Evaluation of Efficacity and Safety of Oseltamivir and Zanamivir

Gastric Influenza Clinical Trial

— BIVIR  

Official title:

Evaluation of Combination Therapy With Oseltamivir and Zanamivir Versus Monotherapy in the Treatment of Virologically Confirmed Influenza in Primary Care a Randomises Double Blind Controlled Trial Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00799760
• Other study ID #: P060209
• Secondary ID: AOM 082092008-00
• Status: Terminated
• Phase: Phase 3
• First received: November 28, 2008
• Last updated: March 16, 2012
• Start date: December 2008
• Est. completion date: November 2010

Study information

• Verified date: November 2008
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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)

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 541
• Est. completion date: November 2010
• Est. primary completion date: November 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Gastric Influenza
• Influenza, Human

Intervention

Drug:
• oseltamivir + zanamivir
oral oseltamivir 75mg twice daily + zanamivir 10 mg inhaled by mouth twice daily during 5 days
• oseltamivir + zanamivir's placebo
oral oseltamivir 75mg twice daily+ placebo inhaled by mouth twice daily during 5 day
• oseltamivir's placebo + zanamivir
oral placebo twice daily + zanamivir 10 mg inhaled by mouth twice daily during 5 day

Locations

Country	Name	City	State
France	Centre Investigateur 155	Deulemont

Sponsors (3)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	GlaxoSmithKline, Hoffmann-La Roche

Country where clinical trial is conducted

France, 

References & Publications (1)

Blanchon T, Mentré F, Charlois-Ou C, Dornic Q, Mosnier A, Bouscambert M, Carrat F, Duval X, Enouf V, Leport C; Bivir Study Group. Factors associated with clinical and virological response in patients treated with oseltamivir or zanamivir for influenza A d — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	RT-PCR for influenza A virus in nasal secretion		2 days	No
Secondary	Time to resolution of influenzal illness Severity of illness		14 days	No
Secondary	Severity of illness		14 Days	No
Secondary	Adverse event (graded on a four -point scale:mild-moderate- severe-life threatening)		14 days	Yes
Secondary	Compliance to antiviral treatment		14 days	No
Secondary	Number of persons with influenza illness in households contact		14 days	No
Secondary	Evaluation of restricted activity (requirement for additional health car)		14 days	No
Secondary	Frequency of and need for antibiotic treatment of influenza (otitis media, bronchitis, sinusitis, and pneumonia )		14 days	No
Secondary	Frequency of resistance to antiviral drugs		14 days	No