Efficacy of Addition of Naproxen in the Treatment of Critically Ill Patients Hospitalized for COVID-19 Infection
Keywords
Abstract
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.
Dates
| Last Verified: | 03/31/2020 |
| First Submitted: | 03/25/2020 |
| Estimated Enrollment Submitted: | 03/25/2020 |
| First Posted: | 03/26/2020 |
| Last Update Submitted: | 04/11/2020 |
| Last Update Posted: | 04/13/2020 |
| Actual Study Start Date: | 04/12/2020 |
| Estimated Primary Completion Date: | 05/12/2021 |
| Estimated Study Completion Date: | 07/12/2021 |
Condition or disease
Intervention/treatment
Drug: 1: Naproxen
Drug: 2: Standard of care
Phase
Arm Groups
| 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) |
| Placebo Comparator: 2: Standard of care Standard of care |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | 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 |
Outcome
Primary Outcome Measures
1. Mortality all causes at day30 [at day30]
Secondary Outcome Measures
1. Number of days alive free of mechanical ventilation [during 30 days after randomization]
2. Number of days alive outside [during 30 days after randomization]
3. Number of days alive outside hospital [during 30 days after randomization]
4. Maximal changes in Sofa score [in the first 7 days after randomization]
5. Time to negativation of virus titer in the nasopharyngeal aspirate (NPA) [during 90 days after randomization]
