NAI 114373

Purpose / Objectives

Primary Outcome

Secondary Outcomes

• Changes in the Katz Index of Independence in Activities of Daily Living (ADL) score and time to return to pre-morbid level of activity
• Mortality rate at Day 14 and Day 28
• Disease progression and complications of influenza
• Summary of ventilation status
• Duration of hospitalization and ICU (intense care unit) stay 
• Time to improvement of vital signs
• Time to reduction in viral load and percentage of patients with undetectable viral RNA obtained from upper and lower respiratory samples
• Changes in viral susceptibility 
• Pharmacokinetics of IV Zanamivir as measured by minimum or maximum serum concentration
• Safety and tolerability as measured by the incidence of adverse events and laboratory abnormalities 
• ECG(electrocardiogram) data 

Diagnosis

• Influenza

Target population

Age

16-

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 (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:

  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.

Study design

• Phase III
• Multicenter
• Three-arm
• Double-blind
• Randomized

Intervention

Drug: 300mg intravenous (IV) zanamivir and oral oseltamivir placebo

Drug: 600mg intravenous (IV) zanamivir and oral oseltamivir placebo

Drug: 75mg oral oseltamivir and intravenous zanamivir placebo

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