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

Phase 3

Terminated

• Conditions: COVID-19

• Registration Number: NCT04325633
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

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.

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 Timeline

• Study First Submitted: 2020-03-26
• Study First Submitted QC: 2020-03-26
• Study First Posted: 2020-03-27
• Study Start: 2020-04-24
• Primary Completion: 2020-12-15
• Study Completion: 2020-12-15
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-24
• Last Update Posted: 2021-02-25

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 30

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Mortality all causes at day30	at day30

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Urgences, Avicenne Hospital; 🇫🇷 Bobigny, France

Réanimation médico-chirurgicale, Avicenne Hospital; 🇫🇷 Bobigny, France