants positive at Baseline.

End point type

Secondary

End point timeframe

Baseline, 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

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[58]	162 ^[59]	163 ^[60]
Units: log10 TCID50/mL
median (full range (min-max))
Day 3 n=78, 76, 89	-2.01 (-5 to 0.8)	-2.01 (-4.8 to 1.3)	-2.01 (-5.3 to 2.8)
Day 5 n=66, 69, 80	-2.51 (-5.5 to 0)	-2.26 (-5.3 to 0)	-2.26 (-5.3 to 2)
Day 8 n=6, 7, 10	-1.64 (-5.5 to 0)	-2.01 (-4.3 to -0.3)	-2.26 (-4.3 to 0)
Day 10 n=4, 3, 4	-3.76 (-5.5 to -0.3)	-0.3 (-1.3 to -0.3)	-2.26 (-3.8 to -1.3)
Day 11 n=3,3, 4	-3.01 (-5.5 to -0.3)	-0.3 (-1.3 to -0.3)	-2.26 (-3.8 to -1.3)
S/R Day 5 n=0, 1, 1	99999 (-99999 to 99999)	-4.3 (-4.3 to -4.3)	-3 (-3 to -3)
S/R Day 6 n=1, 1, 1	-2.5 (-2.5 to -2.5)	-4.3 (-4.3 to -4.3)	0 (0 to 0)

Notes
[58] - IPP Population
[59] - IPP Population
[60] - IPP Population

No statistical analyses for this end point

Secondary: Change from Baseline viral load (influenza A or B) by qPCR from nasopharyngeal swabs positive at Baseline

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End point title

Change from Baseline viral load (influenza A or B) by qPCR from nasopharyngeal swabs positive at Baseline

End point description

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.Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). "99999" indicates that data are not available/analysis was not performed. Data presented is for participants positive at Baseline

End point type

Secondary

End point timeframe

Baseline, 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

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[61]	162 ^[62]	163 ^[63]
Units: log10 vp/mL
median (full range (min-max))
Day 3 n=126, 127, 129	-1.5 (-5.4 to 2.2)	-1.83 (-4.9 to 2)	-1.75 (-6 to 2.8)
Day 5 n=110, 114, 114	-2.51 (-5.8 to 3.2)	-2.71 (-6.2 to 3.1)	-2.73 (-6.3 to 2.3)
Day 8 n=15, 12, 16	-2.38 (-4.4 to 1)	-3.16 (-5.5 to -0.3)	-1.78 (-5.7 to 1.1)
Day 10 n=13, 6, 8	-2.75 (-6 to -0.9)	-3.03 (-3.5 to 1.5)	-2.63 (-4.6 to 0.9)
Day 11 n=9,4, 7	-3.58 (-4.9 to -0.6)	-2.6 (-3.1 to 1.7)	-3.29 (-4.9 to -1)
S/R Day 5 n=0, 1, 1	99999 (-99999 to 99999)	-3.8 (-3.8 to -3.8)	-5.7 (-5.7 to -5.7)
S/R Day 6 n=1, 1, 2	-5.2 (-5.2 to -5.2)	-5.4 (-5.4 to -5.4)	-3.84 (-4 to -3.7)

Notes
[61] - IPP Population
[62] - IPP Population
[63] - IPP Population

No statistical analyses for this end point

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)

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End point title

Number of participants with no detectable viral RNA and the absence of cultivable virus in lower respiratory samples (bronchoalveolar lavage sample [BAL], endotracheal aspirate)

End point description

Lower respiratory samples included BAL and endotracheal aspirates. Endotracheal aspirates were requested in participants (par.) who were intubated. Samples were collected daily from Baseline/Day 1 through Day 5 and Day 6 (if the last day of randomized treatment [trt]). 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. Only those par. available at the specified time points were analyzed (represented by n=X, X, X in the category titles). BAL samples were only collected if the procedure was being carried out for the routine management of the par. Data also presented for par. positive at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day 1) and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[64]	162 ^[65]	163 ^[66]
Units: Participants
number (not applicable)
Influenza A and B Day 1; n=21, 17, 21	0	0	0
Influenza A and B Day 2; n=17, 15, 14	0	4	1
Influenza A and B Day 3; n=16, 10, 15	1	2	0
Influenza A and B Day 4; n=16,10, 15	2	2	2
Influenza A and B Day 5; n=15,10, 15	3	4	2
Influenza A and B Day 6; n= 14, 5, 9	3	1	3
Influenza A and B Day 8; n=5, 3, 7	2	0	2
Influenza A and B Day 10; n=4, 3, 3	0	0	0
Influenza A and B S/R Day 1; n=0, 0, 1	0	0	0
Influenza A and B S/R Day 3; n=1, 0, 1	0	0	1
Influenza A and B S/R Day 5; n=1, 0, 0	0	0	0
Influenza A and B PT + 2 Days; n= 9, 3, 9	4	1	3
Influenza A and B PT + 5 Days; n= 11, 2, 6	4	1	0
Influenza A and B PT + 9 Days; n= 5, 2, 4	4	1	3
Influenza A and B PT + 16 Days; n= 4, 1, 3	3	1	2
Influenza A and B PT + 28 Days; n= 1, 0, 1	1	0	1

