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Clinical Trial Results:
An Open-Label, Multi-Center, Single Arm Study to Evaluate the Safety and Tolerability of Intravenous Zanamivir in the Treatment of Hospitalized Adult, Adolescent and Pediatric Subjects with Confirmed Influenza Infection

Summary
EudraCT number	2009-016035-35
Trial protocol	FR ES DE GB Outside EU/EEA
Global end of trial date	13 Feb 2015

Results information
Results version number	v1(current)
This version publication date	10 Jul 2016
First version publication date	10 Jul 2016
Other versions

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

NAI113678

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, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001318-PIP01-12

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

24 Jun 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Feb 2015

Was the trial ended prematurely?

Main objective of the trial

To assess the safety and tolerability of IV zanamivir in the treatment of hospitalized adult, adolescent and pediatric subjects with influenza infection.

Protection of trial subjects

N/A

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Nov 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 32

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

France: 36

Country: Number of subjects enrolled

Thailand: 12

Country: Number of subjects enrolled

Australia: 9

Country: Number of subjects enrolled

South Africa: 1

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

Russian Federation: 1

Country: Number of subjects enrolled

United States: 95

Country: Number of subjects enrolled

Japan: 3

Worldwide total number of subjects

201

EEA total number of subjects

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)

106

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Male or female participants who were >= 6 months of age, hospitalized with laboratory-confirmed influenza, and able to receive study drug within 7 days of influenza symptom onset were enrolled in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 6: Adults (18 years and older)

Arm description

Participants >=18 years of age received 600 milligrams (mg) zanamivir by intravenous (IV) infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

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

Cohort 1: Infants (6 months to <1 year of age)

Arm description

Participants 6 months to <1 year of age received 14 mg per kilogram (mg/kg) zanamivir by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

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

14 mg/kg twice daily, adjusted for renal function

Cohort 2: Children (1 to <2 years of age)

Arm description

Participants 1 year to <2 years of age received 14 mg/kg zanamivir by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

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

14 mg/kg twice daily, adjusted for renal function

Cohort 3: Children (2 to <6 years of age)

Arm description

Participants 2 years to <6 years of age received 14 mg/kg zanamivir with a maximum dose of 600 mg by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

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

14 mg/kg twice daily, adjusted for renal function

Cohort 4: Children (6 to <13 years of age)

Arm description

Participants 6 years to <13 years of age received 12 mg/kg zanamivir with a maximum dose of 600 mg by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

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

12 mg/kg (maximum dose of 600 mg) twice daily, adjusted for renal function

Cohort 5: Adolescents (13 to <18 years of age)

Arm description

Participants 13 to <18 years of age received 12 mg/kg zanamivir with a maximum dose of 600 mg by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

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

12 mg/kg (maximum dose of 600 mg) twice daily, adjusted for renal function

Number of subjects in period 1	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Started	130	7	11	12	27	14
Completed	107	7	9	12	26	11
Not completed	23	0	2	0	1	3
Adverse event, serious fatal	20	-	1	-	1	3
Consent withdrawn by subject	1	-	-	-	-	-
Physician decision	1	-	-	-	-	-
Lost to follow-up	1	-	1	-	-	-

Baseline characteristics

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Reporting group title

Cohort 6: Adults (18 years and older)

Reporting group description

Reporting group title

Cohort 1: Infants (6 months to <1 year of age)

Reporting group description

Reporting group title

Cohort 2: Children (1 to <2 years of age)

Reporting group description

Reporting group title

Cohort 3: Children (2 to <6 years of age)

Reporting group description

Reporting group title

Cohort 4: Children (6 to <13 years of age)

Reporting group description

Reporting group title

Cohort 5: Adolescents (13 to <18 years of age)

Reporting group description

Reporting group values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)	Total
Number of subjects	130	7	11	12	27	14	201
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	48.3 ± 16.19	0.76 ± 0.127	1.33 ± 0.22	3.74 ± 1.201	8.67 ± 1.861	15.36 ± 1.151	-
Gender categorical
Units: Subjects
Female	56	1	4	4	9	6	80
Male	74	6	7	8	18	8	121
Race, Customized
Units: Subjects
African American/African Heritage	10	1	4	1	4	3	23
American Indian or Alaska Native	1	0	0	0	0	0	1
Asian - East Asian Heritage	4	0	0	0	0	0	4
Asian - South East Asian Heritage	10	0	0	0	0	0	10
Asian - Japanese Heritage	0	1	0	2	0	0	3
Native Hawaiian or Other Pacific Islander	0	0	0	0	1	0	1
White - Arabic/North African Heritage	6	0	0	1	1	0	8
White - White/Caucasian/European Heritage	97	5	7	7	18	11	145
Unknown	2	0	0	0	1	0	3
Mixed Race	0	0	0	1	2	0	3

End points

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Reporting group title

Cohort 6: Adults (18 years and older)

Reporting group description

Reporting group title

Cohort 1: Infants (6 months to <1 year of age)

Reporting group description

Reporting group title

Cohort 2: Children (1 to <2 years of age)

Reporting group description

Reporting group title

Cohort 3: Children (2 to <6 years of age)

Reporting group description

Reporting group title

Cohort 4: Children (6 to <13 years of age)

Reporting group description

Reporting group title

Cohort 5: Adolescents (13 to <18 years of age)

Reporting group description

Subject analysis set title

Cohort 6: Adults (18 years and older)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants >=18 years of age received 600 mg zanamivir by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

Subject analysis set title

Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants 6 months to <18 years of age received 14 mg/kg zanamivir (participants from 6 months to <6 years of age) or 12 mg/kg zanamivir (participants from 6 years to <18 years of age) with a maximum dose of 600 mg by IV infusion over 30 minutes twice daily, adjusted for renal function for 5 days. Treatment could be extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

Subject analysis set title

Cohort 6: Adults (18 years and older); zanamivir <=5 days

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants >=18 years of age received 600 mg zanamivir by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days.

Subject analysis set title

Cohort 6: Adults (18 years and older); zanamivir >5 days

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants >=18 years of age received 600 mg zanamivir by IV infusion over 30 minutes twice daily, adjusted for renal function, for >5 days and up to 10 days if viral shedding or clinical symptoms warranted further treatment.

Subject analysis set title

Cohort 1: Infants (6 months to <1 year of age)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants 6 months to <1 year of age received 14 mg/kg zanamivir by IV infusion over 30 minutes twice daily, adjusted for renal function, for 5 days. Treatment could have been extended for up to 5 additional days if viral shedding or clinical symptoms warranted further treatment.

Subject analysis set title

Cohort 2: Children (1 to <2 years of age)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 3: Children (2 to <6 years of age)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 4: Children (6 to <13 years of age)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 5: Adolescents (13 to <18 years of age)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: 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 ^[1]

End point description

End point type

Primary

End point timeframe

Up to post-treatment (PT) + 23 days

Notes
[1] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[2]	71 ^[3]
Units: Participants	28	5

Notes
[2] - Safety Population: participants who received >=1 dose of study medication.
[3] - Safety Population: participants who received >=1 dose of study medication.

No statistical analyses for this end point

Primary: Number of participants with any severe or Grade 3/4 AEs

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End point title

Number of participants with any severe or Grade 3/4 AEs ^[4]

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. AEs that occured 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 adult and pediatric AEs. Grade 3=severe; Grade 4=potentially life threatening.

End point type

Primary

End point timeframe

Up to post-treatment (PT) + 23 days

Notes
[4] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[5]	71 ^[6]
Units: Participants	57	23

Notes
[5] - Safety Population
[6] - Safety Population

No statistical analyses for this end point

Primary: 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 ^[7]

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. AEs that occured 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 assesed by the Investigator as related or not related to the study treatment.

End point type

Primary

End point timeframe

Up to post-treatment (PT) + 23 days

Notes
[7] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[8]	71 ^[9]
Units: Participants	16	2

Notes
[8] - Safety Population
[9] - Safety Population

No statistical analyses for this end point

Primary: 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 ^[10]

End point description

End point type

Primary

End point timeframe

Up to 10 days

Notes
[10] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[11]	71 ^[12]
Units: Participants	17	2

Notes
[11] - Safety Population
[12] - Safety Population

No statistical analyses for this end point

Primary: 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 ^[13]

End point description

End point type

Primary

End point timeframe

Up to post-treatment (PT) + 23 days

Notes
[13] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[14]	71 ^[15]
Units: Participants	20	5

Notes
[14] - Safety Population
[15] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with the indicated clinical chemistry values relative to the normal range at Baseline (Day 1) and Day 5

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End point title

Number of participants with the indicated clinical chemistry values relative to the normal range at Baseline (Day 1) and Day 5 ^[16]

