Efficacy of Addition of Naproxen in the Treatment of Critically Ill Patients Hospitalized for COVID-19 Infection (ENACOVID)

The symptoms of respiratory distress caused by COVID-19 may be reduced by drugs combining anti-inflammatory and antiviral effects. This dual effect may simultaneously protect severely-ill patients and reduce the viral load, therefore limiting virus dissemination We want to demonstrate the superiority of naproxen (anti-inflamatory drug) treatment addition to standard of care compared to standard of care in term of 30-day mortality.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: 1: Naproxen; Drug: 2: Standard of care

Detailed Description

Coronavirus Disease 2019 (COVID-19) is due to SARS-CoV-2 infection. (1,2) The exacerbated inflammatory response in COVID-19 infected critically ill patients calls for appropriate anti inflammatory therapeutics combined with antiviral effects. Thus, drugs combining anti-inflammatory and antiviral effects may reduce the symptoms of respiratory distress caused by COVID-19. This dual effect may simultaneously protect severely ill patients and reduce the viral load, therefore limiting virus dissemination. Naproxen, an approved anti-inflammatory drug, is an inhibitor of both cyclo oxygenase (COX-2) and of Influenza A virus nucleoprotein (NP). The NP of Coronavirus (CoV), positive-sense single-stranded viruses, share with negative-sense single-stranded viruses as Influenza the ability to bind to- and protect genomic RNA by forming self-associated oligomers in a helical structure with RNA. Naproxen was shown to bind the Influenza A virus NP making electrostatic and hydrophobic interactions with conserved residues of the RNA binding groove and C terminal domain. (3) Consequently, naproxen binding competed with NP association with viral RNA and impeded the NP self-association process which strongly reduced viral transcription/replication. This drug may have the potential to present antiviral properties against SARS-CoV-2 suggested by modelling work based on the structures of CoV NP. The high sequence conservation within the coronavirus family, including severe acute respiratory syndrome (SARS-CoV) and the present SARSCoV-2 coronavirus allows to perform this comparison. (4) A recent clinical trial shown that the combination of clarithromycin, naproxen and oseltamivir reduced mortality of patients hospitalized for H3N2 Influenza infection. (5). Inappropriate inflammatory response in CODIV-19 patients was demonstrated in a recent study where Intensive Care Unit (ICU) patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNF? compared with non-ICU patients.(2) We suggest that naproxen could combine a broad-spectrum antiviral activity with its well-known anti inflammatory action that could help reducing severe respiratory mortality associated with COVID-19.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bobigny, France, 93000
    • Réanimation médico-chirurgicale, Avicenne Hospital
  • Bobigny, France, 93000
    • Urgences, Avicenne Hospital

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:

• COVID-19 infected patient
• Age 18 years or older
• Presence of pneumonia
• PaO2/FiO2 < 300 mm Hg or SpO2 < 93% in air ambient or need to supplementary oxygen administration in order to maintain SpO2 range in [94-98%] or lung infiltrates > 50%
• Medical insurance

Exclusion Criteria:

• Presence of do-not-resuscitate order
• Pregnancy
• Prisoners
• Known Naproxen allergy or intolerance
• Severe renal failure

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
Experimental: 1: Naproxen; Administration of naproxen 250 mg twice and lansoprazole 30 mg daily for prevention of gastropathy induced by stress or a nonsteroidal anti-inflammatory drug (NSAID) in addition to standard of care (SOC)	Drug: 1: Naproxen; Description : Administration of naproxen 250 mg twice and lansoprazole 30 mg daily for prevention of gastropathy induced by stress or a nonsteroidal anti-inflammatory drug (NSAID) in addition to standard of care (SOC); Drug: 2: Standard of care; Standard of care
Placebo Comparator: 2: Standard of care; Standard of care	Drug: 2: Standard of care; Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mortality all causes at day30	at day30

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of days alive free of mechanical ventilation	during 30 days after randomization
Number of days alive outside	during 30 days after randomization
Number of days alive outside hospital	during 30 days after randomization
Maximal changes in Sofa score	in the first 7 days after randomization
Time to negativation of virus titer in the nasopharyngeal aspirate (NPA)	during 90 days after randomization

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Frédéric Adnet, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2020
• Primary Completion (Actual): December 15, 2020
• Study Completion (Actual): December 15, 2020

Study Registration Dates

• First Submitted: March 26, 2020
• First Submitted That Met QC Criteria: March 26, 2020
• First Posted (Actual): March 27, 2020

Study Record Updates

• Last Update Posted (Actual): February 25, 2021
• Last Update Submitted That Met QC Criteria: February 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; SARS-COV-2; Naproxen; Nonsteroidal anti-inflamatory drug
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gout Suppressants; Naproxen
• Other Study ID Numbers: APHP200387

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No