Notes
[64] - IPP Population
[65] - IPP Population
[66] - IPP Population

No statistical analyses for this end point

Secondary: Median time to no detectable viral RNA and the absence of cultivable virus in any obtained sample (upper and lower respiratory samples)

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End point title

Median time to no detectable viral RNA and the absence of cultivable virus in any obtained sample (upper and lower respiratory samples)

End point description

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. Only those participants available at the specified time points were analyzed (represented by n=X, X, X in the category titles). Data also presented for participants positive at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day 1) and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[67]	162 ^[68]	163 ^[69]
Units: Days
median (full range (min-max))
Influenza A and B, n=114, 118, 115	4 (1 to 34)	3 (1 to 35)	4 (1 to 57)
Positive at baseline; n=102, 104, 102	4 (2 to 34)	4 (2 to 35)	4 (2 to 57)

Notes
[67] - IPP Population
[68] - IPP Population
[69] - IPP Population

No statistical analyses for this end point

Secondary: Resistance-associated mutations events detected in the NA and HA gene of influenza A and B viruses in nasopharyngeal swabs and endotracheal/BAL samples

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End point title

Resistance-associated mutations events detected in the NA and HA gene of influenza A and B viruses in nasopharyngeal swabs and endotracheal/BAL samples

End point description

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.

End point type

Secondary

End point timeframe

Baseline and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	163 ^[70]	162 ^[71]	163 ^[72]
Units: Participants
number (not applicable)
NA Gene,H3N2: Y155F	5	7	5
NA Gene,H3N2:S245N	4	4	0
NA Gene,H3N2:I222V	0	1	2
NA Gene,H3N2:N294S/N	2	0	0
NA Gene,H3N2:V149A	0	1	1
NA Gene,H3N2:D198D/G	0	0	1
NA Gene,H3N2:G248G/E	1	0	0
NA Gene,H3N2:N294D/N	0	1	0
NA Gene,H3N2:R292R/K	0	0	1
NA Gene,H3N2:T325I	1	0	0
NA Gene,H3N2:Y155H	0	0	1
NA Gene,H1N1: H275H/Y	0	1	4
NA Gene,H1N1:H275Y	0	1	3
NA Gene,H1N1:Q313R	1	0	2
NA Gene,H1N1:D199N	1	0	0
NA Gene,H1N1:E278G/E	0	0	1
NA Gene,H1N1:I223I/K	0	0	1
NA Gene,H1N1:Q136Q/R	0	0	1
NA Gene,H1N1:S247N	1	0	0
NA Gene,H1N1:S247S/I	1	0	0
NA Gene,H1N1:S247S/N	0	1	0
NA Gene,B: E148G	1	0	0
NA Gene,B: G141E	0	0	1
NA Gene,B: M403I	1	0	0
HA Gene, H3N2:R142G	18	21	21
HA Gene, H3N2:S198A	13	8	11
HA Gene, H3N2:A138S	3	1	2
HA Gene, H3N2:R142K	0	0	2
HA Gene, H3N2:A304A/P	0	0	1
HA Gene, H3N2:A304D	0	1	0
HA Gene, H3N2:L194P/L	1	0	0
HA Gene, H3N2:Q75H	0	1	0
HA Gene, H3N2:S124G	0	0	1
HA Gene, H3N2:S262N	0	1	0
HA Gene, H3N2:H1N1: S183P	1	0	2
HA Gene, H1N1 :D222D/G	0	0	2
HA Gene, H1N1 :D222D/N	0	2	0
HA Gene, H1N1 :D222N	0	0	2
HA Gene, H1N1 :S162N	0	0	2
HA Gene, H1N1 :D187E	0	1	0
HA Gene, H1N1 :D222G	1	0	0
HA Gene, H1N1 :D222S/D/N/G	1	0	0
HA Gene, H1N1 :L151P/L	0	1	0
HA Gene, H1N1 :V152I	0	0	1