End point description

Blood samples for laboratory assessments were collected at Baseline (Day [D] 1), Days 3 and 5, and on post-treatment +2 days (if hospitalized) and post-treatment +23 days. Clinical chemistry parameters summarized here include alanine aminotransferase (ALT), direct bilirubin (DB), total bilirubin (TB), and creatinine. The number of participants with values that were high (H)/normal (N)/low (L) relative to the normal range at Baseline (D 1) and D 5 for the indicated clinical chemistry parameters are summarized. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[16] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[17]	71 ^[18]
Units: Participants
D 1, H ALT, n=129, 71	48	21
D 1, N ALT, n=129, 71	79	49
D 1, L ALT, n=129, 71	1	1
D 5, H ALT, n=102, 45	41	16
D 5, N ALT, n=102, 45	60	27
D 5, L ALT, n=102, 45	1	1
D 1, H DB, n=83, 60	17	9
D 1, N DB, n=83, 60	61	45
D 1, L DB, n=83, 60	2	3
D 5, H DB, n=70, 36	20	4
D 5, N DB, n=70, 36	46	28
D 5, L DB, n=70, 36	1	1
D 1, H TB, n=128, 71	11	13
D 1, N TB, n=128, 71	110	50
D 1, L TB, n=128, 71	7	7
D 5, H TB, n=102, 42	13	6
D 5, N TB, n=102, 42	85	32
D 5, L TB, n=102, 42	4	2
D 1, H Creatinine, n=128, 71	27	6
D 1, N Creatinine, n=128, 71	50	56
D 1, L Creatinine, n=128, 71	51	9
D 5, H Creatinine, n=111, 46	31	7
D 5, N Creatinine, n=111, 46	46	34
D 5, L Creatinine, n=111, 46	34	5

Notes
[17] - Safety Population
[18] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with the indicated hematology values relative to the normal range at Baseline (Day 1) and Day 5

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End point title

Number of participants with the indicated hematology values relative to the normal range at Baseline (Day 1) and Day 5 ^[19]

End point description

Blood samples for laboratory assessments were collected at Baseline (Day [D] 1), Days 3 and 5, and on post-treatment +2 days (if hospitalized) and post-treatment +23 days. Hematology parameters summarized here include hemoglobin, total neutrophils (TN), and white blood cell (WBC) count. The number of participants with values that were high (H)/normal (N)/low (L) relative to the normal range at Baseline (D 1) and D 5 for the indicated hematology parameters are summarized. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[19] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[20]	71 ^[21]
Units: Participants
D 1, H Hemoglobin, n=130, 71	0	1
D 1, N Hemoglobin, n=130, 71	48	30
D 1, L Hemoglobin, n=130, 71	82	40
D 5, H Hemoglobin, n=114, 47	1	0
D 5, N Hemoglobin, n=114, 47	25	16
D 5, L Hemoglobin, n=114, 47	88	31
D 1, H TN, n=123, 70	51	34
D 1, N TN, n=123, 70	59	29
D 1, L TN, n=123, 70	13	7
D 5, H TN, n=106, 45	49	20
D 5, N TN, n=106, 45	49	18
D 5, L TN, n=106, 45	8	7
D 1, H WBC Count, n=130, 71	29	9
D 1, N WBC Count, n=130, 71	71	42
D 1, L WBC Count, n=130, 71	30	20
D 5, H WBC Count, n=114, 47	50	12
D 5, N WBC Count, n=114, 47	49	30
D 5, L WBC Count, n=114, 47	15	5

Notes
[20] - Safety Population
[21] - Safety Population

No statistical analyses for this end point

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

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End point title

Number of participants with the indicated treatment-emergent (TE) Grade 3/4 clinical chemistry toxicities ^[22]

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 summarized here include ALT, TB, and creatinine. 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 last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Primary

End point timeframe

Up to post-treatment (PT) + 23 days

Notes
[22] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[23]	71 ^[24]
Units: Participants
ALT, Grade 3, n=128, 68	10	1
ALT, Grade 4, n=128, 68	5	0
TB, Grade 3, n=127, 68	3	1
TB, Grade 4, n=127, 68	3	4
Creatinine, Grade 3, n=129, 68	6	3
Creatinine, Grade 4, n=129, 68	5	2

Notes
[23] - Safety Population
[24] - Safety Population

No statistical analyses for this end point

Primary: 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 ^[25]

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 summarized here include hemoglobin, TN, 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 last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Primary

End point timeframe

Up to post-treatment (PT) + 23 days

Notes
[25] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohorts 1-5: Pediatrics/adolescents (6 months to <18 years)
Number of subjects analysed	130 ^[26]	71 ^[27]
Units: Participants
Hemoglobin, Grade 3, n=129, 68	40	12
Hemoglobin, Grade 4, n=129, 68	9	2
TN, Grade 3, n=122, 66	0	3
TN, Grade 4, n=122, 66	1	2
WBC count, Grade 3, n=129, 68	2	1
WBC count, Grade 4, n=129, 68	2	0

Notes
[26] - Safety Population
[27] - Safety Population

No statistical analyses for this end point

Primary: Median heart rate at Baseline (Day 1) and Day 5

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End point title

Median heart rate at Baseline (Day 1) and Day 5 ^[28]

End point description

Heart rate was measured at Baseline (Day 1); Days 2, 3, 4, 5, 6, 7, 8, 9, and 10; post-treatment +2 days, +5 days, +9 days, +16 days (assessments to be done if participant remained hospitalized), and +23 days. Heart rate was assessed once daily during inpatient or outpatient follow-up visits. Heart rate values at Baseline (Day 1) and Day 5 are summarized. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X, X in the category titles).

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[28] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older); zanamivir <=5 days	Cohort 6: Adults (18 years and older); zanamivir >5 days	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	87 ^[29]	43 ^[30]	7 ^[31]	11 ^[32]	12 ^[33]	27 ^[34]	14 ^[35]
Units: Beats per minute (bpm)
median (full range (min-max))
Day 1, n=87, 43, 7, 11, 12, 27, 14	93 (58 to 143)	95 (50 to 140)	119 (95 to 156)	144 (121 to 195)	115.5 (92 to 160)	112 (59 to 185)	99 (74 to 134)
Day 5, n=73, 42, 7, 6, 9, 15, 10	87 (50 to 140)	93.5 (60 to 134)	127 (93 to 152)	122.5 (98 to 146)	112 (85 to 123)	102 (67 to 128)	79.5 (58 to 113)

Notes
[29] - Safety Population
[30] - Safety Population
[31] - Safety Population
[32] - Safety Population
[33] - Safety Population
[34] - Safety Population
[35] - Safety Population

No statistical analyses for this end point

Primary: Median systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline (Day 1) and Day 5

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End point title

Median systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline (Day 1) and Day 5 ^[36]

End point description

SBP and DBP were measured at Baseline (Day 1), Days 2, 3, 4, 5, 6, 7, 8, 9, and 10; post-treatment +2 days, +5 days, +9 days, +16 days (assessments to be done if participant remained hospitalized), and +23 days. SBP and DBP were assessed once daily during inpatient or outpatient follow-up visits. SBP and DBP values at Baseline (Day 1) and Day 5 are summarized. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X, X in the category titles).

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[36] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older); zanamivir <=5 days	Cohort 6: Adults (18 years and older); zanamivir >5 days	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	87 ^[37]	43 ^[38]	7 ^[39]	11 ^[40]	12 ^[41]	27 ^[42]	14 ^[43]
Units: Millimeters of mercury (mmHg)
median (full range (min-max))
SBP, Day 1, n=87, 43, 7, 11, 12, 27, 14	126 (70 to 175)	118 (80 to 180)	102 (83 to 116)	100 (77 to 144)	105.5 (82 to 124)	108 (70 to 136)	107 (95 to 137)
SBP, Day 5, n=73, 43, 7, 5, 9, 15, 10	128 (51 to 182)	132 (88 to 220)	103 (86 to 130)	98 (87 to 120)	117 (83 to 140)	110 (96 to 135)	108.5 (95 to 121)
DBP, Day 1, n=87, 43, 7, 11, 12, 27, 14	68 (32 to 96)	63 (40 to 97)	53 (42 to 64)	60 (39 to 78)	58 (37 to 86)	57 (41 to 82)	62 (36 to 74)
DBP, Day 5, n=73, 43, 7, 5, 9, 15, 10	70 (29 to 106)	66 (50 to 100)	60 (42 to 83)	60 (45 to 73)	67 (43 to 89)	68 (47 to 80)	54.5 (35 to 72)

Notes
[37] - Safety Population
[38] - Safety Population
[39] - Safety Population
[40] - Safety Population
[41] - Safety Population
[42] - Safety Population
[43] - Safety Population

No statistical analyses for this end point

Primary: Median oxygen saturation measured via transcutaneous oximetry (TCPO2) at Baseline (Day 1) and Day 5

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End point title

Median oxygen saturation measured via transcutaneous oximetry (TCPO2) at Baseline (Day 1) and Day 5 ^[44]

End point description

TCPO2 is a noninvasive test that directly measures the oxygen level of tissue beneath the skin. Because oxygen is carried to tissues by blood flow in the arteries, TCPO2 is an indirect measure of blood flow. The percent (%) oxygen saturation was measured at Baseline (Day 1), Days 2, 3, 4, 5, 6, 7, 8, 9, and 10; and post-treatment +2 days, +5 days, +9 days, +16 days (assessments to be done if participant remained hospitalized), and +23 days. Oxygen saturation was assessed once daily during inpatient follow-up visits. The median oxygen saturation values at Baseline (Day 1) and Day 5 are summarized. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X, X in the category titles).

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[44] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older); zanamivir <=5 days	Cohort 6: Adults (18 years and older); zanamivir >5 days	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	87 ^[45]	43 ^[46]	7 ^[47]	11 ^[48]	12 ^[49]	27 ^[50]	14 ^[51]
Units: Percentage of oxygen level in blood
median (full range (min-max))
Day 1, n=87, 43, 7, 11, 12, 27, 14	97 (82 to 100)	96 (70 to 100)	98 (76 to 100)	100 (93 to 100)	98 (93 to 100)	98 (91 to 100)	97.5 (94 to 100)
Day 5, n=70, 43, 7, 6, 9, 15, 9	97 (73 to 100)	96 (45 to 100)	100 (96 to 100)	95.5 (85 to 100)	97 (95 to 100)	97 (50 to 100)	96 (70 to 100)

Notes
[45] - Safety Population
[46] - Safety Population
[47] - Safety Population
[48] - Safety Population
[49] - Safety Population
[50] - Safety Population
[51] - Safety Population

No statistical analyses for this end point

Primary: Median respiration rate at Baseline (Day 1) and Day 5

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End point title

Median respiration rate at Baseline (Day 1) and Day 5 ^[52]

End point description

Respiration rate was measured at Baseline (Day 1), Days 2, 3, 4, 5, 6, 7, 8, 9, and 10; and post-treatment +2 days, +5 days, +9 days, +16 days (assessments to be done if participant remained hospitalized), and +23 days. Respiration rate was assessed once daily during inpatient or outpatient follow-up visits. The median respiration rate at Baseline (Day 1) and Day 5 is summarized. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X, X in the category titles).

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[52] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older); zanamivir <=5 days	Cohort 6: Adults (18 years and older); zanamivir >5 days	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	87 ^[53]	43 ^[54]	7 ^[55]	11 ^[56]	12 ^[57]	27 ^[58]	14 ^[59]
Units: Breaths per minute
median (full range (min-max))
Day 1, n=87, 43, 7, 11, 12, 27, 14	23 (6 to 47)	22 (10 to 40)	32 (28 to 46)	34 (20 to 40)	29.5 (22 to 66)	20 (4 to 49)	21 (0 to 98)
Day 5, n=67, 42, 7, 6, 9, 15, 10	20 (10 to 42)	23.5 (8 to 41)	40 (28 to 48)	31 (10 to 50)	30 (22 to 44)	23 (8 to 48)	19 (0 to 28)

Notes
[53] - Safety Population
[54] - Safety Population
[55] - Safety Population
[56] - Safety Population
[57] - Safety Population
[58] - Safety Population
[59] - Safety Population

No statistical analyses for this end point

Primary: Median body temperature at Baseline (Day 1) and Day 5

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End point title

Median body temperature at Baseline (Day 1) and Day 5 ^[60]

End point description

Body temperature was recorded at Baseline (Day 1), Days 2, 3, 4, 5, 6, 7, 8, 9, and 10; and post-treatment +2 days, +5 days, +9 days, +16 days (assessments to be done if participant remained hospitalized), and +23 days. Body temperature was recorded once daily during inpatient or outpatient follow-up visits. Median body temperature at Baseline (Day 1) and Day 5 is summarized. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X, X in the category titles).

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[60] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older); zanamivir <=5 days	Cohort 6: Adults (18 years and older); zanamivir >5 days	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	87 ^[61]	43 ^[62]	7 ^[63]	11 ^[64]	12 ^[65]	27 ^[66]	14 ^[67]
Units: Degrees centigrade
median (full range (min-max))
Day 1, n=87, 43, 7, 11, 12, 27, 14	37.3 (33.4 to 40.1)	37.3 (35.3 to 40.4)	36.8 (36 to 40)	37.3 (34 to 40)	37.5 (36 to 39)	37.3 (33 to 39)	37.5 (36 to 40)
Day 5, n=73, 42, 7, 6, 9, 15, 10	37 (35.3 to 38.8)	37.15 (34.5 to 39.8)	37 (36 to 38)	36.8 (36 to 38)	37.3 (37 to 38)	37.1 (37 to 39)	37.1 (37 to 39)

Notes
[61] - Safety Population
[62] - Safety Population
[63] - Safety Population
[64] - Safety Population
[65] - Safety Population
[66] - Safety Population
[67] - Safety Population

No statistical analyses for this end point

Primary: Number of participants assessed as normal/abnormal (clinically significant [CS] and not clinically significant [NCS]) for 12-lead electrocardiogram (ECG) at Baseline (Day 1)

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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) ^[68]

End point description

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

End point type

Primary

End point timeframe

Baseline (Day 1)

Notes
[68] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[69]	7 ^[70]	11 ^[71]	12 ^[72]	27 ^[73]	14 ^[74]
Units: Participants
Normal, n=128, 7, 10, 12, 25, 13	68	5	7	8	20	8
Abnormal NCS, n=128, 7, 10, 12, 25, 13	57	2	2	4	5	5
Abnormal CS, n=128, 7, 10, 12, 25, 13	7	0	1	0	0	0

Notes
[69] - Safety Population
[70] - Safety Population
[71] - Safety Population
[72] - Safety Population
[73] - Safety Population
[74] - Safety Population

No statistical analyses for this end point

Primary: Median corrected QT interval (QTc) for heart rate by Fridericia’s formula (QTcF) and Bazett’s formula (QTcB) at Baseline (Day 1) and Day 5

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End point title

Median corrected QT interval (QTc) for heart rate by Fridericia’s formula (QTcF) and Bazett’s formula (QTcB) at Baseline (Day 1) and Day 5 ^[75]

End point description

Twelve-lead ECGs were recorded for the parameters of QTcF and QTcB. The first set of pre-dose ECG values at Baseline (Day 1) and the pre-dose ECG values at Day 5 are presented. Baseline is defined as the last pre-treatment value collected. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X, X in the category titles). "99999" indicates that data are not available/analysis was not performed.

End point type

Primary

End point timeframe

Baseline (Day 1) and Day 5

Notes
[75] - 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: Statistical analysis was not conducted for this endpoint; there are no data to report.

End point values	Cohort 6: Adults (18 years and older); zanamivir <=5 days	Cohort 6: Adults (18 years and older); zanamivir >5 days	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	87 ^[76]	43 ^[77]	7 ^[78]	11 ^[79]	12 ^[80]	27 ^[81]	14 ^[82]
Units: Milliseconds
median (full range (min-max))
QTcF, Baseline, n=87, 42, 6, 9, 11, 24, 13	400.6 (204 to 584)	413.5 (285 to 502)	356 (0 to 465)	362 (331 to 426)	365 (297 to 483)	387.5 (267 to 544)	387 (271 to 424)
QTcF, Day 5, n=68, 40, 0, 1, 3, 3, 5	406.6 (298 to 610)	405.5 (339 to 555)	99999 (99999 to 99999)	373 (373 to 373)	394 (291 to 411)	353 (310 to 392)	389 (179 to 409)
QTcB, Baseline, n=87, 42, 6, 9, 11, 24, 13	424 (231 to 642)	432 (310 to 514)	412 (0 to 443)	422 (389 to 502)	410 (330 to 493)	422.5 (264 to 497)	415 (316 to 467)
QTcB, Day 5, n=68, 40, 0, 1, 3, 3, 5	422 (325 to 649)	434 (334 to 535)	99999 (99999 to 99999)	416 (416 to 416)	444 (321 to 475)	380 (350 to 410)	399 (189 to 422)

Notes
[76] - Safety Population
[77] - Safety Population
[78] - Safety Population
[79] - Safety Population
[80] - Safety Population
[81] - Safety Population
[82] - Safety 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

Time to virologic improvement is defined as a 2-log drop in viral load or undetectable viral ribonucleic acid (RNA) as measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal samples (PCR positive at Baseline). Only those participants available at the specified time points were analyzed.

End point type

Secondary

End point timeframe

Up to post-treatment (PT) + 23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	76 ^[83]	5 ^[84]	7 ^[85]	9 ^[86]	13 ^[87]	7 ^[88]
Units: Days
median (full range (min-max))	3 (1 to 26)	4 (2 to 9)	4 (3 to 25)	3 (3 to 7)	5 (3 to 6)	4 (2 to 13)

Notes
[83] - ITT-E Population
[84] - ITT-E Population
[85] - ITT-E Population
[86] - ITT-E Population
[87] - ITT-E Population
[88] - ITT-E Population

No statistical analyses for this end point

Secondary: Median change from Baseline (Influenza A or B quantitative PCR, as appropriate) in viral load at the indicated time points

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End point title

Median change from Baseline (Influenza A or B quantitative PCR, as appropriate) in viral load at the indicated time points

