Efficacy and Safety of Combination Therapies With Oseltamivir & Zanamivir or Oseltamivir & Amantadine Versus Oseltamivir Monotherapy in the Treatment of Seasonal Influenza A Infection - Full Text View

Sponsored by:	Hospices Civils de Lyon
Information provided by:	Hospices Civils de Lyon
ClinicalTrials.gov Identifier:	NCT00830323

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 II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Parallel Assignment
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:

MedlinePlus related topics: Flu Hospice Care

Drug Information available for: Amantadine sulfate Zanamivir Oseltamivir Tamiflu Amantadine hydrochloride Amantadine

U.S. FDA Resources

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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]

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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Assess the frequency, genetic basis, and duration of antiviral resistance to each arm during and after therapy [ Time Frame: 168 hours ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]

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

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00830323

Contacts

Contact: BRUNO LINA, MD, PhD

(0)4 72 12 96 17 ext +33

bruno.lina@chu-lyon.fr

Locations

France
Hospices civils de Lyon	Recruiting
LYON, France
Contact: BRUNO LINA, MD, PhD (0)4 72 12 96 17 bruno.lina@chu-lyon.fr

Sponsors and Collaborators

Hospices Civils de Lyon

Investigators

Principal Investigator:

BRUNO LINA, MD,PhD

Hospices Civils de Lyon

More Information

No publications provided

Responsible Party:	Laboratoire de Virologie/Centre de Biologie et de Pathologie EST ( Pr Bruno LINA )
Study ID Numbers:	2008-517
Study First Received:	January 26, 2009
Last Updated:	January 26, 2009
ClinicalTrials.gov Identifier:	NCT00830323 History of Changes
Health Authority:	France: Afssaps - French Health Products Safety Agency

Study placed in the following topic categories:

Anti-Infective Agents
Neurotransmitter Agents
Orthomyxoviridae Infections
Zanamivir
Antiviral Agents
Oseltamivir
Virus Diseases
Dopamine

Respiratory Tract Infections
Respiratory Tract Diseases
Analgesics, Non-Narcotic
Influenza, Human
Dopamine Agents
Peripheral Nervous System Agents
Analgesics
Amantadine

Additional relevant MeSH terms:

Communicable Diseases
Anti-Infective Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents
Physiological Effects of Drugs
Antiparkinson Agents
Orthomyxoviridae Infections
Infection
Zanamivir
Respiratory Tract Diseases
Respiratory Tract Infections
Sensory System Agents
Therapeutic Uses

Analgesics
RNA Virus Infections
Enzyme Inhibitors
Antiviral Agents
Pharmacologic Actions
Oseltamivir
Virus Diseases
Analgesics, Non-Narcotic
Influenza, Human
Dopamine Agents
Peripheral Nervous System Agents
Amantadine
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 03, 2009