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Viral Clearance with 75 mg Twice Daily or 225 mg Twice Daily Oseltamivir Therapy in Critically Ill Patients with Pandemic (H1N1) 2009 Influenza Anand Kumar, MD Section of Critical Care Medicine Section of Infectious Diseases University of Manitoba, Winnipeg, Canada And the ROSII Study Group A Randomized, Double-Blinded Controlled Trial Comparing High vs Standard Dose Oseltamivir in Severe, Influenza Infection in ICU (ROSII) Steering Committee: Anand Kumar, Dean Fergusson, Arthur Slutsky, Neil Simonsen, Sean Bagshaw, Robert Fowler, Brent Winston, Alison McGeer Data Safety Monitoring Board: Steve Opal, Bruce Light, Chris Doig Data Coordination Centre: Applied Health Research Centre, Li Ka Shing Knowledge Institute, Toronto Central laboratory: National Microbiology Laboratory, Canadian Science Centre for Human and Animal Health, Public Health Agency of Canada, Winnipeg Funding: Public Health Agency of Canada, Hoffmann –La Roche Ltd Participating Sites 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Foothills Medical Centre/Peter Lougheed Hospital, Calgary –Brent Winston Queen Elizabeth II Health Sciences Center, Halifax –Richard Hall Sunnybrook Hospital, Toronto –Robert Fowler The Ottawa Hospital (Civic and General), Ottawa –Lauralyn McIntyre Health Sciences Centre, St. Boniface Hospital and Grace Hospital, Winnipeg –Anand Kumar University of Alberta Hospital, Edmonton –Sean Bagshaw Royal Alexandra Hospital, Edmonton –Demetrios Kutsogiannis St. Michael’s Hospital, Toronto –John Marshall St. Joseph’s Hospital, Hamilton –Deb Cook Health Sciences Centre, St. John’s –Natalie Bandrauk Rouge Valley Hospital (Centenary and Ajax)/Lakeridge Hospital, Toronto – Michael Silverman Victoria General Hospital/Royal Jubiliee Hospital, Victoria –Gordon Wood Stollery Children's Hospital , Edmonton –Ari Joffe Royal Victoria Hospital/Montreal General Hospital, Montreal – Kosar Khwaja Introduction • Pandemic (H1N1) 2009 influenza A resulted in a large number of severe cases of viral pneumonitis associated with substantial morbidity and mortality during the 2009 and 2010 seasons. • Although double (150 mg twice daily) or triple dose (225 mg three time daily) therapy is often utilized in management of this infection as well as other severe influenza syndromes associated with H5N1 and H9N7 infection, there is a lack of data on the potential microbiologic or clinical utility of this approach. Study Rationale • Current dosing recommendations are predicated on mild disease in ambulatory patients. Critically ill patients (in contrast to ambulatory patients) may have substantial differences in physiology such that higher doses for more prolonged periods may be beneficial. • Given that ventilator requirements and mortality are high (approximately 20% ninety day mortality in patients with respiratory distress and/or critical illness secondary to influenza, clinical outcomes may be improved if the optimal dose of antiviral therapy can be found. • Since a mortality based study was not feasible due to the very large number of patients (n~1,000) required, viral clearance may be useful as an alternate end-point as microbiological pathogen clearance is generally conceded to be correlated well with outcome. • Influenza virus clearance in itself has major clinical implications in regards to the need for continued isolation, a source of significant manpower demand in the ICU. Methods • double blinded, randomized controlled study of suspected adult cases of severe influenza requiring intensive care unit admission • October 2009 and May 2011 • 25 Canadian sites • Planned sample size 240 subjects • randomized to either standard (75mg twice daily) or triple dose (225 mg twice daily) oseltamivir therapy for 10 days Methods • primary endpoint was complete viral clearance at the fifth day of therapy among initial polymerase chain reaction (PCR)-positive (nasal swab or tracheal aspirate) patients • secondary endpoints included 30 day, ICU and hospital survival and, where appropriate, duration of mechanical ventilation. Inclusion Criteria • Age ≥ 12 years • Suspected or confirmed influenza A infection • Requirement for ICU admission due to respiratory distress or critical illness defined as one of: – a) Inspired oxygen need of >50% for at least 4 hours – Estimated FiO2 for non-intubated patients – b) mechanical ventilation – c) Patient is receiving inotrope or vasopressor • Negative pregnancy test women 12-60 years Notable Exclusions • ≥ three doses of 150 mg or higher oseltamivir in 36 hours before study entry • ≥ four doses of 75 mg oseltamivir immediately in 36 hours before study entry • Unreliable enteral absorption (e.g. patients with partial or complete mechanical bowel obstruction, intestinal ischemia, infarction, and short bowel syndrome) • Pregnancy or breast feeding • Chronic renal failure requiring chronic hemodialysis • Severe chronic liver disease (Child-Pugh Score 11-15) • Anticipated death <24 hours • Do not intubate order (No CPR acceptable) Methods • primary endpoint was complete viral clearance by PCR (adjusted copy#/ml <L6.0 = Log10 adjusted copy # /ml< 0.78) at the fifth day of therapy among initial (PCR-positive (nasal swab or tracheal aspirate) patients • secondary endpoints included 30 day, ICU and hospital survival and, where appropriate, duration of mechanical ventilation. Patient Characteristics Patient Characteristics Primary End-point: Day 5 Viral Clearance Pearson test Fisher’s exact test 0.131 0.08 0.015 Results Sequential Organ Failure (SOFA) Score 12 SOFA Score 10 High dose (225 mg twice daily) Standard dose (75 mg twice daily) 8 6 4 2 0 0 5 10 15 Day 20 25 30 Results • No differences in secondary endpoints including ventilation at day 14, 28 or 60, need for rescue therapy or survival to ICU discharge, hospital discharge or 60 day survival. Conclusion • High (triple) dose oseltamivir therapy is associated with significantly better influenza virus clearance at day 5 of therapy • No evidence of improvement in secondary endpoints including SOFA score, LOS and mortality were noted in this small sample set • There was also no evidence of toxicity with the higher dose in this small trial • The results provide a biologic rationale for the possibility that higher dose therapy may potentially be useful in severe influenza infection and have implications for the required duration of infection control/isolation measures.