End point description

Change from Baseline in viral load was measured from nasopharyngeal swab samples, as determined by RT-PCR (PCR positive at Baseline). Nasopharyngeal swab samples were collected at Baseline (Day 1); Day 2, Day 3, Day 4, Day 5, Day 7, and Day 10; and, only if the participants had continued symptoms and were hospitalized, post-treatment (PT) samples were collected at +2 days, +5 days, +9 days, +16 days, and +23 days. 'PT +23 days' also comprises viral load values at early study withdrawal. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X in the category titles). "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Baseline (Day 1); Days 2, 3, 4, 5, 7, and 10; and post-treatment +2, +5, +9, +16, +23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[89]	7 ^[90]	11 ^[91]	12 ^[92]	27 ^[93]	14 ^[94]
Units: Log10 copies per milliliter
median (full range (min-max))
Day 2, n=89, 0, 0, 2, 3, 2	-0.92 (-4 to 2)	99999 (99999 to 99999)	99999 (99999 to 99999)	-3.75 (-3.87 to 3.63)	-1.16 (-1.87 to 0.5)	-2.28 (-2.55 to -2.01)
Day 3, n=82, 4, 7, 10, 15, 7	-1.42 (-3.38 to 1.08)	-1.655 (-3.15 to -0.94)	-1.93 (-4.36 to 0.55)	-2.215 (-6.16 to -0.49)	-1.33 (-5.19 to 0.62)	-2.55 (-4.01 to -0.29)
Day 4, n=84, 0, 0, 2, 2, 1	-1.59 (-5.4 to 1.38)	99999 (99999 to 99999)	99999 (99999 to 99999)	-4.895 (-5.01 to -4.78)	-2.06 (-2.06 to -1.52)	-2.55 (-2.55 to -2.55)
Day 5, n=75, 5, 4, 8, 12, 5	-1.57 (-5.06 to 2.05)	-2.72 (-4.92 to -0.12)	-3.705 (-6.2 to 0.24)	-3.285 (-6.16 to -1.81)	-2.93 (-6.71 to -1.53)	-2.55 (-4.01 to -1.4)
Day 7, n=23, 1, 1, 1, 3, 1	-1.58 (-3.52 to 3.02)	-1.82 (-1.82 to -1.82)	-6.2 (-6.2 to -6.2)	-3.03 (-3.03 to -3.03)	-3.04 (-3.46 to -1.26)	-1.61 (-1.61 to -1.61)
Day 10, n=19, 0, 2, 1, 4, 1	-1.75 (-4 to 2.04)	99999 (99999 to 99999)	-5.385 (-6.2 to -4.57)	-6.43 (-6.43 to -6.43)	-4.76 (-5.42 to -2.48)	-1.67 (-1.67 to -1.67)
PT +2 days, n=32, 0, 1, 2, 6, 3	-1.38 (-4.86 to 0.46)	99999 (99999 to 99999)	-6.2 (-6.2 to -6.2)	-2.495 (-2.91 to -2.08)	-3.825 (-5.42 to -1.6)	-3.06 (-4.61 to -1.63)
PT +5 days, n=26, 0, 2, 0, 5, 2	-1.84 (-5.21 to -0.4)	99999 (99999 to 99999)	-5.385 (-6.2 to -4.57)	99999 (99999 to 99999)	-4.19 (-5.42 to -1.6)	-3.275 (-3.43 to -3.12)
PT +9 days, n=27, 0, 1, 0, 3, 2	-2.58 (-5.21 to -0.41)	99999 (99999 to 99999)	-6.2 (-6.2 to -6.2)	99999 (99999 to 99999)	-4.19 (-5.42 to -1.6)	-3.865 (-4.61 to -3.12)
PT +16 days, n=21, 0, 1, 0, 4, 1	-2.48 (-5.21 to -0.41)	99999 (99999 to 99999)	-2.95 (-2.95 to -2.95)	99999 (99999 to 99999)	-3.825 (-4.56 to -1.6)	-4.61 (-4.61 to -4.61)
PT +23 days, n=21, 2, 4, 0, 4, 0	-2.89 (-5.21 to -0.46)	-4.455 (-4.92 to -3.99)	-4.67 (-6.2 to -2.95)	99999 (99999 to 99999)	-3.825 (-4.56 to -1.6)	99999 (99999 to 99999)

Notes
[89] - ITT-E Population
[90] - ITT-E Population
[91] - ITT-E Population
[92] - ITT-E Population
[93] - ITT-E Population
[94] - ITT-E Population

No statistical analyses for this end point

Secondary: Mean viral susceptibility to zanamivir at Baseline (Day 1) and all Post-Baseline visits collectively

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End point title

Mean viral susceptibility to zanamivir at Baseline (Day 1) and all Post-Baseline visits collectively ^[95]

End point description

Viral susceptibility to zanamivir at Baseline and at all post-Baseline visits collectively was assessed by neuraminidase (NA) enzyme inhibition assay. The mean IC50 data are summarized by subtype (A/H1N1, A/H3N2, B) and by visit. IC50 is defined as the concentration of zanamvir required to inhibit NA activity by 50%. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Baseline and up to post-treatment (PT) + 23 days

Notes
[95] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not conducted for all arms; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)
Number of subjects analysed	130 ^[96]
Units: Nanomolar (nM)
arithmetic mean (standard deviation)
A/H1N1, Day 1, n=22	0.2091 ± 0.06886
A/H1N1, All Post-Baseline, n=8	0.18 ± 0.04
A/H3N2, Day 1, n=5	0.266 ± 0.08385
A/H3N2, All Post-Baseline, n=2	0.23 ± 0.01414
B, Day 1, n=2	1.61 ± 0.35355
B, All Post-Baseline, n=0	99999 ± 99999

Notes
[96] - ITT-E Population

No statistical analyses for this end point

Secondary: Number of participants with treatment-emergent (TE) mutations

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End point title

Number of participants with treatment-emergent (TE) mutations ^[97]

End point description

Viral RNA isolated from participants at Baseline (Day 1) and post-Baseline visits were sequenced to determine the presence of TE neuraminidase (NA) and hemagglutinin (HA) mutations resulting from selective pressure. A mutation was considered to be TE if it was not present at Baseline and was present in the post-Baseline sample analyzed.These mutations were classified as either known to confer zanamvir resistance or novel mutations with unknown clinical significance.

End point type

Secondary

End point timeframe

Baseline and up to post-treatment (PT) + 23 days

Notes
[97] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not conducted for all arms; there are no data to report.

End point values	Cohort 6: Adults (18 years and older)
Number of subjects analysed	130 ^[98]
Units: Participants
Known Zanamivir-Resistant NA Mutations	0
Novel NA Mutations	5
Resistant HA Mutations	2
Novel HA Mutations	4

Notes
[98] - ITT-E Population

No statistical analyses for this end point

Secondary: Median time to resolution of individual vital signs

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End point title

Median time to resolution of individual vital signs

End point description

Times to return to afebrile status (normal body temperature), normal respiratory status, normal heart rate, and normal systolic blood pressure were assessed. Afebrile status is defined as a temperature <=36.6 axilla, <=37.2 oral, or <=37.7 rectal, core or typanic, degrees Centigrade. A return to normal respiratory status is defined as either: (a) return to pre-morbid oxygen requirement; or (b) return to no need for supplemental oxygen; or (c) respiratory rate <=60, <=40, <=34, <=30, <=24 or <=24 breaths/minute (without supplemental oxygen) for Cohorts 1-6 respectively . A normal HR is defined as <=160, <=150, <=140, <=120, <=100 or <=100 bpm for Cohorts 1-6 respectively, and a normal SBP is defined as >=70, >=74, >=76, >=80, >=90 or >=90 mmHg for Cohorts 1-6 respectively. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X, X, X in the category titles).

End point type

Secondary

End point timeframe

Up to post-treatment (PT) + 23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[99]	7 ^[100]	11 ^[101]	12 ^[102]	27 ^[103]	14 ^[104]
Units: Days
median (full range (min-max))
Afebrile Status, n=120, 7, 11, 7, 24, 13	3 (2 to 34)	4 (2 to 26)	2 (1 to 30)	25 (2 to 32)	3 (2 to 26)	3 (2 to 15)
Respiratory Status, n=89, 7, 10, 12, 23, 9	8 (2 to 36)	5 (2 to 16)	2 (1 to 21)	3.5 (2 to 21)	3 (2 to 33)	2 (2 to 20)
HR, n=121, 7, 11, 12, 27, 13	2 (2 to 22)	2 (2 to 2)	2 (1 to 25)	2 (2 to 3)	2 (2 to 31)	2 (2 to 5)
SBP, n=128, 7, 11, 12, 27, 14	2 (2 to 3)	2 (2 to 2)	2 (1 to 3)	2 (2 to 3)	2 (2 to 24)	2 (2 to 3)

Notes
[99] - ITT-E Population
[100] - ITT-E Population
[101] - ITT-E Population
[102] - ITT-E Population
[103] - ITT-E Population
[104] - ITT-E Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated ventilation status: modality of supplemental oxygen delivery and mechanical ventilation

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End point title

Number of participants with the indicated ventilation status: modality of supplemental oxygen delivery and mechanical ventilation

End point description

Ventilation status was measured at Baseline (Day 1); Days 2, 3, 4, 5, 6, 7, 8, 9, and 10; and post-treatment +2 days, +5 days, +9 days, +16 days (assessments to be done if participant remained hospitalized), and +23 days. Ventilation status was assessed once daily during inpatient follow-up visits. The number of participants reported for machine-assisted: extracorporeal membrane oxygenation (ECMO), endotracheal mechanical ventilation, and supplemental oxygen delivery (SOD) at “any time (AT) on study” and at Baseline (Day 1) are summarized.

End point type

Secondary

End point timeframe

Up to post-treatment (PT) + 23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[105]	7 ^[106]	11 ^[107]	12 ^[108]	27 ^[109]	14 ^[110]
Units: Participants
AT on Study, Machine-Assisted: ECMO	4	0	1	0	2	1
AT on Study, Machine-Assisted: Endotracheal	74	3	5	4	14	4
AT on Study, SOD	91	3	5	7	13	5
Day 1, Machine-Assisted: ECMO	3	0	1	0	2	1
Day 1, Machine-Assisted: Endotracheal	60	2	3	4	11	4
Day 1, SOD	46	1	3	1	6	1

Notes
[105] - ITT-E Population
[106] - ITT-E Population
[107] - ITT-E Population
[108] - ITT-E Population
[109] - ITT-E Population
[110] - ITT-E Population

No statistical analyses for this end point

Secondary: Duration of mechanical ventilation and supplemental oxygen use

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End point title

Duration of mechanical ventilation and supplemental oxygen use

End point description

Due to the conditional nature of data collection post treatment, the duration of mechanical ventilation and supplemental oxygen use were not determined.

