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NBSB Pandemic Influenza Working Group
Detailed Report
phase-3 studies in Japan have recently completed enrollment, but data from these studies
is not yet available. The completed phase-2 study in Japan in 2008-2009 was a
rigorously designed and executed randomized, double-blind, placebo-controlled trial
comparing one short IV infusion of peramivir (two different doses were tested, 300mg
and 600mg) with placebo in acute uncomplicated influenza. The primary endpoint was
time to alleviation of symptoms (TTAS). The efficacy outcome was unequivocally
positive, with all efficacy endpoints showing significant improvement over placebo. The
time to alleviation of symptoms was 81.8 hours for placebo, and was shortened by about
22 hours with peramivir (p=0.0046). Time to resolution of fever was also significantly
improved in the peramivir groups compared to placebo. Change in viral load, determined
by nasal-pharyngeal swabs at baseline and at several protocol-specified post-treatment
timepoints, is another important outcome, as it is a direct measure of antiviral activity.
These evaluations showed that viral clearance was significantly accelerated in the 600mg
peramivir group compared to placebo.
The safety experience for peramivir was very satisfactory in this study. Reported AEs
were mild, and no serious AEs were reported in the 198 subjects administered peramivir
in the study. The reported AEs were of similar frequency and severity grade in the
placebo and treatment groups. These efficacy and safety results formed the basis of the
peramivir phase 3 program in Japan.
BioCryst’s phase-2 study of peramivir in patients with influenza requiring hospitalization
was difficult to perform, and is the only study ever completed in this patient population.
It required multiple sites and countries and enrollment extended over 2 Northern
Hemisphere and 1 Southern Hemisphere season. An important issue for influenza
clinical research is lack of awareness of influenza in the hospital setting. This problem
seems partly due to lack of reliable diagnostic tests in emergency rooms – it is estimated
that only 5% of patients hospitalized with influenza actually receive that diagnosis.
Better access to confirmatory diagnostic tests would greatly improve the ability to recruit
patients for such studies.
A placebo-controlled study was not practical for ethical reasons, so oral oseltamivir was
used as a control, even though it is not approved for this indication. Two different doses
of IV peramivir were evaluated, 200mg daily for 5 days and 400mg daily for 5 days. The
primary endpoint was time to clinical stability, which was adapted from studies of
community-acquired pneumonia.
A main goal of this study was to evaluate peramivir in a patient population with more
serious disease or underlying risk factors for complications. The patient population
enrolled consisted mostly of individuals admitted with chronic illness that worsened with
influenza, and not patients with influenza-pneumonia. The study patients had good
clinical outcomes, and BioCryst was pleased with the rapidity of clearance of the virus.
Viral cultures were obtained from nasopharyngeal swabs at regular intervals. Overall,
viral load was reduced rapidly with treatment. Detailed analyses of the viral culture data
indicated that the baseline viral load was higher in subjects with less that 48 hrs of
symptoms at enrollment, and in influenza B subjects. In the influenza B subjects, a
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