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

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

Inclusion Criteria:

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

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

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

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

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

AND at least 2 out of the following 4:

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

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

4. Heart rate >100 beats per minute.

5. Systolic blood pressure <90 mmHg.

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

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

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

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

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

Exclusion Criteria:

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

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

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

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

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

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

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

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

1. ALT or AST 3xULN and bilirubin 2xULN

2. ALT 5xULN

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

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

- Females who are pregnant or are breastfeeding.

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

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