Title: A Phase 3, International, Double-Blind, Double-Dummy Study to Evaluate the Efficacy and Safety of 300 mg or 600 mg of Intravenous Zanamivir Twice Daily Compared to Oral Oseltamivir Twice Daily in the Treatment of Hospitalized Adults and Adolescents 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 300 mg or 600 mg twice daily compared to oral oseltamivir 75 mg twice daily 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.
- Male or female aged 16 years.
- Vital signs criteria defined as 3 or more of the following at Baseline:
- Presence of fever [oral temperature of 38°C or equivalent] at Baseline. However, this requirement is waived if the subjects has been administered antipyretics 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:
- Arterial oxygen saturation less than 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 arterial oxygen saturation of at least 3% below the patient's historical baseline oxygen saturation will satisfy this criterion.
- Respiration rate >24 breaths per minute. For those subjects who require ventilatory support or oxygen supplementation, this requirement is waived.
- Heart rate >100 beats per minute.
- Systolic blood pressure less than 90 mmHg.
- Onset of influenza symptoms within 6 days prior to study enrollment.
- Clinical symptoms of influenza with positive influenza diagnostic test result.
- Severity of any medical illness that, in the Investigator's judgement, justifies hospitalization of the subject for treatment and supportive care
- Subjects who have taken more than a total of 3 days (6 doses) of approved anti-influenza therapy (i.e. oral oseltamivir, oral inhaled zanamivir, oral amantadine, oral rimantadine, or oral ribavirin) 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. Underlying chronic liver disease with evidence of severe liver impairment (Child-Pugh Class C).
- 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.
Thomas Kerkering, M.D.
Karen G. Baker
Clinical Research Nurse