End point type

Secondary

End point timeframe

Up to discharge from the hospital

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	0 ^[111]	0 ^[112]	0 ^[113]	0 ^[114]	0 ^[115]	0 ^[116]
Units: Days
median (full range (min-max))	( to )	( to )	( to )	( to )	( to )	( to )

Notes
[111] - ITT-E Population
[112] - ITT-E Population
[113] - ITT-E Population
[114] - ITT-E Population
[115] - ITT-E Population
[116] - ITT-E Population

No statistical analyses for this end point

Secondary: Median time to return to pre-morbid functional status

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End point title

Median time to return to pre-morbid functional status

End point description

Time to return to pre-morbid functional status was assessed on a 3-point scale (bed rest, limited ambulation, or unrestricted). Only those participants available at the specified time points were analyzed.

End point type

Secondary

End point timeframe

Up to post-treatment (PT) + 23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	76 ^[117]	7 ^[118]	9 ^[119]	11 ^[120]	22 ^[121]	9 ^[122]
Units: Days
median (full range (min-max))	10 (2 to 48)	8 (2 to 27)	3 (2 to 27)	5 (2 to 28)	5.5 (2 to 34)	4 (2 to 8)

Notes
[117] - ITT-E Population
[118] - ITT-E Population
[119] - ITT-E Population
[120] - ITT-E Population
[121] - ITT-E Population
[122] - ITT-E Population

No statistical analyses for this end point

Secondary: Number of participants with the indicated mortality status at Day 14 and Day 28

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End point title

Number of participants with the indicated mortality status at Day 14 and Day 28

End point description

The number of participants who died on or before Study Day 14 and Study Day 28 was summarized. Only those participants available at the specified time points were analyzed.

End point type

Secondary

End point timeframe

Day 14 and Day 28

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[123]	7 ^[124]	11 ^[125]	12 ^[126]	27 ^[127]	14 ^[128]
Units: Participants
Died on or before Study Day 14, No	113	7	11	12	26	12
Died on or before Study Day 14, Yes	17	0	0	0	1	2
Died on or before Study Day 28, No	108	7	10	12	26	11
Died on or before Study Day 28, Yes	22	0	1	0	1	3

Notes
[123] - ITT-E Population
[124] - ITT-E Population
[125] - ITT-E Population
[126] - ITT-E Population
[127] - ITT-E Population
[128] - ITT-E Population

No statistical analyses for this end point

Secondary: Median time to clinical response (sustained resolution) of all vital signs (composite)

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End point title

Median time to clinical response (sustained resolution) of all vital signs (composite)

End point description

Sustained resolution of the following vital signs (composite) was assessed: afebrile status, normal oxygen saturation, normal respiratory status, normal HR, and normal BP. Clinical response is defined as the resolution of at least four of five vital signs within the following resolution criteria, maintained for 24 hours or hospital discharge, whichever occurred first: Temperature in degrees Centigrade (<=36.6 axilla, <=37.2 oral, <=37.7 rectal, core or tympanic); oxygen saturation (>=95%, without supplemental oxygen); respiratory status (return to pre-morbid oxygen requirement, or no need for supplemental oxygen, or respiratory rate <=60, <=40, <=34, <=30, <=24 or <=24 breaths/minute without supplemental oxygen for Cohorts 1-6 respectively); HR (<=160, <=150, <=140, <=120, <=100 or <=100 bpm for Cohorts 1-6 respectively); SBP (>=70, >=74, >=76, >=80, >=90 or >=90 mmHg for Cohorts 1-6 respectively). Only those participants available at the specified time points were analyzed.

End point type

Secondary

End point timeframe

Up to post-treatment (PT) + 23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	81 ^[129]	7 ^[130]	10 ^[131]	12 ^[132]	25 ^[133]	11 ^[134]
Units: Days
median (full range (min-max))	9 (2 to 32)	7 (2 to 23)	3.5 (1 to 21)	6.5 (2 to 37)	4 (1 to 42)	5 (2 to 32)

Notes
[129] - ITT-E Population
[130] - ITT-E Population
[131] - ITT-E Population
[132] - ITT-E Population
[133] - ITT-E Population
[134] - ITT-E Population

No statistical analyses for this end point

Secondary: Number of participants with any AE categorized as an influenza complication

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End point title

Number of participants with any AE categorized as an influenza complication

End point description

End point type

Secondary

End point timeframe

Up to post-treatment (PT) + 23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[135]	7 ^[136]	11 ^[137]	12 ^[138]	27 ^[139]	14 ^[140]
Units: Participants	45	4	4	3	8	3

Notes
[135] - ITT-E Population
[136] - ITT-E Population
[137] - ITT-E Population
[138] - ITT-E Population
[139] - ITT-E Population
[140] - ITT-E Population

No statistical analyses for this end point

Secondary: Number of participants who used any concomitant antibiotic medications for complications of influenza

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End point title

Number of participants who used any concomitant antibiotic medications for complications of influenza

End point description

Concomitant medications (prescription and non-prescription) were permitted during the course of the study at the Investigator’s discretion (except for prohibited medications: during the treatment period with IV zanamivir, other influenza antiviral drugs were not permitted). The number of participants who were treated with antibiotics for influenza complications was summarized.

End point type

Secondary

End point timeframe

Up to post-treatment (PT) + 23 days

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[141]	7 ^[142]	11 ^[143]	12 ^[144]	27 ^[145]	14 ^[146]
Units: Participants	63	5	7	7	12	6

Notes
[141] - ITT-E Population
[142] - ITT-E Population
[143] - ITT-E Population
[144] - ITT-E Population
[145] - ITT-E Population
[146] - ITT-E Population

No statistical analyses for this end point

Secondary: Median duration of hospitalization and intensive care unit (ICU) stays

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End point title

Median duration of hospitalization and intensive care unit (ICU) stays

End point description

The duration of hospitalization (H) reflects the number of hospitalization days between the date of the first dose of investigational product and the date of discharge. ICU stay includes total duration in ICU and may include days in ICU before entry into the study. For participants with a missing discharge date who were not discharged at the end of the study, the date of discharge was imputed to the last follow-up visit (post-treatment +23 days). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Up to discharge from hospital

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[147]	7 ^[148]	11 ^[149]	12 ^[150]	27 ^[151]	14 ^[152]
Units: Days
median (full range (min-max))
Duration of H, n=130, 7, 11, 12, 27, 14	15 (1 to 133)	7 (2 to 23)	4 (2 to 44)	6.5 (3 to 37)	6 (1 to 45)	6.5 (2 to 42)
Duration of H-ICU, n=108, 4, 6, 8, 19, 9	11.5 (1 to 104)	7.5 (5 to 24)	5 (3 to 19)	5.5 (2 to 26)	8 (2 to 50)	8 (4 to 39)

Notes
[147] - ITT-E Population
[148] - ITT-E Population
[149] - ITT-E Population
[150] - ITT-E Population
[151] - ITT-E Population
[152] - ITT-E Population

No statistical analyses for this end point

Secondary: Geometric mean maximum serum concentration (Cmax) of zanamivir at the end of infusion

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End point title

Geometric mean maximum serum concentration (Cmax) of zanamivir at the end of infusion

End point description

The Cmax of zanamivir was evaluated at the end of infusion. Serial blood samples for pharmacokinetic (PK) analysis were collected if possible in conjunction with the initial dose on Day 1 (5-7 serial samples) and over a dosing interval during repeat dosing on Days 3, 4, or 5 (5 serial samples). PK data for all participants with available blood samples were analyzed. PK data for those participants who were neither on extracorporeal membrane oxygenation (ECMO) nor on continuous renal replacement therapy (CRRT), who had CLcr >=80 mL/minutes (>=80mL/minute/1.73m^2 for cohorts 1-4) and who received an initial dose (ID) and a maintenance dose (MD) of 14 mg/kg (6 months to <6 years of age), 12 mg/kg, not to exceed 600 mg (6 to <18 years of age) or 600 mg zanamivir (>=18 years of age) (represented by n=X in the category titles) were summarized. "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Day 1 and Days 3, 4, or 5

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[153]	7 ^[154]	6 ^[155]	12 ^[156]	15 ^[157]	13 ^[158]
Units: Micrograms per mL
geometric mean (geometric coefficient of variation)
ID, 600 mg, CLcr>=80, n=67, 0, 0, 0, 0, 6	32.77 ± 34	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	34.47 ± 27
ID, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 9, 3	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	44.16 ± 47	4.99 ± 3997
ID, 14 mg/kg, CLcr>=80, n=0, 4, 5, 9, 0, 0	99999 ± 99999	36.21 ± 21	37.78 ± 24	41.54 ± 23	99999 ± 99999	99999 ± 99999
MD, 600 mg, CLcr>=80, n=72, 0, 0, 0, 0, 2	35.3 ± 32	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	25.73 ± 52
MD, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 4, 0	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	45.18 ± 48	99999 ± 99999
MD, 14 mg/kg, CLcr>=80, n=0, 0, 1, 4, 0, 0	99999 ± 99999	99999 ± 99999	38.01 ± 99999	43.19 ± 9	99999 ± 99999	99999 ± 99999

Notes
[153] - PK Parameter Population: participants with one or more estimated zanamivir PK parameters
[154] - PK Parameter Population: participants with one or more estimated zanamivir PK parameters
[155] - PK Parameter Population: participants with one or more estimated zanamivir PK parameters
[156] - PK Parameter Population: participants with one or more estimated zanamivir PK parameters
[157] - PK Parameter Population: participants with one or more estimated zanamivir PK parameters
[158] - PK Parameter Population: participants with one or more estimated zanamivir PK parameters

