Efficacy and Safety of Combination Therapies With Oseltamivir & Zanamivir or Oseltamivir & Amantadine Versus Oseltamivir Monotherapy in the Treatment of Seasonal Influenza A Infection (Combina)

Neuraminidase inhibitors (NAI) are effective anti-influenza antiviral treatment. During their use in experimentally infected patients, it has been shown that the viral load detected in the nasal fluid is decreasing significantly faster than in non treated patients. During clinical practice, the emergence of NAI-resistant strains has been observed. These strains remain rare, but their emergence seemed to be related to the mis-use of the NAI products (insufficient duration or dosage). This observation as well as the detection of NAI-resistant viruses in the community raises concerns about putative emergence of resistant clones in the specific context of a pandemic, when the use of NAI will be very large in the aim of reducing transmission, and subsequently the impact of the emerging virus.

In this context, it is important to determine the putative interest of alternative strategies.

Although zanamivir and oseltamivir are both issued from the same class , this combination may lead to a more rapid viral clearance in the infected cases, and to a reduction in the emergence of resistant sub-clones, and alternatively, might lead to a competitive inhibition. The evaluation of these combinations needs to be conducted in vivo.

Among available anti influenza antivirals, M2 blockers have been previously used. Although their efficacy against A H5N1 remains to be ascertained, their use in combination with NAI should also be evaluated in the context of a preparation for a possible pandemic and determination of the stockpile.

Therefore, the evaluation of combination therapies in the treatment of a virologically suspected influenza will be investigated in primary care during the winter season 2008-2009.

Study Overview

• Status: Terminated
• Conditions: Influenza A Infection
• Intervention / Treatment: Drug: oseltamivir + zanamivir; Drug: oseltamivir+ amantadine; Drug: oseltamivir

Detailed Description

Study Schedule:

• Patient's follow up: 7 days with 10 visits V1, V2, V3, V4, V5 every 12 hours V6, V7, V8, V9, V10 every 24 hours
• V1: conducted by the GP rapid test diagnostic for influenza A, urine pregnancy test for women, inclusion /randomisation, nasal sample, initiation of treatment.
• V2 to V9: conducted by a nurse at the patient's home; nasal sample, symptoms scoring, safety assessment (side effects)
• V 10: conducted by GP; medical evaluation (follow up evaluation)

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Hospices Civils de Lyon

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Influenza season declared
• Subjects aged>18 years and < 65 years presenting within 36h documented of onset influenza illness
• Who have fever >38°C
• Who present at least one 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
• Primary care follow up

Exclusion Criteria:

• Influenza Vaccination in the 12 months prior the beginning of the study
• Asthma, Chronic bronchitis
• Woman with a positive urine pregnancy test
• Active breast feeding
• Woman without contraception
• Clearance of creatinine< 30 ml/min Chronic renal disease
• History of depression, psychiatric disorders, epilepsy
• Patients receiving cortocosteroids, immunosuppressants or antipsychotic antiemetic drugs
• Known oseltamivir or zanamivir hypersensibility
• Non member of the social security or CMU

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: oseltamivir + zanamivir; oseltamivir (75mg bd for 5 days, oral) zanamivir (5mg bd for 5 days, inhaled by mouth)
Experimental: Arm 2	Drug: oseltamivir+ amantadine; oseltamivir (75mg bd for 5 days, oral) + amantadine (100mg bd for 5 days, oral)
Active Comparator: Arm 3	Drug: oseltamivir; oseltamivir (75mg bd for 5 days, oral)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
describe the antiviral efficacy in the 3 arms in the treatment of seasonal influenza infection as assessed by negative viral detection in nose swabs at the fifth swab [H48±3]	48 hours
Describe the antiviral efficacy in 3 arms in the treatment of seasonal influenza infection as assessed by negativity of RT-PCR for viral RNA in nose and throat swabs at the 5th swab [H48±3] and at the 7th swab [H84±3].	84 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
Describe the antiviral efficacy in combination therapy arms (1,2) and in monotherapy arm (3) in the treatment of seasonal influenza infection as assessed by time to sustained negativity of RT-PCR for viral RNA or viral culture in any sample.	168 hours
Assess viral replication dynamics (duration and level of viral replication) in the respiratory tract in the combination and standard-dose cohorts.	168 hours
Assess the frequency, genetic basis, and duration of antiviral resistance to each arm during and after therapy	168 hours
Describe the time to alleviation of illness in the 3 arms defined as the time from the beginning of the study treatment to the time that 7 typical key symptoms of natural influenza had reduced to absent or mi	168 hours
Describe the tolerability of combination and in standard-dose arms as assessed by clinical adverse events that are possibly or probably related to each single agent (Incidence and duration)	168 hours

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: BRUNO LINA, MD,PhD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Anticipated): August 1, 2009
• Study Completion (Anticipated): August 1, 2009

Study Registration Dates

• First Submitted: January 26, 2009
• First Submitted That Met QC Criteria: January 26, 2009
• First Posted (Estimate): January 27, 2009

Study Record Updates

• Last Update Posted (Estimate): September 30, 2010
• Last Update Submitted That Met QC Criteria: September 29, 2010
• Last Verified: October 1, 2009

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Disease Attributes; Orthomyxoviridae Infections; Infections; Communicable Diseases; Influenza, Human; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Zanamivir; Oseltamivir; Amantadine
• Other Study ID Numbers: 2008-517