Health Condition 1: null- Moderate to severe influenza
Conditions
Interventions
Intervention1: IV Zanamivir 300 mg twice daily:
Zanamivir aqueous solution may be administered as supplied or as an influsion in 0.9%
sodium chloride for intravenous administration. Dosage may be 300
Sponsors
GlaxoSmithKline Pharmaceuticals Ltd
Eligibility
Inclusion criteria
Inclusion criteria: 1. Male or female aged >=16 years; a female is eligible to enter and participate in the study if she is: a. of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or, b. of child-bearing potential, has a negative pregnancy test at Baseline, and agrees to one of the following methods for avoidance of pregnancy during the study and until the Post-Treatment +28 Days Follow-up Assessment: • Abstinence; or, • Oral contraceptive, either combined or progestogen alone; or, • Injectable progestogen; or, • Implants of levonorgestrel; or, • Estrogenic vaginal ring; or, • Percutaneous contraceptive patches; or • Intrauterine device (IUD) or intrauterine system (IUS) showing that the expected failure rate is less than 1% per year as stated in the IUD or IUS Product Label; or, • Has a male partner who is sterilized; or, • Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository). 2. Vital signs criteria defined as 3 or more of the following at Baseline: • Presence of fever [oral temperature of >=38°C (>=100.4°F), rectal, tympanic of >=38.5°C (>=101.3°F), or axilla >=37.4°C (>=99.3°F)] at Baseline. However, this requirement is waived if: i. The subject has a history of fever within the 24 hours prior to Baseline and has been administered any antipyretic(s) in the 24 hours prior to Baseline; or, ii. The subject has no history of documented fever as defined above, but reports a symptom of feverishness at some time during the 48 hours prior to Baseline. AND at least 2 out of the following 4: • Arterial oxygen saturation =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 patientâ??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 3. 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. 4. Clinical symptoms of influenza with positive diagnostic test result. • Subjects who have 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. OR Clinical symptoms of influenza with negative RAT or other influenza test result.
Exclusion criteria
Exclusion criteria: Exclusion Criteria Subjects meeting any of the following criteria must not be enrolled in the study: 1. Subjects who have taken more than a total of 3 days (6 doses) of approved antiinfluenza 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. 2. Subjects who, in the opinion of the investigator, are not likely to survive beyond 48 hours from Baseline. 3. Subjects who are considered to require concurrent therapy with another influenza antiviral medication. 4. Subjects who are known or suspected to be hypersensitive to any component of the study medications. 5. Subjects with creatinine clearance 10 mL/min who are not being treated with continuous renal replacement therapy (CRRT). 6. Subjects who require Extra Corporeal Membrane Oxygenation (ECMO) at Baseline (enrolled subject who subsequently require ECMO may continue in the study). 7. 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 (CVVH, CVVHD, CVVHDF, SLED, SCUF, CAVH, CAVHD, CAVHDF). 8. Liver toxicity criteria based on local laboratory results obtained within 24 hours of Baseline: • ALT or AST >=3xULN and bilirubin >=2xULN • ALT >=5xULN 9. Underlying chronic liver disease with evidence of severe liver impairment (Child- Pugh Class C). 10. 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. 11. Females who are pregnant (positive urine or serum pregnancy test at Baseline) or are breastfeeding. 12. Treatment with investigational parenteral anti-influenza drugs (IV peramivir, IV zanamivir or IV oseltamivir) in the 4 weeks prior to Baseline. 13. QT criteria at Baseline as defined below: • QTcB or QTcF 500 msec • If a subject has bundle branch block then criteria is QTcB or QTcF 530 msec 14. French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days. Subjects who meet the above criteria are considered eligible for the study. This includes, but is not limited to, subjects who are intubated/mechanically ventilated, immunocompromised, HIV positive or have renal impairment requiring approved renal replacement therapies
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess the efficacy of treatment with 300 mg or 600 mg of intravenous (IV) zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily on time toclinical response (TTCR).Timepoint: To assess the efficacy of treatment with 300 mg or 600 mg of intravenous (IV) zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily on time toclinical response (TTCR)assessed daily | — |
Secondary
| Measure | Time frame |
|---|---|
| To evaluate zanamivir pharmacokinetics (peak and trough serum concentrations) from 300 mg or 600 mg IV zanamivir in hospitalized adult and adolescent subjects.Timepoint: Until completion;To assess reduction in viral load from nasopharyngeal swabs (and lower respiratory tract samples, if available) following treatment with 300 mg or 600 mg of IV zanamivir twice daily compared to 75 mg oral oseltamivir twice daily.Timepoint: until completion;To assess the safety and tolerability of 300 mg and 600 mg of IV zanamivir in comparison to 75 mg oral oseltamivir twice daily in the treatment of hospitalized adult and adolescent subjects with influenza infection.Timepoint: Until completion;To assess viral susceptibility and development of resistance to zanamivir and oseltamivir.Timepoint: Until completion;To evaluate clinical improvement of influenzausing a variety of measures including improvement in Katz Activities of Daily Living (ADL) score and ADL activities, improvement in level of activity, duration and severity of influenza symptoms, duration of hospital stay, duration of Intensive Care Unit (ICU) stayTimepoint: until completion;To evaluate time to clinical response and antiviral efficacy in the subset of subjects with influenza virus with reduced susceptibility to oseltamivir and/or presence of H275Y mutation.Timepoint: until completion | — |
Countries
Australia, Belgium, Brazil, Canada, China, Czech Republic, Denmark, France, Germany, Greece, Hong Kong, Hungary, India, Mexico, Netherlands, New Zealand, Norway, Poland, Republic of Korea, Russian Federation, Slovakia, South Africa, Spain, Taiwan, Thailand, United Kingdom, United States of America
Contacts
Public ContactMr Kedar Nayak
GlaxoSmithKline Pharmaceuticals Limited
Outcome results
None listed