No statistical analyses for this end point

Secondary: Geometric mean area under the serum drug concentration-time curve (AUC) over a 12-hour dosing interval (AUC[0-tau]) and AUC extrapolated to infinity (AUC[0-inf]) of zanamivir

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End point title

Geometric mean area under the serum drug concentration-time curve (AUC) over a 12-hour dosing interval (AUC[0-tau]) and AUC extrapolated to infinity (AUC[0-inf]) of zanamivir

End point description

The AUC(0-tau) during the repeat dose interval and AUC(0-inf) for the initial dose were evaluated. Serial blood samples for PK analysis were collected if possible in conjunction with the initial dose on Day 1 (5-7 serial samples) and over a dosing interval during repeat dosing on Days 3, 4, or 5 (5 serial samples). PK data for all participants with available blood samples were analyzed. PK data for those participants not on ECMO or CRRT with a CLcr >=80 mL/minutes (>=80 mL/minute/1.73m^2 for cohorts 1-4) and who received an ID and a MD of 14 mg/kg (6 months to <6 years of age), 12 mg/kg, not to exceed 600 mg (6 to <18 years of age) or 600 mg zanamivir (>=18 years of age) (represented by n=X in the category titles) were summarized. "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Day 1 and Days 3, 4, or 5

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[159]	7 ^[160]	6 ^[161]	12 ^[162]	15 ^[163]	13 ^[164]
Units: Micrograms per hour per milliliter
geometric mean (geometric coefficient of variation)
AUC(0-inf), ID, 600 mg, CLcr>=80, n=63,0,0,0,0,5	82.86 ± 36	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	91.07 ± 27
AUC(0-inf), ID, 12 mg/kg, CLcr>=80, n=0,0,0,0,8,1	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	107.21 ± 41	135.22 ± 99999
AUC(0-inf), ID, 14 mg/kg, CLcr>=80, n=0,3,4,9,0,0	99999 ± 99999	75.31 ± 23	72.42 ± 14	80.28 ± 38	99999 ± 99999	99999 ± 99999
AUC(0-tau), MD, 600 mg, CLcr>=80, n=65,0,0, 0,0,2	90.33 ± 36	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	64.52 ± 30
AUC(0-tau), MD, 12 mg/kg, CLcr>=80, n=0,0,0,0,4,0	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	90.33 ± 45	99999 ± 99999
AUC(0-tau), MD, 14 mg/kg, CLcr>=80, n=0,0,1,4,0,0	99999 ± 99999	99999 ± 99999	68.2 ± 99999	81.02 ± 28	99999 ± 99999	99999 ± 99999

Notes
[159] - PK Parameter Population
[160] - PK Parameter Population
[161] - PK Parameter Population
[162] - PK Parameter Population
[163] - PK Parameter Population
[164] - PK Parameter Population

No statistical analyses for this end point

Secondary: Geometric mean terminal half life (t1/2) of zanamivir

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End point title

Geometric mean terminal half life (t1/2) of zanamivir

End point description

The t1/2 of zanamivir was evaluated. Terminal half life is defined as the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity. Serial blood samples for PK analysis were collected if possible in conjunction with the initial dose on Day 1 (5-7 serial samples) and over a dosing interval during repeat dosing on Day 3, 4, or 5 (5 serial samples). PK data for all participants with available blood samples were analyzed. PK data for those participants not on ECMO or CRRT with a CLcr>=80 mL/minutes (>=80 mL/minute/1.73m^2 for cohorts 1-4) and who received an ID and a MD of 14 mg/kg (6 months to <6 years of age), 12 mg/kg, not to exceed 600 mg (6 to <18 years of age) or 600 mg zanamivir (>=18 years of age) (represented by n=X in the category titles) were summarized. "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Day 1 and Days 3, 4, or 5

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[165]	7 ^[166]	6 ^[167]	12 ^[168]	15 ^[169]	13 ^[170]
Units: Hours
geometric mean (geometric coefficient of variation)
ID, 600 mg, CLcr>=80, n=67, 0, 0, 0, 0, 5	2.39 ± 31	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	2.06 ± 47
ID, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 8, 1	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	2.57 ± 55	2.16 ± 99999
ID, 14 mg/kg, CLcr>=80, n=0, 3, 5, 9, 0, 0	99999 ± 99999	1.84 ± 19	2.49 ± 118	1.6 ± 34	99999 ± 99999	99999 ± 99999
MD, 600 mg, CLcr>=80, n=68, 0, 0, 0, 0, 2	2.56 ± 34	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	1.73 ± 21
MD, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 4, 0	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	1.81 ± 41	99999 ± 99999
MD, 14 mg/kg, CLcr>=80, n=0, 0, 1, 4, 0, 0	99999 ± 99999	99999 ± 99999	1.68 ± 99999	1.76 ± 20	99999 ± 99999	99999 ± 99999

Notes
[165] - PK Parameter Population
[166] - PK Parameter Population
[167] - PK Parameter Population
[168] - PK Parameter Population
[169] - PK Parameter Population
[170] - PK Parameter Population

No statistical analyses for this end point

Secondary: Geometric mean serum clearance of zanamivir

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End point title

Geometric mean serum clearance of zanamivir

End point description

The serum clearance of zanamivir was evaluated. Clearance is defined as the volume of zanamivir per unit time eliminated from serum. Serial blood samples for PK analysis were collected if possible in conjunction with the initial dose on Day 1 (5-7 serial samples) and over a dosing interval during repeat dosing on Days 3, 4, or 5 (5 serial samples). PK data for all participants with available blood samples were analyzed. PK data for those participants not on ECMO or CRRT with a CLcr >=80 mL/minutes (>=80 mL/minute/1.73m^2 for cohorts 1-4) and who received an ID and a MD 14 mg/kg (6 months to <6 years of age), 12 mg/kg, not to exceed 600 mg (6 to <18 years of age) or 600 mg zanamivir (>=18 years of age) (represented by n=X in the category titles) were summarized. "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Day 1 and Days 3, 4, or 5

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[171]	7 ^[172]	6 ^[173]	12 ^[174]	15 ^[175]	13 ^[176]
Units: mL per minutes
geometric mean (geometric coefficient of variation)
ID, 600 mg, CLcr>=80, n=63, 0, 0, 0, 0, 5	120.68 ± 36	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	109.83 ± 27
ID, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 8, 1	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	46.7 ± 47	53.7 ± 99999
ID, 14 mg/kg, CLcr>=80, n=0, 3, 4, 9, 0, 0	99999 ± 99999	27.31 ± 32	31 ± 12	41.95 ± 37	99999 ± 99999	99999 ± 99999
MD, 600 mg, CLcr>=80, n=65, 0, 0, 0, 0, 2	110.71 ± 36	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	155.03 ± 30
MD, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 4, 0	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	68.61 ± 34	99999 ± 99999
MD, 14 mg/kg, CLcr>=80, n=0, 0, 1, 4, 0, 0	99999 ± 99999	99999 ± 99999	31.78 ± 99999	40.35 ± 35	99999 ± 99999	99999 ± 99999

Notes
[171] - PK Parameter Population
[172] - PK Parameter Population
[173] - PK Parameter Population
[174] - PK Parameter Population
[175] - PK Parameter Population
[176] - PK Parameter Population

No statistical analyses for this end point

Secondary: Geometric mean volume of distribution (Vd) of zanamivir

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End point title

Geometric mean volume of distribution (Vd) of zanamivir

End point description

TThe Vd of zanamivir was evaluated. Volume of distribution is defined as the apparent volume in which zanamivir is distributed. Serial blood samples for PK analysis were collected if possible in conjunction with the initial dose on Day 1 (5-7 serial samples) and over a dosing interval during repeat dosing on Days 3, 4, or 5 (5 serial samples). PK data for all participants with available blood samples were analyzed. PK data for those participants not on ECMO or CRRT with a CLcr >= 80 mL/minutes (>=80 mL/minute/1.73m^2 for cohorts 1-4) and who received an ID and a MD of 14 mg/kg (6 months to <6 years of age), 12 mg/kg, not to exceed 600 mg (6 to <18 years of age) or 600 mg zanamivir (>=18 years of age) (represented by n=X in the category titles) were summarized. "99999" indicates that data are not available/analysis was not performed.

