A Study of Intravenous Zanamivir in the Treatment of Hospitalized Patients With Influenza Infection

An Open-label, Multi-centre, Single Arm Study to Evaluate the Safety and Efficacy of Intravenous Zanamivir in the Treatment of Hospitalized Patients With Confirmed Influenza Infection (NAI115215)

This study will be an open-label, multi-center, single arm study to evaluate the safety and efficacy of IV zanamivir 600mg twice daily for 5 days in hospitalized subjects with laboratory confirmed influenza infection.

Adult subjects and adolescent subjects (≥50 kg) with normal renal function will receive 600mg per dose. Subjects with renal impairment will receive an adjusted dose based on calculated creatinine clearance. The initial 5 day treatment course may be extended for up to 5 additional days if viral shedding is determined to be ongoing or if clinical symptoms warrant further treatment with IV zanamivir.

The study duration is approximately 28 days for subjects whose treatment duration is 5 days, and up to approximately 33 days for subjects whose treatment duration is extended to a maximum of 10 days. The study will consist of Pre-dose Baseline Assessments (Day 1), During Treatment Assessments (Days 1 to 5, and up to Day 10), and Follow-up Assessments on the following days: Post-Treatment +2, +5, +9, +16 and +23 Days. For subjects who have been discharged from hospital, the Post-Treatment +2, +5, +9 and +16 Days Assessments can be made by telephone contact.

Inclusion Criteria:

• Male or female aged greater than or equal to 16 years of age; 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.

• Subjects who have laboratory confirmed influenza as determined by a positive result in a rapid antigen test (RAT) for influenza A or influenza B, or a laboratory test for influenza including but not limited to influenza virus antigen test, virus culture or RT-PCR test.

• Presence of fever [oral temperature of >=38 deg C, rectal, tympanic of >=38.5 deg C or axilla >=37.4 deg C] at Baseline. However, this requirement is waived if the subject has a history of fever within the 48 hours prior to Baseline and has been administered any antipyretic(s) in the 48 hours prior to Baseline.

• Hospitalized subjects with symptomatic influenza as defined by ANY of the following.

  1. Moderate to severe tachypnea (respiratory rate >=24/minute) OR
  2. Moderate to severe dyspnea (unable to speak in full sentences) OR
  3. Arterial oxygen saturation <95% on room air by trans-cutaneous method, or need for any supplemental oxygenation or ventilatory support [mechanical ventilation, bi-level positive airway pressure (bipap), continuous positive airway pressure (cpap)], 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 OR
  4. Hemodynamic instability, defined as systolic blood pressure <90 mmHg or heart rate >100 beats per minute OR
  5. Subject who became dehydrated and need whole-body management by hospitalization.

• 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.

• Subjects/legally acceptable representative of unconscious adults willing and able to give written informed consent to participate in the study, and subjects willing to adhere to the procedures stated in the protocol.

Exclusion Criteria:

• 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 who require Extra Corporeal Membrane Oxygenation (ECMO) at Baseline (enrolled subject who subsequently require ECMO may continue in the study).

• Liver toxicity criteria based on local laboratory results obtained at Baseline:

  1. ALT or AST >=3xULN and bilirubin >=2xULN
  2. ALT >=5xULN

• 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 or sub-investigator, will interfere with the safety of the individual subject.

• Females who are pregnant (positive urine or serum pregnancy test at Baseline) or are breastfeeding.

• QT criteria at Baseline as defined below:

  1. QTcB or QTcF >480 msec
  2. If a subject has bundle branch block then criteria is QTcB or QTcF >510 msec

• Subject has participated in any study using an investigational drug during the previous 30 days.