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

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.

Study Overview

• Status: Completed
• Conditions: Influenza A Virus Infection
• Intervention / Treatment: Drug: Gutron® treatment

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bron, France, 69500
    • Cabinet Médical du Dr ALIBERT
  • Bron, France, 69500
    • Cabinet Médical du Dr CURE
  • Bron, France, 69677
    • Centre d'Investigation Clinique de Lyon
  • Decine Charpieu, France, 69150
    • Cabinet du Dr DAHAN
  • Décine Charpieu, France, 69150
    • Cabinet du Dr MADELON
  • Lyon, France, 69001
    • Cabinet Médical du Dr HILLION
  • Lyon, France, 69003
    • Cabient Médical du Dr PIOS
  • Lyon, France, 69003
    • Cabinet du Dr ATTALI
  • Lyon, France, 69003
    • Cabinet du Dr COUTY
  • Lyon, France, 69003
    • Hôpital D'Instruction des Armées Desgenettes
  • Lyon, France, 69005
    • Cabinet Médical du Dr FORGEOIS
  • Lyon, France, 69005
    • Cabinet Médical du Dr TERRASSE
  • Lyon, France, 69006
    • Cabinet du Dr THIBAUT
  • Lyon, France, 69006
    • Cabinet Médical du Dr BUGEL
  • Lyon, France, 69006
    • Cabinet Médical du Dr CHAPDANIEL
  • Lyon, France, 69007
    • Cabinet du Dr AKIKI
  • Lyon, France, 69007
    • Cabinet du Dr BOURAS
  • Lyon, France, 69007
    • Cabinet du Dr GREVE
  • Lyon, France, 69007
    • Cabinet du Dr MANOELIAN
  • Lyon, France, 69007
    • Cabinet du Dr ROCHE
  • Lyon, France, 69009
    • Cabinet du Dr AZULAY TEBOUL
  • Lyon, France, 69009
    • Cabinet du Dr DRUT
  • Lyon, France, 69009
    • Cabinet Médical du Dr SAINT-OLIVE
  • Meyzieu, France, 69330
    • Cabinet du Dr JACQUET
  • Saint Priest, France, 69800
    • Cabinet du Dr CHAMPETIER
  • Saint Priest, France, 69800
    • Cbinet Médical du Dr CEZANNE-BERT
  • Saint-Symphorien d'Ozon, France, 69360
    • Cabinet Médical du Dr DUBOIS
  • Saint-priest, France, 69800
    • Cabinet Médical du Dr SMIT
  • St Pierre de Chandieu, France, 69780
    • Cabinet du Dr FARHAT
  • Venissieux, France, 69200
    • Cabinet du Dr CHAIZE
  • Venissieux, France, 69200
    • Cabinet Médical du Dr MARTIN
  • Venissieux, France, 69200
    • Cabinet Médical du Dr THEOULE
  • Villefontaine, France, 38090
    • Cabinet Médical du Dr MOREAU
  • Villeurbanne, France, 69100
    • Cabinet Médical du Dr BUFFLER
  • Villeurbanne, France, 69100
    • Cabinet Médical du Dr KESSOUS
  • Villeurbanne, France, 69100
    • Cabinet Médical du Dr MONLOUBOU
  • Villeurbanne, France, 69100
    • Cabinet Médical du Dr PERDRIX
  • Villeurbanne, France, 69100
    • Cabinet Médical du Dr PILLARS
  • Villeurbanne, France, 69100
    • Cabinet Médical du Dr WEBER

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No treatment
Experimental: Midodrine; Midodrine 2.5 mg orally 3 times daily, 5 day-treatment.	Drug: Gutron® treatment; Midodrine 2.5 mg orally 3 times daily, 5 day-treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of viral replication kinetics between the 2 arms	Comparison of the viral load slopes for 7 days post-study treatment start. Viral load will be measured at day 0, 2, 3, 5, and 7	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with a normalized viral load	A normal viral load is defined as a value below the positive threshold of 3 in RT-qPCR at day 2, 3, 5 and 7	7 days
Duration and severity of flu symptoms		7 days
Frequency, duration and level of replication of the virus in nose samples		7 days
Viral resistance and decrease of sensitivity of collected strains		7 days
Tolerance of midodrine : incidence of adverse effects	Side effects will be checked at each visit and reported for the entire study timeframe.	7 days

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Bruno LINA, MD, PhD, Laboratoire de virologie, Institut de microbiologie, Centre de Biologie et de Pathologie EST, Groupement Hospitalier Est, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: March 2, 2012
• First Submitted That Met QC Criteria: March 2, 2012
• First Posted (Estimate): March 7, 2012

Study Record Updates

• Last Update Posted (Estimate): January 8, 2015
• Last Update Submitted That Met QC Criteria: January 7, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Virus Diseases
• Other Study ID Numbers: 2010.654/58