Download Viral Clearance with 75 mg Twice Daily or 225 mg Twice Daily

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
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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.