Notes
[70] - IPP Population
[71] - IPP Population
[72] - IPP Population

No statistical analyses for this end point

Secondary: Number of participants with any adverse event (AE) considered to be related to study treatment

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End point title

Number of participants with any adverse event (AE) considered to be related to study treatment

End point description

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. The Safety Population is comprised of all randomized participants who received at least one dose of investigational product and assessed according to their actual treatment received, regardless of the randomization assigned.

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[73]	209 ^[74]	205 ^[75]
Units: Participants
number (not applicable)	25	22	35

Notes
[73] - Safety Population
[74] - Safety Population
[75] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with any severe or Grade 3/4 AE

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End point title

Number of participants with any severe or Grade 3/4 AE

End point description

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.

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[76]	209 ^[77]	205 ^[78]
Units: Participants
number (not applicable)	39	45	44

Notes
[76] - Safety Population
[77] - Safety Population
[78] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants who permanently discontinued the study treatment due to an AE

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End point title

Number of participants who permanently discontinued the study treatment due to an AE

End point description

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[79]	209 ^[80]	205 ^[81]
Units: Participants
number (not applicable)	8	10	11

Notes
[79] - Safety Population
[80] - Safety Population
[81] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants who were permanently discontinued from the study due to an AE

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End point title

Number of participants who were permanently discontinued from the study due to an AE

End point description

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[82]	209 ^[83]	205 ^[84]
Units: Participants
number (not applicable)	14	16	13

Notes
[82] - Safety Population
[83] - Safety Population
[84] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with any severe or Grade 3/4 treatment-related AE

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End point title

Number of participants with any severe or Grade 3/4 treatment-related AE

End point description

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.

End point type

Secondary

End point timeframe

Up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[85]	209 ^[86]	205 ^[87]
Units: Participants
number (not applicable)	5	3	7

Notes
[85] - Safety Population
[86] - Safety Population
[87] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated chemistry laboratory values shifts from Baseline (Day 1) and up to 42 days

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End point title

Number of participants with the indicated chemistry laboratory values shifts from Baseline (Day 1) and up to 42 days

End point description

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 summarised.

End point type

Secondary

End point timeframe

Baseline (Day 1) and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[88]	209 ^[89]	205 ^[90]
Units: Participants
number (not applicable)
Albumin G1, n=194,203,202	12	18	15
Albumin G2, n=194,203,202	32	43	40
Albumin G3, n=194,203,202	1	5	0
Albumin G4, n=194,203,202	0	0	0
ALP G1, n=194,203,202	10	15	9
ALP G2, n=194,203,202	0	4	1
ALP G3, n=194,203,202	0	2	0
ALP G4, n=194,203,202	0	0	0
ALT G1, n=194,203,202	13	10	12
ALT G2, n=194,203,202	2	1	1
ALT G3, n=194,203,202	0	0	0
ALT G4, n=194,203,202	0	0	1
AST G1, n=193,202,202	23	27	19
AST G2, n=193,202,202	8	8	6
AST G3, n=193,202,202	2	0	2
AST G4, n=193,202,202	0	0	1
Total Bilirubin G1, n=194,203,202	5	2	2
Total Bilirubin G2, n=194,203,202	3	2	3
Total Bilirubin G3, n=194,203,202	1	2	0
Total Bilirubin G4, n=194,203,202	0	0	1
Creatine Kinase G1, n=194,203,202	10	11	6
Creatine Kinase G2, n=194,203,202	3	3	6
Creatine Kinase G3, n=194,203,202	1	2	4
Creatine Kinase G4, n=194,203,202	1	1	2
CO2 G1, n=193,202,202	34	43	47
CO2 G2, n=193,202,202	4	9	6
CO2 G3, n=193,202,202	0	0	0
CO2 G4, n=193,202,202	0	1	0
Creatinine G1, n=194,203,202	6	5	4
Creatinine G2, n=194,203,202	11	7	4
Creatinine G3, n=194,203,202	8	7	4
Creatinine G4, n=194,203,202	0	0	1
Magnesium G1, n=194,203,202	14	14	15
Magnesium G2, n=194,203,202	7	9	4
Magnesium G3, n=194,203,202	0	0	0
Magnesium G4, n=194,203,202	0	0	0
Hypercalcemia G1, n=193,202,202	0	0	0
Hypercalcemia G2, n=193,202,202	0	0	0
Hypercalcemia G3, n=193,202,202	0	0	0
Hypercalcemia G4, n=193,202,202	0	0	0
Hyperkalemia G1, n=193,202,202	0	1	1
Hyperkalemia G2, n=193,202,202	0	0	0
Hyperkalemia G3, n=193,202,202	0	0	0
Hyperkalemia G4, n=193,202,202	1	0	1
Hypernatremia G1, n=194,203,202	4	10	4
Hypernatremia G2, n=194,203,202	1	1	0
Hypernatremia G3, n=194,203,202	0	1	1
Hypernatremia G4, n=194,203,202	0	0	0
Hypocalcemia G1, n=193,202,202	43	48	40
Hypocalcemia G2, n=193,202,202	26	39	42
Hypocalcemia G3, n=193,202,202	7	8	8
Hypocalcemia G4, n=193,202,202	0	1	0
Hypokalemia G1, n=193,202,202	16	12	21
Hypokalemia G2, n=193,202,202	1	1	1
Hypokalemia G3, n=193,202,202	1	0	0
Hypokalemia G4, n=193,202,202	0	0	0
Hyponatremia G1, n=194,203,202	42	34	26
Hyponatremia G2, n=194,203,202	2	2	4
Hyponatremia G3, n=194,203,202	0	2	0
Hyponatremia G4, n=194,203,202	0	0	1

