Confirmation of the Antiviral Effects of Midodrine Identified With a Gene Expression Signature-based Screening of Inluenza A Virus Infected Cells

Rationale:

Classical antiviral therapies target viral proteins and are consequently subject to resistance. To counteract this limitation, alternative strategies have been developed that target cellular factors. We hypothesized that such an approach could also be useful to identify broad-spectrum antivirals. The influenza A virus was used as a model for its viral diversity and because of the need to develop therapies against unpredictable viruses as recently underlined by the H1N1 pandemic. Gene-expression signature-based screening identified broadly effective influenza A antivirals. Midodrine showed great results in inhibiting viral growth and was the most suited to confirm its efficacy in vivo.

The main objective of the study is to assess the efficacy of midodrine taken at usual recommended dose (7.5mg/day) versus no treatment on viral replication kinetics of virus Influenza A.

Secondary objectives: evaluation of the number of patients with a normalized viral load 2, 3 5 and 7 days post-treatment; description of the anti-viral efficacy of midodrine defined as the delay to obtain a prolonged negativity of viral RNA; description of the tolerance of midodrine, evaluation of the clinical response to study treatment; evaluation of the dynamic of viral replication; analysis of the frequency of emergence of mutants and associated resistance.

Methods:

This is a multicenter, randomized, open-label study comparing patients aged 18 to 65 years infected by influenza A virus. Nasopharyngeal washing will be performed at day 0 (randomization), 2, 3, 5 to show the viral replication evolution.

161 patients will be randomized as follows :

* Arm 1 : Midodrine, 2.5 mg, 3 times a day
* Arm 2 : No treatment The recruitment is performed by general practitioners in the Lyon area.


Eligibility Criteria:
Inclusion Criteria:

* men and women aged 18 to 65 years,
* with no long-term illness,
* presenting flu-like symptoms for less than 42 hours (nasal congestion, sore throat, muscle soreness, asthenia, headache, chills/sweating, fever...),
* infection with influenza A virus confirmed with a quick diagnostic test,
* outpatient care,
* must provide signed and informed consent,
* beneficiary of a health insurance.

Exclusion Criteria:

* severe form of flu,
* pregnant women or positive pregnancy test,
* breastfeeding women,
* women of childbearing-potential with no efficient contraceptive,
* history of chronic respiratory disease : asthma or chronic obstructive pulmonary disease,
* renal failure,
* Raynaud's disease,
* history of epilepsy, confusion, hallucinations or of psychoneurotic state,
* patients with an increased cardiovascular risk (\> 20% according to the Framingham scale) or with a cardiovascular history,
* patients having a congestive heart failure, swollen legs or a posture hypotension,
* patients who received a influenza vaccine for seasons 2011-2012 or 2012-2013,
* known hypersensitivity to any component of the treatment,
* topical use of nasal decongestant (except physiological serum),
* use of steroids, immunosuppressive or antipsychotics drugs (including treatments for nausea),
* use of indirect sympathomimetics drugs (ephedrine, methylphenidate, phenylephrine, pseudoephedrine),
* use of dopaminergic ergot alkaloids (bromocriptine, cabergoline, lisuride, pergolide) or vasoconstrictor ergot alkaloids (dihydroergotamine, ergotamine, methylergométrine, methylsergide),
* known hypertension treated or not,
* history of bradycardia,
* history of urinary retention,
* severe cardiopathy,
* acute angle-closure glaucoma,
* severe obliterative vasculopathy,
* vasospasm,
* thyrotoxicosis,
* pheochromocytoma,
* history of angina pectoris,
* use of guanethidine and related, iproniazide (non selective MAOIs), alpha-blockers and digitalis drugs
* use of neuraminidase inhibitors: oseltamivir, zanamivir; and M2 proton-selective ion channel inhibitors: amantadine and rimantadine