Efficiency of Antagonist Drugs of the Cellular Transcriptomic Signature of Influenza A Virus Infection.

Study Overview
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Brief Summary
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The aim of this study is to evaluate the possibility to repropose marketed drugs as antiviral ones, based on their ability to reverse the transcriptomic signature of the infected cells. This strategy has to be considered is the context of emerging viral diseases and of increase of resistance to antivirals. Concerning infection by Influenza viruses, the main drugs were identified and evaluated on in vitro and in vivo models: diltiazem. Therefore, it will be assess the efficacy of these the drug, compared to placebo, to treat severe flu.

Official Title
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Validation of the Efficiency of Molecules Reproposed on the Basis of Their Cellular Transcriptomic Signature, Antagonist of the Signature Determined in Infection Due to Virus Influenza A.

Conditions
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Flu

Intervention / Treatment
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* Drug: Oseltamivir
* Drug: Diltiazem
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients hospitalized in intensive care units, patients with mechanical ventilation invasive or non-invasive or Optiflow® ventilation system. for a suspicion of severe flu, with a symptoms for less than 96 hours, and a respiratory failure defined by the necessity to resort to mechanical ventilation, invasive or Optiflow® Ventilation System The inclusion is conditioned to the detection of Influenza A viruses by PCR on nasopharyngeal swab. Exclusion Criteria: No consent. Hypersensibility to Oseltamivir Negative PCR on nasopharyngeal swab Symptoms for more than 96 hours. Moribund patients at inclusion. Pregnant/nursing woman. Patients already taking diltiazem in the 48 hours before. Patients having taken more than 3 intakes of oseltamivir before randomization. Hemodynamic instability needing a dose of noradrenaline exceeding 2mg/h Contraindication to diltiazem: sinusal dysfunction without device. auriculo-ventricular heart block without device. Cardiogenic pulmonary oedema. Left cardiac failure bradycardia<40/min Concomitant use of beta-blockers, antiarrythmic drugs, especially amiodarone. Concomitant use of ivabradine, pimozide, nifedipine, ergot alkaloids.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: diltiazem<br>oseltamivir + diltiazem | Drug: Oseltamivir<br>* 150 mg twice a day during 10 days (ANSM guidelines for severe flu).<br>Drug: Diltiazem<br>* 60 mgx3 per day during 10 days.<br>|
| Placebo Comparator: oseltamivir + placebo<br>oseltamivir + placebo of diltiazem | Drug: Oseltamivir<br>* 150 mg twice a day during 10 days (ANSM guidelines for severe flu).<br>Drug: Placebos<br>* Placebo of diltiazem<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of alive patients without detection of influenza A virus by RT-PCR in nasopharyngeal swabs, |  | 7 days after the beginning of the treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delay needed for the negativation of influenza A detection by RT-PCR |  | up to 10days | 
| Overall mortality |  | At 28 days | 
| Length of mechanical ventilation |  | an average of 10 days | 
| Change in Oxygenation (PaO2/FiO2 Ratio) | Arterial blood samples for blood gas analysis are collected during the treatment period. The differences in the mean values of PaO2/FiO2 ratio are registered and analysed. | once day for 10 days and at 28 days | 
| Length of hospitalization |  | an average of 10 days in ICU and of 16 days in hospital | 
| Length of extracorporeal membrane oxygenation (ECMO) if implemented. |  | an average of 10 days | 
| Transcriptomic signature determined by the DNA microarray technology and analysed by bioinformatic tools | evaluation of the capacity of tested molecules to reverse the transcriptomic signature linked to the viral infection | Four time points : at inclusion, the first day after inclusion, the fourth day after inclusion, and the seventh day after inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infectiology, Biology of infectious agents, Flu, Intensive care