End point type

Secondary

End point timeframe

Day 1 and Days 3, 4, or 5

End point values	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age)	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Number of subjects analysed	130 ^[177]	7 ^[178]	6 ^[179]	12 ^[180]	15 ^[181]	13 ^[182]
Units: Liters (L)
geometric mean (geometric coefficient of variation)
ID, 600 mg, CLcr>=80, n=63, 0, 0, 0, 0, 5	22.02 ± 30	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	18.57 ± 26
ID, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 8, 1	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	9.21 ± 48	10.09 ± 99999
ID, 14 mg/kg, CLcr>=80, n=0, 3, 4, 9, 0, 0	99999 ± 99999	3.77 ± 12	3.94 ± 29	5.15 ± 20	99999 ± 99999	99999 ± 99999
MD, 600 mg, CLcr>=80, n=65, 0, 0, 0, 0, 2	21.61 ± 33	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	23.2 ± 25
MD, 12 mg/kg, CLcr>=80, n=0, 0, 0, 0, 8, 0	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	9.82 ± 8	99999 ± 99999
MD, 14 mg/kg, CLcr>=80, n=0, 0, 1, 4, 0, 0	99999 ± 99999	99999 ± 99999	3.77 ± 99999	5.23 ± 32	99999 ± 99999	99999 ± 99999

Notes
[177] - PK Parameter Population
[178] - PK Parameter Population
[179] - PK Parameter Population
[180] - PK Parameter Population
[181] - PK Parameter Population
[182] - PK Parameter Population

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Non-serious adverse events (AEs) were collected from the start of study medication until follow-up (up to 33 days). Serious adverse events (SAEs) assessed as related to study participation were recorded from time of consent until any follow-up contact.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Cohort 6: Adults (18 years and older)

Reporting group description

Reporting group title

Cohort 1: Infants (6 months to <1 year of age)

Reporting group description

Reporting group title

Cohort 2: Children (1 to <2 years of age)

Reporting group description

Reporting group title

Cohort 3: Children (2 to <6 years of age

Reporting group description

Reporting group title

Cohort 4: Children (6 to <13 years of age)

Reporting group description

Reporting group title

Cohort 5: Adolescents (13 to <18 years of age)

Reporting group description

Serious adverse events	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Total subjects affected by serious adverse events
subjects affected / exposed	44 / 130 (33.85%)	1 / 7 (14.29%)	2 / 11 (18.18%)	0 / 12 (0.00%)	8 / 27 (29.63%)	4 / 14 (28.57%)
number of deaths (all causes)	33	0	1	0	1	3
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Multi-organ failure
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pyrexia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	7 / 130 (5.38%)	1 / 7 (14.29%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 5	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Brain herniation
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac disorders
Cardiac arrest
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Torsade de pointes
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Encephalopathy
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Cyclic vomiting syndrome
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Toxic skin eruption
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	7 / 130 (5.38%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acinetobacter bacteraemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Endocarditis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Superinfection bacterial
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral pericarditis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Cohort 6: Adults (18 years and older)	Cohort 1: Infants (6 months to <1 year of age)	Cohort 2: Children (1 to <2 years of age)	Cohort 3: Children (2 to <6 years of age	Cohort 4: Children (6 to <13 years of age)	Cohort 5: Adolescents (13 to <18 years of age)
Total subjects affected by non serious adverse events
subjects affected / exposed	100 / 130 (76.92%)	4 / 7 (57.14%)	7 / 11 (63.64%)	8 / 12 (66.67%)	20 / 27 (74.07%)	9 / 14 (64.29%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic myeloid leukaemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	15 / 130 (11.54%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	2 / 27 (7.41%)	0 / 14 (0.00%)
occurrences all number	26	0	1	0	2	0
Hypertension
subjects affected / exposed	11 / 130 (8.46%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	19	0	1	0	1	0
Deep vein thrombosis
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 12 (16.67%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	2	0	0
Thrombophlebitis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	4	0	0	0	0	0
Phlebitis
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Venous thrombosis
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Arterial thrombosis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Circulatory collapse
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Extremity necrosis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Haematoma
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypoperfusion
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Jugular vein thrombosis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Poor peripheral circulation
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Venous thrombosis limb
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	14 / 130 (10.77%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 12 (8.33%)	4 / 27 (14.81%)	1 / 14 (7.14%)
occurrences all number	14	1	0	1	4	1
Oedema
subjects affected / exposed	7 / 130 (5.38%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	7	0	0	1	0	0
Asthenia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	1 / 14 (7.14%)
occurrences all number	2	0	0	0	1	1
Pain
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	4	0	0	0	0	1
Drug withdrawal syndrome
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	2 / 27 (7.41%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	2	0
Chest pain
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Generalised oedema
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	1	0
Infusion site extravasation
subjects affected / exposed	1 / 130 (0.77%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	1	0	0	0	0
Catheter site haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Device occlusion
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Facial pain
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypothermia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Injection site reaction
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Multi-organ failure
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Oedema peripheral
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Thrombosis in device
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Unintentional medical device removal
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	0	0	0	0
Reproductive system and breast disorders
Perineal rash
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	6 / 130 (4.62%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	6	0	0	0	0	0
Dyspnoea
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	5	0	0	0	0	0
Bronchospasm
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Pneumothorax
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Pulmonary oedema
subjects affected / exposed	2 / 130 (1.54%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	1	0	0	0	0
Respiratory distress
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	1	0	1	0
Respiratory failure
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	0	1	0	1
Stridor
subjects affected / exposed	0 / 130 (0.00%)	2 / 7 (28.57%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	2	0	0	1	0
Cough
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	1	0	0
Epistaxis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	1	0
Acute pulmonary oedema
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Acute respiratory distress syndrome
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Acute respiratory failure
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Adenoidal hypertrophy
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0
Dysphonia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Haemoptysis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Interstitial lung disease
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0
Lung disorder
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Nasal dryness
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Pneumonia aspiration
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Pulmonary congestion
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Pulmonary hypertension
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Rhinorrhoea
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0
Tachypnoea
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Thoracic haemorrhage
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Wheezing
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	12 / 130 (9.23%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	12	0	0	0	1	0
Insomnia
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	4	0	0	0	1	0
Mental status changes
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	2	0	0	1	0	1
Agitation
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Delirium
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	1	0
Conduct disorder
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Confusional state
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Drug dependence
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Withdrawal syndrome
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	11 / 130 (8.46%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	11	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	5 / 130 (3.85%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	5	0	0	0	1	0
Blood creatinine phosphokinase increased
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	2	0	1	0	1	0
Hepatic enzyme increased
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Activated partial thromboplastin time prolonged
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	1	0
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Oxygen saturation decreased
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Transaminases increased
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood pressure increased
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood sodium increased
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood triglycerides increased
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Chest X-ray abnormal
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastric occult blood positive
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Haematrocrit decreased
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
International normalised ratio increased
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Liver function test abnormal
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Occult blood positive
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Prothrombin time prolonged
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Pseudomonas test positive
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Troponin I increased
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Injury, poisoning and procedural complications
Excoriation
subjects affected / exposed	1 / 130 (0.77%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	1	0	0	0	0
Contusion
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Endotracheal intubation complication
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Foot fracture
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Overdose
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Procedural pain
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	6 / 130 (4.62%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	6	0	0	0	0	0
Tachycardia
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Arrhythmia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Bundle branch block right
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Aortic valve incompetence
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Bradycardia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Bundle branch block left
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Cardiac failure congestive
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Dilatation ventricular
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Left ventricular dysfunction
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Left ventricular hypertrophy
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Mitral valve incompetence
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Right atrial dilatation
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Tricuspid valve incompetence
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Ventricular arrhythmia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	1	0
Critical illness polyneuropathy
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Dizziness
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	0	0	0	1
Neuromyopathy
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Aphasia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Apraxia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Brain injury
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Brain oedema
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Dizziness exertional
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Epilepsy
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Migraine
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Polyneuropathy
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Psychomotor hyperactivity
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	11 / 130 (8.46%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	3 / 27 (11.11%)	1 / 14 (7.14%)
occurrences all number	12	0	1	0	3	1
Neutropenia
subjects affected / exposed	1 / 130 (0.77%)	1 / 7 (14.29%)	2 / 11 (18.18%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	1	2	0	0	0
Thrombocytopenia
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	4	0	0	0	0	0
Leukocytosis
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	1	0	0	0
Leukopenia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	1	0
Thrombocytosis
subjects affected / exposed	2 / 130 (1.54%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	1	0	0	0	0
Coagulopathy
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	0	0	0	1
Agranulocytosis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Bandaemia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Eosinophilia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Haemolytic anaemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Lymphpenia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Normochromic normocytic anaemia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	1	0
Conjunctival oedema
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Diplopia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Dry eye
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Keratopathy
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Pupillary disorder
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal disorders
Constipation
subjects affected / exposed	10 / 130 (7.69%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	3 / 27 (11.11%)	0 / 14 (0.00%)
occurrences all number	10	0	1	0	3	0
Diarrhoea
subjects affected / exposed	10 / 130 (7.69%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	16	0	0	1	0	1
Vomiting
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	2 / 27 (7.41%)	1 / 14 (7.14%)
occurrences all number	4	0	0	1	2	1
Nausea
subjects affected / exposed	6 / 130 (4.62%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	6	0	0	0	1	0
Abdominal pain
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	1	0
Dyspepsia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Abdominal compartment syndrome
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Abdominal discomfort
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Abdominal distension
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastritis erosive
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Ileus
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Impaired gastic emptying
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Mouth haemorrhage
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Oral disorder
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Rectal haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Volvulus
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 27 (3.70%)	1 / 14 (7.14%)
occurrences all number	2	0	1	0	1	1
Hepatocellular injury
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	4	0	0	0	0	0
Cholestasis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Cholelithiasis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Hepatomegaly
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	5 / 130 (3.85%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	5	0	0	2	1	0
Decubitus ulcer
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	2 / 27 (7.41%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	2	0
Skin disorder
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	2 / 27 (7.41%)	0 / 14 (0.00%)
occurrences all number	1	0	1	0	5	0
Dermatitis diaper
subjects affected / exposed	0 / 130 (0.00%)	2 / 7 (28.57%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	0	0	0	0
Drug eruption
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	1	0
Blister
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Prurigo
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Rash erythematous
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Rash macular
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Rash vesicular
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin discolouration
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin exfoliation
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Subcutaneous emphysema
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Urticaria
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal and urinary disorders
Renal failure
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	3	0	0	1	0	2
Renal failure acute
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Dysuria
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Glycosuria
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Polyuria
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal impairment
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal tubular necrosis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	1 / 14 (7.14%)
occurrences all number	1	0	0	0	1	1
Hyperparathyroidism secondary
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Muscle atrophy
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Muscle spasms
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Muscular weakness
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Myalgia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Myositis ossificans
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Neck pain
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Rhabdomyolysis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Infections and infestations
Pneumonia
subjects affected / exposed	2 / 130 (1.54%)	2 / 7 (28.57%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	2	2	0	0	1	0
Urinary tract infection
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	4	0	0	0	1	0
Oral herpes
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	4	0	0	0	0	0
Bronchitis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Candida infection
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Bronchopneumonia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	2 / 11 (18.18%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0	0	0
Lung infection
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0	0	0
Pneumonia bacterial
subjects affected / exposed	1 / 130 (0.77%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	1	0	0	0	0
Sepsis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	1	0	0
Sinusitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	1	0
Bacterial disease carrier
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Bronchiolitis
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0
Clostridium difficile colitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Clostridium difficile infection
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Croup infectious
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Device related infection
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Empyema
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Enterococcal infection
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Genital herpes
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Hordeolum
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Oesophageal candidiasis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Ophthalmic herpes simplex
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Otitis media
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0
Otitis media acute
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Penile infection
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Pneumonia haemophilus
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Pneumonia necrotising
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	1	0	0	0
Pneumonia staphylococcal
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Pneumonia viral
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Pseudomonas bronchitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Respiratory moniliasis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	1	0
Rhinitis
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	0	0
Staphylococcal sepsis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Tracheitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	16 / 130 (12.31%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 12 (8.33%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	17	1	0	1	1	0
Hypoalbuminaemia
subjects affected / exposed	7 / 130 (5.38%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 12 (8.33%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	7	1	0	1	1	0
Hypophosphataemia
subjects affected / exposed	6 / 130 (4.62%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	7	0	1	0	0	0
Hyperglycaemia
subjects affected / exposed	4 / 130 (3.08%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	1 / 14 (7.14%)
occurrences all number	4	0	0	0	1	1
Hypocalcaemia
subjects affected / exposed	6 / 130 (4.62%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	6	0	0	0	0	0
Hyperkalaemia
subjects affected / exposed	5 / 130 (3.85%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	5	0	0	0	0	0
Hypernatraemia
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	1 / 14 (7.14%)
occurrences all number	3	0	0	0	1	1
Acidosis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	4	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Hypomagnesaemia
subjects affected / exposed	1 / 130 (0.77%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	1	0	1	0	0
Hyponatraemia
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Metabolic acidosis
subjects affected / exposed	2 / 130 (1.54%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	1	0	0
Metabolic alkalosis
subjects affected / exposed	3 / 130 (2.31%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0	0	0	0
Food intolerance
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	2 / 27 (7.41%)	0 / 14 (0.00%)
occurrences all number	0	0	0	0	2	0
Hyperphosphataemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	1	0
Hypochloraemia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	1 / 27 (3.70%)	0 / 14 (0.00%)
occurrences all number	0	0	0	1	1	0
Lactic acidosis
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	0	0	0	1
Fluid overload
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Fluid retention
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0
Hyperchloraemia
subjects affected / exposed	0 / 130 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	0	0	1
Hypophagia
subjects affected / exposed	0 / 130 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	1	0	0	0	0
Malnutrition
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0
Vitamin B12 deficiency
subjects affected / exposed	1 / 130 (0.77%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 27 (0.00%)	0 / 14 (0.00%)
occurrences all number	1	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

17 Feb 2010

Protocol Amendment 03 was written to i) modify pediatric/adolescent dose selection in response to recommendations from EU regulators, ii) add an inclusion criterion to include only subjects who have severe or progressive influenza illness on approved (fully licensed) influenza antiviral agents or who are considered unsuitable or inappropriate for treatment with approved influenza antivirals.

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.

Two participants who withdrew consent prior to receiving intravenous zanamivir have not been captured in any of the tables.

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Clinical trials

Clinical Trial Results: An Open-Label, Multi-Center, Single Arm Study to Evaluate the Safety and Tolerability of Intravenous Zanamivir in the Treatment of Hospitalized Adult, Adolescent and Pediatric Subjects with Confirmed Influenza Infection

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Primary: Number of participants with any severe or Grade 3/4 AEs

Primary: Number of participants with any severe or Grade 3/4 AEs

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

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

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

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

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

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

Primary: Number of participants with the indicated clinical chemistry values relative to the normal range at Baseline (Day 1) and Day 5

Primary: Number of participants with the indicated clinical chemistry values relative to the normal range at Baseline (Day 1) and Day 5

Primary: Number of participants with the indicated hematology values relative to the normal range at Baseline (Day 1) and Day 5

Primary: Number of participants with the indicated hematology values relative to the normal range at Baseline (Day 1) and Day 5

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

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

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

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

Primary: Median heart rate at Baseline (Day 1) and Day 5

Primary: Median heart rate at Baseline (Day 1) and Day 5

Primary: Median systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline (Day 1) and Day 5

Primary: Median systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Baseline (Day 1) and Day 5

Primary: Median oxygen saturation measured via transcutaneous oximetry (TCPO2) at Baseline (Day 1) and Day 5

Primary: Median oxygen saturation measured via transcutaneous oximetry (TCPO2) at Baseline (Day 1) and Day 5

Primary: Median respiration rate at Baseline (Day 1) and Day 5

Primary: Median respiration rate at Baseline (Day 1) and Day 5

Primary: Median body temperature at Baseline (Day 1) and Day 5

Primary: Median body temperature at Baseline (Day 1) and Day 5

Primary: Number of participants assessed as normal/abnormal (clinically significant [CS] and not clinically significant [NCS]) for 12-lead electrocardiogram (ECG) at Baseline (Day 1)

Primary: Number of participants assessed as normal/abnormal (clinically significant [CS] and not clinically significant [NCS]) for 12-lead electrocardiogram (ECG) at Baseline (Day 1)

Primary: Median corrected QT interval (QTc) for heart rate by Fridericia’s formula (QTcF) and Bazett’s formula (QTcB) at Baseline (Day 1) and Day 5

Primary: Median corrected QT interval (QTc) for heart rate by Fridericia’s formula (QTcF) and Bazett’s formula (QTcB) at Baseline (Day 1) and Day 5

Secondary: Median time to virologic improvement

Secondary: Median time to virologic improvement

Secondary: Median change from Baseline (Influenza A or B quantitative PCR, as appropriate) in viral load at the indicated time points

Secondary: Median change from Baseline (Influenza A or B quantitative PCR, as appropriate) in viral load at the indicated time points

Secondary: Mean viral susceptibility to zanamivir at Baseline (Day 1) and all Post-Baseline visits collectively

Secondary: Mean viral susceptibility to zanamivir at Baseline (Day 1) and all Post-Baseline visits collectively

Secondary: Number of participants with treatment-emergent (TE) mutations

Secondary: Number of participants with treatment-emergent (TE) mutations

Secondary: Median time to resolution of individual vital signs

Secondary: Median time to resolution of individual vital signs

Secondary: Number of participants with the indicated ventilation status: modality of supplemental oxygen delivery and mechanical ventilation

Secondary: Number of participants with the indicated ventilation status: modality of supplemental oxygen delivery and mechanical ventilation

Secondary: Duration of mechanical ventilation and supplemental oxygen use

Secondary: Duration of mechanical ventilation and supplemental oxygen use

Secondary: Median time to return to pre-morbid functional status

Secondary: Median time to return to pre-morbid functional status

Secondary: Number of participants with the indicated mortality status at Day 14 and Day 28

Secondary: Number of participants with the indicated mortality status at Day 14 and Day 28

Secondary: Median time to clinical response (sustained resolution) of all vital signs (composite)

Secondary: Median time to clinical response (sustained resolution) of all vital signs (composite)

Secondary: Number of participants with any AE categorized as an influenza complication

Secondary: Number of participants with any AE categorized as an influenza complication

Secondary: Number of participants who used any concomitant antibiotic medications for complications of influenza

Secondary: Number of participants who used any concomitant antibiotic medications for complications of influenza

Secondary: Median duration of hospitalization and intensive care unit (ICU) stays

Secondary: Median duration of hospitalization and intensive care unit (ICU) stays

Secondary: Geometric mean maximum serum concentration (Cmax) of zanamivir at the end of infusion

Secondary: Geometric mean maximum serum concentration (Cmax) of zanamivir at the end of infusion

Secondary: Geometric mean area under the serum drug concentration-time curve (AUC) over a 12-hour dosing interval (AUC[0-tau]) and AUC extrapolated to infinity (AUC[0-inf]) of zanamivir

Secondary: Geometric mean area under the serum drug concentration-time curve (AUC) over a 12-hour dosing interval (AUC[0-tau]) and AUC extrapolated to infinity (AUC[0-inf]) of zanamivir

Secondary: Geometric mean terminal half life (t1/2) of zanamivir

Secondary: Geometric mean terminal half life (t1/2) of zanamivir

Secondary: Geometric mean serum clearance of zanamivir

Secondary: Geometric mean serum clearance of zanamivir

Secondary: Geometric mean volume of distribution (Vd) of zanamivir

Secondary: Geometric mean volume of distribution (Vd) of zanamivir

Adverse events

Adverse events

Clinical Trial Results:
An Open-Label, Multi-Center, Single Arm Study to Evaluate the Safety and Tolerability of Intravenous Zanamivir in the Treatment of Hospitalized Adult, Adolescent and Pediatric Subjects with Confirmed Influenza Infection