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

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

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

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.