Notes
[88] - Safety Population
[89] - Safety Population
[90] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated hematology values shifts from Baseline (Day 1) and up to 42 days

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End point title

Number of participants with the indicated hematology values shifts from Baseline (Day 1) and up to 42 days

End point description

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.

End point type

Secondary

End point timeframe

Baseline (Day 1) and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[91]	209 ^[92]	205 ^[93]
Units: Participants
number (not applicable)
Hemoglobin G1, n=194,202,200	28	25	28
Hemoglobin G2, n=194,202,200	11	19	13
Hemoglobin G3, n=194,202,200	14	10	8
Hemoglobin G4, n=194,202,200	0	4	1
Lymphocytes G1, n=186,199,198	8	18	10
Lymphocytes G2, n=186,199,198	11	15	11
Lymphocytes G3, n=186,199,198	16	21	18
Lymphocytes G4, n=186,199,198	18	19	14
Neutrophils G1, n=193,202,200	2	2	3
Neutrophils G2, n=193,202,200	2	0	0
Neutrophils G3, n=193,202,200	0	1	0
Neutrophils G4, n=193,202,200	1	0	3
Platelets G1, n=194,200,198	8	22	21
Platelets G2, n=194,200,198	18	12	16
Platelets G3, n=194,200,198	4	3	2
Platelets G4, n=194,200,198	2	1	2
Leukocytes G1, n=194,202,200	3	2	1
Leukocytes G2, n=194,202,200	3	5	3
Leukocytes G3, n=194,202,200	0	1	0
Leukocytes G4, n=194,202,200	1	0	2

Notes
[91] - Safety Population
[92] - Safety Population
[93] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated treatment-emergent (TE) Grade (G) 3/4 clinical chemistry toxicities

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End point title

Number of participants with the indicated treatment-emergent (TE) Grade (G) 3/4 clinical chemistry toxicities

