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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Flu
• Intervention / Treatment: Drug: Oseltamivir; Drug: Diltiazem; Drug: Placebos

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • CHU Amiens Picardie
  • Arras, France
    • CH Arras
  • Belfort, France
    • Ch Hnfc Site de Belfort
  • Bourgoin-Jallieu, France
    • Ch Pierre Oudot Bourgoin Jallieu
  • Brest, France
    • CHRU Brest
  • Béthune, France
    • CH Bethune
  • Douai, France
    • CH DOUAI
  • Garches, France
    • Hôpital Raymond Poincaré
  • Lens, France
    • CH LENS
  • Lille, France
    • Hôpital Roger Salengro, CHRU
  • Lyon, France
    • Hôpital Edouard Herriot Hospices Civils de Lyon
  • Montauban, France
    • CH de Montauban
  • Orléans, France
    • Ch Regional Orleans
  • Paris, France
    • Gpe Hosp Cochin Saint Vincent de Paul - Paris
  • Paris, France
    • Hu Paris Sud Site Kremlin Bicetre Aphp
  • Strasbourg, France
    • Hôpitaux Universitaires de Strasbourg
  • Tours, France
    • Hôpital Bretonneau
  • Valenciennes, France
    • CH de Valenciennes
  • Versailles, France
    • Centre Hospitalier de Versailles - Le Chesnay Rocquencourt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: diltiazem; oseltamivir + diltiazem	Drug: Oseltamivir; 150 mg twice a day during 10 days (ANSM guidelines for severe flu).; Drug: Diltiazem; 60 mgx3 per day during 10 days.
PLACEBO_COMPARATOR: oseltamivir + placebo; oseltamivir + placebo of diltiazem	Drug: Oseltamivir; 150 mg twice a day during 10 days (ANSM guidelines for severe flu).; Drug: Placebos; Placebo of diltiazem

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Julien Poissy, MD, PhD, University Hospital, Lille

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 23, 2017
• Primary Completion (ACTUAL): May 4, 2022
• Study Completion (ACTUAL): May 4, 2022

Study Registration Dates

• First Submitted: July 4, 2017
• First Submitted That Met QC Criteria: July 6, 2017
• First Posted (ACTUAL): July 11, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 2, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Infectiology; Flu; Intensive care; Biology of infectious agents
• Additional Relevant MeSH Terms: Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Oseltamivir; Diltiazem
• Other Study ID Numbers: 2015_65; 2016-004222-42 (EUDRACT_NUMBER); PHRC_N -15-0442 (OTHER: PHRC number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No