Evaluation of Efficacity and Safety of Oseltamivir and Zanamivir
Evaluation of Efficacity and Safety of Oseltamivir and Zanamivir
In order to prevent the high mortality due to an hypothetic pandemic caused by a newly
 emerging influenza A virus, antiviral drugs are seen as essential requirements for control of
 initial influenza outbreaks.Two antivirals are available for the treatment oseltamivir and
 zanamivir. Emergence of Oseltamivir resistance has been recently reported. . It appeared
 opportune to assess the efficacy and safety of biotherapy of neuraminidase inhibitors ,will
 be investigated by a randomized, placebo controlled, double blind study in France, during the
 next winter season . This study will be conducted in 300 centres of primary care with 900
 adults with a virologically suspected influenza A infection. Individuals will be randomized
 to 1 of the 3 treatment groups: oseltamivir +zanamivir, or oseltamivir+placebo or placebo
 +zanamivir.The primary judgment criteria will be the proportion of patients with negative RT
 PCR negative in nasal secretions at Day 2.
In the near future, a pandemic caused by a newly emerging influenza A virus has been
 predicted by the WHO. In order to prevent the high mortality due to the pandemic, antiviral
 drugs are seen as essential requirements for control of initial influenza outbreaks.

 Zanamivir (GSK) and Oseltamivir (Roche) are stockpiled by the French government in the
 setting of pre-pandemic plan. In France, Zanamivir and Oseltamivir are both registered for
 the prophylactic and therapeutic use against influenza A.

 Previous studies have shown that neuraminidase inhibitors (oseltamivir and zanamivir, based
 treatment) are associated with shorter illness duration and resulted in significant decrease
 of viral load in the nasal secretions.

 In Winter season 2007-2008 the presence of oseltamivir-resistant viruses circulating in the
 community in several European countries is in marked contrast to the previous winter seasons,
 when oseltamivir resistance was detected in <1% of circulating strains from . Patients
 infected by viruses with neuraminidases carrying these mutations, didn't present unusual
 disease syndromes.

 Although zanamivir and oseltamivir are both issued from the same class ,a combination of
 these two neuraminidase inhibitors could reduce the duration and severity of acute influenza
 and the incidence of secondary complications, reduce the spread of influenza, and the
 frequency of neuraminidase inhibitors mutations. An evaluation of the combination of
 oseltamivir and zanamivir versus zanamivir with placebo versus oseltamivir associated with
 placebo in the treatment of a virologically suspected influenza in primary care will be
 investigated in a randomised double blind placebo controlled trial study in France during the
 winter season 2008-2009.

 Primary outcome measure:

 Evaluate viral efficacy after 2 days of biotherapy oseltamivir and zanamivir versus zanamivir
 with placebo versus oseltamivir associated with placebo.

 Patients and methods:

 Randomised double blind, placebo controlled multicenter trial conducted during the influenza
 season 2008-2009 Arm 1: oral oseltamivir 75mg twice daily + zanamivir 10 mg inhaled by mouth
 twice daily during 5 days Arm 2: oral oseltamivir 75mg twice daily+ placebo inhaled by mouth
 twice daily during 5 days Arm 3: oral placebo twice daily + zanamivir 10 mg inhaled by mouth
 twice daily during 5 days.

 Schedule:

 D0: rapid test diagnostic for influenza A urine pregnancy test for women inclusion
 /randomisation initiation of treatment D2:nasal sample for influenza RNA RTPCR D5:End of
 treatment D7:medical evaluation (follow up evaluation) D14:nurse call (clinical evaluation)
Inclusion Criteria:

 -  Influenza season declared

 -  Subjects aged>18 years presenting within 36h documented of onset influenza illness

 -  Who have fever >38°C

 -  who present at least on of the following respiratory symptoms( cough, sore throat,
 nasal symptoms)

 -  and one of the following constitutional symptoms(headache, myalgia, sweats and or
 chills or fatigue)

 -  positive rapid diagnostic test for influenza A

 -  who have giving written informed consent prior to enrollment

 -  Patient examined before the inclusion

 -  able to complete a questionnaire.

 Exclusion Criteria:

 -  Influenza Vaccination in the 12 months prior the beginning of the study

 -  Patient unable to use diskhaler of Zanamivir

 -  Asthma, Chronic bronchitis,

 -  Woman with a positive urine pregnancy test

 -  Clearance of creatinine< 30 ml/min Chronic renal disease

 -  History of depression, psychiatric disorders

 -  oseltamivir or zanamivir hypersensibility

 -  patient treated by oseltamivir or zanamivir or amantadine 14 days before

 -  Non member of the social security or CMU