End point description

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.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Day 1) and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[94]	209 ^[95]	205 ^[96]
Units: Participants
number (not applicable)
Albumin, G3; n=194, 203, 202	6	3	4
Albumin, G4; n=194, 203, 202	0	0	0
ALP, G3; n=194, 203, 202	0	2	0
ALP, G4; n=194, 203, 202	1	0	1
ALT, G3; n=194, 203, 202	2	2	4
ALT, G4; n=194, 203, 202	0	2	1
AST, G3; n=193, 202, 202	2	4	5
AST, G4; n=193, 202, 202	1	2	1
Total Bilirubin, G3; n=194, 203, 202	2	2	1
Total Bilirubin, G4; n=194, 203, 202	0	0	0
Creatine Kinase, G3; n=194, 203, 202	2	3	2
Creatine Kinase, G4; n=194, 203, 202	3	1	1
Carbon Dioxide, G3; n=193, 202, 202	0	0	0
Carbon Dioxide, G4; n=193, 202, 202	1	0	0
Creatinine, G3; n=194, 203, 202	3	6	1
Creatinine, G4; n=194, 203, 202	3	2	0
Magnesium, G3; n=194, 203, 202	1	0	0
Magnesium, G4; n=194, 203, 202	0	0	1
Hypercalcemia, G3; n=194, 202, 202	0	0	0
Hypercalcemia, G4; n=194, 202, 202	0	0	0
Hyperkalemia, G3; n=193, 202, 202	2	0	1
Hyperkalemia, G4; n=193, 202, 202	1	5	3
Hypernatremia, G3; n=194, 203, 202	0	1	5
Hypernatremia, G4; n=194, 203, 202	0	0	0
Hypocalcemia, G3; n=193, 202, 202	10	7	8
Hypocalcemia, G4; n=193, 202, 202	2	4	4
Hypokalemia, G3; n=193, 202, 202	0	0	0
Hypokalemia, G4; n=193, 202, 202	0	0	0
Hyponatremia, G3; n=194, 203, 202	1	0	0
Hyponatremia G4, n=194,203,202	0	0	0

Notes
[94] - Safety Population
[95] - Safety Population
[96] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated treatment-emergent (TE) Grade 3/4 hematology toxicities

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End point title

Number of participants with the indicated treatment-emergent (TE) Grade 3/4 hematology toxicities

End point description

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.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Day 1) and up to 42 days

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	201 ^[97]	209 ^[98]	205 ^[99]
Units: Participants
number (not applicable)
Hemoglobin, G3; n=194, 202, 200	29	24	26
Hemoglobin, G4; n=194, 202, 200	2	5	8
Lymphocytes, G3; n=186, 199, 198	6	5	11
Lymphocytes, G4; n=186, 199, 198	3	14	7
Total Neutrophils, G3; n=193, 202, 200	1	2	2
Total Neutrophils, G4; n=193, 202, 200	4	4	3
Platelet count, G3; n=194, 200, 198	4	4	5
Platelet count, G4; n=194, 200, 198	3	3	2
Leukocytes Count, G3; n=194, 202, 200	1	1	0
Leukocytes Count, G4; n=194, 202, 200	2	1	3

Notes
[97] - Safety Population
[98] - Safety Population
[99] - Safety Population

No statistical analyses for this end point

Secondary: Median quantity of oxygen delivery measured at Baseline (Day 1) and during the study

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End point title

Median quantity of oxygen delivery measured at Baseline (Day 1) and during the study

End point description

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.

End point type

Secondary

End point timeframe

Baseline (Day 1) and during the study

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	0 ^[100]	0 ^[101]	0 ^[102]
Units: Percentage of oxygen level in blood
median (full range (min-max))	( to )	( to )	( to )

Notes
[100] - This end point was not analyzed.
[101] - This end point was not analysed
[102] - This end point was not analysed

No statistical analyses for this end point

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

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End point title

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

End point description

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. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Baseline/Day 1 and Day 4

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	197 ^[103]	208 ^[104]	203 ^[105]
Units: Participants
number (not applicable)
Normal	100	121	99
Abnormal - Not Clinically Significant	97	86	102
Abnormal – Clinically Significant	5	4	7

Notes
[103] - Safety Population
[104] - Safety Population
[105] - Safety Population

No statistical analyses for this end point

Secondary: Serum concentration of intravenous (IV) zanamivir

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End point title

Serum concentration of intravenous (IV) zanamivir

End point description

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. The PK Population is comprised of all participants who received IV zanamivir and underwent sparse PK sampling during the study from which one or more serum zanamivir concentrations was determined. Data was summarised 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. "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Day 1 and Day 4

End point values	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Number of subjects analysed	180 ^[106]	187 ^[107]	0 ^[108]
Units: microgram/Liter (mcg/L)
arithmetic mean (standard deviation)
CL <15, Day 1, 30 min, n=1,3,0	14454.6 ( 99999 )	26410.8 ( 21335.43 )	( )
CL <15, Day 4, pre-dose n=1,2,0	293.2 ( 99999 )	9635.6 ( 8270.67 )	( )
CL <15, Day 4, 30 min n=1,1,0	1329.4 ( 99999 )	19828.9 ( 99999 )	( )
CL <15, Day 4, 11-12 hr n=1,1,0	605.1 ( 99999 )	15459.1 ( 99999 )	( )
CL 15-<30, Day 13, 30 min, n=13,9,0	20403.3 ( 11623.28 )	41102.8 ( 13884.08 )	( )
CL 15-<30, Day 4, pre-dose n=10,6,0	5906.4 ( 7167.87 )	4995.6 ( 1966.72 )	( )
CL 15-<30, Day 4, 30 min n=10,6,0	13636.4 ( 14029.44 )	13378 ( 2581.36 )	( )
CL 15-<30, Day 4, 11-12 hr n=8,5,0	7600.3 ( 8061.65 )	4953.4 ( 2232.16 )	( )
CL 30-<50, Day 1, 30 min, n=28,18,0	18756.8 ( 12806.43 )	42467.3 ( 14574.82 )	( )
CL 30-<50, Day 4, pre-dose n=12,15,0	2094.8 ( 1300.99 )	7637.4 ( 7212.1 )	( )
CL 30-<50, Day 4, 30 min n=12,13,0	12334.4 ( 12121.18 )	159292.1 ( 473267.3 )	( )
CL 30-<50, Day 4, 11-12 hr n=11,13,0	2932.5 ( 2425.81 )	19549.2 ( 40577.76 )	( )
CL 50-<80, Day 1, 30 min, n=36,49,0	19146.7 ( 8853.11 )	49666.1 ( 111785.9 )	( )
CL 50-<80, Day 4, pre-dose n=31,25,0	2793.3 ( 4694.43 )	13107.7 ( 33768.61 )	( )
CL 50-<80, Day 4, 30 min n=32,25,0	31541.3 ( 93381 )	22220.4 ( 10064.83 )	( )
CL 50-<80, Day 4, 11-12 hr n=30,23,0	1345.9 ( 1122.18 )	22623.9 ( 57663.24 )	( )
CL >=80, Day 1, 30 min, n=93,96,0	18561.7 ( 10332.14 )	35139.2 ( 17693.85 )	( )
CL >=80, Day 4, pre-dose n=99,107,0	2342.6 ( 6672.12 )	19379.8 ( 105056.3 )	( )
CL >=80, Day 4, 30 min n=100,106,,0	21580.7 ( 22062.69 )	75255.1 ( 167670.6 )	( )
CL >=80, Day 4, 11-12 hr n=94,99,0	2036.2 ( 4412.75 )	19428.7 ( 142284.7 )	( )
Missing, Day 1, 30 min n=0,2,0	99999 ( 99999 )	41109.7 ( 3831.74 )	( )

Notes
[106] - PK Population
[107] - PK Population
[108] - This end point was not analyzed

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until follow-up (up to 42 days).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

IV zanamivir 300 mg

Reporting group description

Participants >=16 years of age received intravenous (IV) zanamivir 300 milligrams (mg) twice daily, adjusted for renal function for 5–10 days.

Reporting group title

IV zanamivir 600 mg

Reporting group description

Participants >=16 years of age received IV zanamivir 600 mg twice daily, adjusted for renal function for 5–10 days.

Reporting group title

Oral oseltamivir 75 mg

Reporting group description

Participants >=16 years of age received oral oseltamvir 75 mg twice daily, adjusted for renal function for 5–10 days.

Serious adverse events	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Total subjects affected by serious adverse events
subjects affected / exposed	38 / 201 (18.91%)	33 / 209 (15.79%)	38 / 205 (18.54%)
number of deaths (all causes)	15	15	11
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Distributive shock
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hypotension
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Surgical and medical procedures
Mechanical ventilation
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Multi-organ failure
subjects affected / exposed	2 / 201 (1.00%)	2 / 209 (0.96%)	2 / 205 (0.98%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 2
Catheter site haemorrhage
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	5 / 201 (2.49%)	4 / 209 (1.91%)	5 / 205 (2.44%)
occurrences causally related to treatment / all	0 / 5	1 / 4	0 / 5
deaths causally related to treatment / all	0 / 3	1 / 3	0 / 2
Acute respiratory distress syndrome
subjects affected / exposed	4 / 201 (1.99%)	3 / 209 (1.44%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 4	0 / 3	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 201 (0.50%)	2 / 209 (0.96%)	2 / 205 (0.98%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Bronchospasm
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	2 / 205 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 201 (0.00%)	2 / 209 (0.96%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hypoxia
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pneumothorax
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Respiratory disorder
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 201 (0.50%)	1 / 209 (0.48%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delirium febrile
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ECG signs of ventricular hypertrophy
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 201 (0.50%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endotracheal intubation complication
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheostomy malfunction
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	2 / 201 (1.00%)	1 / 209 (0.48%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Cardiac failure congestive
subjects affected / exposed	1 / 201 (0.50%)	1 / 209 (0.48%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1
Cardiac failure
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 201 (0.50%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Angina pectoris
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardiomyopathy
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Nervous system disorders
Encephalopathy
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Intraventricular haemorrhage
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Neuromyopathy
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	2 / 205 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Neutropenia
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	2 / 205 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Subcutaneous emphysema
subjects affected / exposed	1 / 201 (0.50%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Decubitus ulcer
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dermatitis allergic
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	4 / 201 (1.99%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
IgA nephropathy
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	7 / 201 (3.48%)	1 / 209 (0.48%)	4 / 205 (1.95%)
occurrences causally related to treatment / all	0 / 7	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 1
Septic shock
subjects affected / exposed	4 / 201 (1.99%)	1 / 209 (0.48%)	2 / 205 (0.98%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 4	0 / 1	0 / 2
Sepsis
subjects affected / exposed	1 / 201 (0.50%)	1 / 209 (0.48%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Bronchitis
subjects affected / exposed	2 / 201 (1.00%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 201 (0.50%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	0 / 201 (0.00%)	0 / 209 (0.00%)	1 / 205 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia necrotising
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 201 (0.00%)	1 / 209 (0.48%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vestibular neuronitis
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	1 / 201 (0.50%)	0 / 209 (0.00%)	0 / 205 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	IV zanamivir 300 mg	IV zanamivir 600 mg	Oral oseltamivir 75 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	17 / 201 (8.46%)	26 / 209 (12.44%)	24 / 205 (11.71%)
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	10 / 201 (4.98%)	15 / 209 (7.18%)	14 / 205 (6.83%)
occurrences all number	11	20	14
Constipation
subjects affected / exposed	7 / 201 (3.48%)	13 / 209 (6.22%)	10 / 205 (4.88%)
occurrences all number	8	16	10

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Were there any global substantial amendments to the protocol? Yes

31 Jan 2011

(i) the liver criteria stopping exemption was deleted, (ii) update and clarification to inclusion criteria 1, 2, 4 and 5, and exclusion criteria 5, 7, 13 and 14, and (iii) update to the background information and some minor clarifications within the protocol. The majority of changes detailed in points (i) and (ii) were made in response to requests from regulatory authorities and Ethics Committees.

01 Jun 2012

(i) included a contingency study design change to allow for continuation of the study in the event of widespread oseltamivir resistance by temporarily or permanently discontinuing the oseltamivir arm, (ii) removal of exclusion criterion 13 (QTc entry criteria) and removal of Day 4 ECG measurements, and (iii) includes updates and clarifications within the protocol. The major change detailed in point (i) was made in response to comments from regulatory and health agencies to allow the study to be completed in the event of significant oseltamivir resistance developing during the course of the study.

24 Jan 2014

(i) changes to the data analysis and statistical considerations section of the protocol, including details of a second interim analysis, (ii) included a few clarifications and updates within the protocol. The major change detailed in point (i) was made following the outcome of the first interim analysis where the IDMC recommended that the study continue with all three treatment arms, resulting in an increase to the sample size from 462 to 600 participants. A second interim analysis was included to inform on whether it was appropriate to continue to recruit 600 participants. The statistical analysis framework was updated to allow for consideration of additional evidence beyond the original primary and secondary endpoints.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Median time to clinical response (TTCR) in participants with confirmed influenza

Primary: Median time to clinical response (TTCR) in participants with confirmed influenza

Primary: Percentage of participants with confirmed influenza acheiving a clinical response

Primary: Percentage of participants with confirmed influenza acheiving a clinical response

Secondary: Percent of participants with respiratory improvement

Secondary: Percent of participants with respiratory improvement

Secondary: Number of participants with all cause and attributable mortality at Day 14, at Day 28, and at the End of Study Visit

Secondary: Number of participants with all cause and attributable mortality at Day 14, at Day 28, and at the End of Study Visit

Secondary: Change from Baseline in the Katz Activities of Daily Living (ADL) score and each ADL activity score

Secondary: Change from Baseline in the Katz Activities of Daily Living (ADL) score and each ADL activity score

Secondary: Median time to return to pre-morbid functional status as measured by the Katz ADL score and each ADL activity score

Secondary: Median time to return to pre-morbid functional status as measured by the Katz ADL score and each ADL activity score

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

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

Secondary: Median time to return to the pre-morbid level of activity as measured by the 3-point scale

Secondary: Median time to return to the pre-morbid level of activity as measured by the 3-point scale

Secondary: Number of participants with the indicated clinical symptoms of influenza

Secondary: Number of participants with the indicated clinical symptoms of influenza

Secondary: Median duration of clinical symptoms of influenza

Secondary: Median duration of clinical symptoms of influenza

Secondary: Number of participants with complications of influenza and associated antibiotic use

Secondary: Number of participants with complications of influenza and associated antibiotic use

Secondary: Number of participants with the indicated ventilation status: modality of invasive and non-invasive ventilator support and oxygen supplementation

Secondary: Number of participants with the indicated ventilation status: modality of invasive and non-invasive ventilator support and oxygen supplementation

Secondary: Median time duration of invasive and non-invasive ventilator support and oxygen supplementation

Secondary: Median time duration of invasive and non-invasive ventilator support and oxygen supplementation

Secondary: Median time of duration of hospitalization and Intensive Care Unit (ICU) stay

Secondary: Median time of duration of hospitalization and Intensive Care Unit (ICU) stay

Secondary: Median time to the absence of fever and improved respiratory status, oxygen saturation, heart rate, and systolic blood pressure

Secondary: Median time to the absence of fever and improved respiratory status, oxygen saturation, heart rate, and systolic blood pressure

Secondary: Median time to virologic improvement

Secondary: Median time to virologic improvement

Secondary: Change from Baseline in quantitative virus culture from nasopharyngeal swabs positive at Baseline

Secondary: Change from Baseline in quantitative virus culture from nasopharyngeal swabs positive at Baseline

Secondary: Change from Baseline viral load (influenza A or B) by qPCR from nasopharyngeal swabs positive at Baseline

Secondary: Change from Baseline viral load (influenza A or B) by qPCR from nasopharyngeal swabs positive at Baseline

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)

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)

Secondary: Median time to no detectable viral RNA and the absence of cultivable virus in any obtained sample (upper and lower respiratory samples)

Secondary: Median time to no detectable viral RNA and the absence of cultivable virus in any obtained sample (upper and lower respiratory samples)

Secondary: Resistance-associated mutations events detected in the NA and HA gene of influenza A and B viruses in nasopharyngeal swabs and endotracheal/BAL samples

Secondary: Resistance-associated mutations events detected in the NA and HA gene of influenza A and B viruses in nasopharyngeal swabs and endotracheal/BAL samples

Secondary: Number of participants with any adverse event (AE) considered to be related to study treatment

Secondary: Number of participants with any adverse event (AE) considered to be related to study treatment

Secondary: Number of participants with any severe or Grade 3/4 AE

Secondary: Number of participants with any severe or Grade 3/4 AE

Secondary: Number of participants who permanently discontinued the study treatment due to an AE

Secondary: Number of participants who permanently discontinued the study treatment due to an AE

Secondary: Number of participants who were permanently discontinued from the study due to an AE

Secondary: Number of participants who were permanently discontinued from the study due to an AE

Secondary: Number of participants with any severe or Grade 3/4 treatment-related AE

Secondary: Number of participants with any severe or Grade 3/4 treatment-related AE

Secondary: Number of participants with the indicated chemistry laboratory values shifts from Baseline (Day 1) and up to 42 days

Secondary: Number of participants with the indicated chemistry laboratory values shifts from 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

Secondary: Number of participants with the indicated hematology values shifts from 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

Secondary: Number of participants with the indicated treatment-emergent (TE) Grade (G) 3/4 clinical chemistry toxicities

Secondary: Number of participants with the indicated treatment-emergent (TE) Grade 3/4 hematology toxicities

Secondary: Number of participants with the indicated treatment-emergent (TE) Grade 3/4 hematology toxicities

Secondary: Median quantity of oxygen delivery measured at Baseline (Day 1) and during the study

Secondary: Median quantity of oxygen delivery measured at 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

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

Secondary: Serum concentration of intravenous (IV) zanamivir

Secondary: Serum concentration of intravenous (IV) zanamivir

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)