Clinical trial NCT04325633: Efficacy of Addition of Naproxen in the Treatment of Critically Ill Patients Hospitalized for COVID-19 Infection
Official title: Efficacy of Addition of Naproxen in the Treatment of Critically Ill Patients Hospitalized for COVID-19 Infection
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: COVID-19
Keywords: COVID-19
SARS-COV-2
Naproxen
Nonsteroidal anti-inflamatory drug
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-03-27
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Mortality all causes at day30
timeFrame: at day30
Secondary outcomes:
measure: Number of days alive free of mechanical ventilation
timeFrame: during 30 days after randomization
measure: Number of days alive outside
timeFrame: during 30 days after randomization
measure: Number of days alive outside hospital
timeFrame: during 30 days after randomization
measure: Maximal changes in Sofa score
timeFrame: in the first 7 days after randomization
measure: Time to negativation of virus titer in the nasopharyngeal aspirate (NPA)
timeFrame: during 90 days after randomization
Other outcomes:
Locations:
city: Bobigny
country: France
facility: Réanimation médico-chirurgicale, Avicenne Hospital
city: Bobigny
country: France
facility: Urgences, Avicenne Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Frédéric ADNET, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: