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

This study has been terminated.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00830323
First Posted: January 27, 2009
Last Update Posted: September 30, 2010
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by:
Hospices Civils de Lyon
  Purpose

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.


Condition Intervention Phase
Influenza A Infection Drug: oseltamivir + zanamivir Drug: oseltamivir+ amantadine Drug: oseltamivir Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Combination Therapies With Oseltamivir & Zanamivir or Oseltamivir & Amantadine Versus Oseltamivir Monotherapy in the Treatment of Seasonal Influenza A Infection

Resource links provided by NLM:


Further study details as provided by Hospices Civils de Lyon:

Primary Outcome Measures:
  • 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] [ Time Frame: 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]. [ Time Frame: 84 hours ]

Secondary Outcome Measures:
  • 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. [ Time Frame: 168 hours ]
  • Assess viral replication dynamics (duration and level of viral replication) in the respiratory tract in the combination and standard-dose cohorts. [ Time Frame: 168 hours ]
  • Assess the frequency, genetic basis, and duration of antiviral resistance to each arm during and after therapy [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 168 hours ]

Estimated Enrollment: 60
Study Start Date: January 2009
Estimated Study Completion Date: August 2009
Estimated Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)

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)
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00830323


Locations
France
Hospices civils de Lyon
Lyon, France
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
Principal Investigator: BRUNO LINA, MD,PhD Hospices Civils de Lyon
  More Information

Responsible Party: Pr Bruno LINA, Laboratoire de Virologie/Centre de Biologie et de Pathologie EST
ClinicalTrials.gov Identifier: NCT00830323     History of Changes
Other Study ID Numbers: 2008-517
First Submitted: January 26, 2009
First Posted: January 27, 2009
Last Update Posted: September 30, 2010
Last Verified: October 2009

Additional relevant MeSH terms:
Infection
Communicable Diseases
Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Oseltamivir
Amantadine
Zanamivir
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents