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

Phase 2

Completed

• Conditions: Influenza A Virus Infection
• Interventions: Drug: Gutron® treatment

• Registration Number: NCT01546506
• Lead Sponsor: Hospices Civils de Lyon

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-02
• Study First Submitted: 2012-03-02
• Study First Submitted QC: 2012-03-02
• Study First Posted: 2012-03-07
• Primary Completion: 2014-03
• Study Completion: 2014-03
• Status Verified: 2015-01
• Last Update Submitted: 2015-01-07
• Last Update Posted: 2015-01-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 79

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Midodrine	Gutron® treatment	Midodrine 2.5 mg orally 3 times daily, 5 day-treatment.

Primary Outcome Measures

Name	Time	Method
Comparison of viral replication kinetics between the 2 arms	7 days	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

Secondary Outcome Measures

Name	Time	Method
Frequency, duration and level of replication of the virus in nose samples	7 days
Percentage of patients with a normalized viral load	7 days	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
Duration and severity of flu symptoms	7 days
Viral resistance and decrease of sensitivity of collected strains	7 days
Tolerance of midodrine : incidence of adverse effects	7 days	Side effects will be checked at each visit and reported for the entire study timeframe.

Trial Locations

Locations (39)

Cabinet Médical du Dr ALIBERT; 🇫🇷 Bron, France

Centre d'Investigation Clinique de Lyon; 🇫🇷 Bron, France

Cabinet Médical du Dr CURE; 🇫🇷 Bron, France

Cabinet du Dr DAHAN; 🇫🇷 Decine Charpieu, France

Cabinet du Dr MADELON; 🇫🇷 Décine Charpieu, France

Cabient Médical du Dr PIOS; 🇫🇷 Lyon, France

Cabinet du Dr COUTY; 🇫🇷 Lyon, France

Cabinet Médical du Dr HILLION; 🇫🇷 Lyon, France

Cabinet du Dr ATTALI; 🇫🇷 Lyon, France

Cabinet Médical du Dr TERRASSE; 🇫🇷 Lyon, France

Cabinet du Dr THIBAUT; 🇫🇷 Lyon, France

Hôpital D'Instruction des Armées Desgenettes; 🇫🇷 Lyon, France

Cabinet Médical du Dr FORGEOIS; 🇫🇷 Lyon, France

Cabinet Médical du Dr BUGEL; 🇫🇷 Lyon, France

Cabinet Médical du Dr CHAPDANIEL; 🇫🇷 Lyon, France

Cabinet du Dr GREVE; 🇫🇷 Lyon, France

Cabinet du Dr BOURAS; 🇫🇷 Lyon, France

Cabinet du Dr MANOELIAN; 🇫🇷 Lyon, France

Cabinet Médical du Dr SAINT-OLIVE; 🇫🇷 Lyon, France

Cabinet du Dr AZULAY TEBOUL; 🇫🇷 Lyon, France

Cabinet du Dr CHAMPETIER; 🇫🇷 Saint Priest, France

Cbinet Médical du Dr CEZANNE-BERT; 🇫🇷 Saint Priest, France

Cabinet Médical du Dr SMIT; 🇫🇷 Saint-priest, France

Cabinet Médical du Dr DUBOIS; 🇫🇷 Saint-Symphorien d'Ozon, France

Cabinet Médical du Dr MARTIN; 🇫🇷 Venissieux, France

Cabinet du Dr FARHAT; 🇫🇷 St Pierre de Chandieu, France

Cabinet du Dr CHAIZE; 🇫🇷 Venissieux, France

Cabinet Médical du Dr THEOULE; 🇫🇷 Venissieux, France

Cabinet Médical du Dr MOREAU; 🇫🇷 Villefontaine, France

Cabinet Médical du Dr BUFFLER; 🇫🇷 Villeurbanne, France

Cabinet Médical du Dr MONLOUBOU; 🇫🇷 Villeurbanne, France

Cabinet Médical du Dr PILLARS; 🇫🇷 Villeurbanne, France

Cabinet Médical du Dr KESSOUS; 🇫🇷 Villeurbanne, France

Cabinet Médical du Dr PERDRIX; 🇫🇷 Villeurbanne, France

Cabinet Médical du Dr WEBER; 🇫🇷 Villeurbanne, France

Cabinet du Dr AKIKI; 🇫🇷 Lyon, France

Cabinet du Dr ROCHE; 🇫🇷 Lyon, France

Cabinet du Dr DRUT; 🇫🇷 Lyon, France

Cabinet du Dr JACQUET; 🇫🇷 Meyzieu, France