Clinical trial NCT04383899: Role of Ibuprofen and Other Medicines on Severity of Coronavirus Disease 2019
Official title: Role of Ibuprofen and Other Medicines on Severity of Coronavirus Disease 2019 (COVID-19) Infections: a Case-control Study
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Coronavirus Infection
Keywords: NSAID
Ibuprofen
chronic pathology
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: Bordeaux PharmacoEpi
First posted: 2020-05-12
Enrollment: 0
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients will be screened at the time of their visit to the participating hospital center; i.e. at the ambulatory screening center adjacent to the hospital not necessarily resulting in patient hospitalization, or directly on admission at the appropriate hospital department (emergencies, intensive care or others).

Brief summary: It has been suggested that ibuprofen might be associated with more severe cases of coronavirus infections, based on the observation that severe COVID cases had been exposed to ibuprofen, resulting in a warning by the French authorities.

This was attributed to:

1. a suggestion that ibuprofen might upregulate ACE-2 thereby increasing the entrance of COVID-19 into the cells,
2. an analogy with bacterial soft-tissue infections where more severe infections on NSAIDs are attributed to an immune-depressive action of NSAIDs, or to belated treatment because of initial symptom suppression,
3. fever is a natural response to viral infection, and reduces virus activity: antipyretic activity might reduce natural defenses against viruses. However fever reduction in critically ill patients had no effect on survival.

However, these assertions are unclear: upregulation of ACEII would increase the risk of infection, not necessarily its severity, and would only apply to the use of NSAIDs before the infection, i.e. chronic exposure. It would be irrelevant to the infection once the patients are infected, i.e., to symptomatic treatment of COVID-19 infection.

Anti-inflammatory effect masking the early symptoms of bacterial infections resulting in later antibiotic or other treatment is not applicable: there is no treatment of the virus that might be affected by masking symptoms.

Antipyretic effect increasing the risk or the severity of infection would apply equally to all antipyretic agents including paracetamol, which share the same mechanism of action for fever reduction.

EMA remains prudent about this assertion

In addition, excess reliance on paracetamol while discouraging the use of ibuprofen might increase the risk of hepatic injury from paracetamol overdose. Paracetamol is the prime drug associated with liver injury and transplantation, in voluntary and inadvertent overdose or even at normal doses. This might be increased by COVID-related liver function alterations.

It is therefore proposed to conduct a case-control study in a cohort of patients admitted to hospital in France with COVID-19 infection.

Detailed description: It has been suggested that ibuprofen might be associated with more severe cases of coronavirus infections, based on the observation that severe COVID cases had been exposed to ibuprofen, resulting in a warning by the French authorities (published in a french journal called "Le Monde" = The world).

This was attributed to:

1. a suggestion that ibuprofen might upregulate ACE-2 thereby increasing the entrance of COVID-19 into the cells.This is based on a single study in streptozotocin-induced diabetic rats where ibuprofen decreases cardiac fibrosis. There seems to be no study in man. (https://www.dw.com/en/coronavirus-confusion-about-safety-of-ibuprofen/a-52824043) These authors noted an increased risk of severe COVID-19 in patients with hypertension or diabetes, and a possible role of Angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) which also upregulate ACE-2, as do also thiazolidinedione antidiabetic drugs. The relevance of this up-regulation seems disputed.
2. an analogy with bacterial soft-tissue infections where more severe infections on NSAIDs are attributed to an immune-depressive action of NSAIDs, or to belated treatment because of initial symptom suppression.
3. fever is a natural response to viral infection, and reduces virus activity: antipyretic activity might reduce natural defenses against viruses. However fever reduction in critically ill patients had no effect on survival. A meta-analysis of fever reduction in children found no difference on outcomes between paracetamol and ibuprofen.

However, these assertions are unclear: upregulation of ACEII would increase the risk of infection, not necessarily its severity, and would only apply to the use of NSAIDs before the infection, i.e. chronic exposure. It would be irrelevant to the infection once the patients are infected, i.e., to symptomatic treatment of COVID-19 infection.

Anti-inflammatory effect masking the early symptoms of bacterial infections resulting in later antibiotic or other treatment is not applicable: there is no treatment of the virus that might be affected by masking symptoms.

Antipyretic effect increasing the risk or the severity of infection would apply equally to all antipyretic agents including paracetamol, which share the same mechanism of action for fever reduction.

EMA remains prudent about this assertion (EMA gives advice on the use of non-steroidal anti-inflammatory drugs for COVID-19, 18 March 2020 EMA/136850/2020).

These findings raise the question of

1. an indication bias, where more severe cases with more symptoms and higher fever might not respond well to the first line antipyretic paracetamol, so that ibuprofen was then used. (reverse causality) The same has been described with soft-tissue infection
2. the reality of an increased risk in patients chronically on drugs that upregulate ACEII, such as NSAIDs, antihypertensive drugs and especially ACEI or ARB, or antidiabetic drugs and especially thiazolidinediones.
3. the impact of concomitant or pre-existing diseases such as diabetes, hypertension or heart failure.

In addition, excess reliance on paracetamol while discouraging the use of ibuprofen might increase the risk of hepatic injury from paracetamol overdose. Paracetamol is the prime drug associated with liver injury and transplantation, in voluntary and inadvertent overdose or even at normal doses. This might be increased by COVID-related liver function alterations.

It is therefore proposed to conduct a case-control study in a cohort of patients admitted to hospital in France with COVID-19 infection, to explore these different questions.

Eligibility criteria: Inclusion Criteria:

- All patients tested for COVID-19 in hospital centers participating to the study.

No exclusion Criteria.

Primary outcomes:
measure: Describe medications used prior to admission associated with worse infection in COVID-19 patients in France.
timeFrame: At inclusion day
measure: Quantify medications used prior to admission associated with worse infection in COVID-19 patients in France.
timeFrame: At inclusion day
Secondary outcomes:
measure: Describe other patient characteristics with worse infection in COVID-19 patients in France.
timeFrame: At inclusion day
measure: Quantify other patient characteristics with worse infection in COVID-19 patients in France.
timeFrame: At inclusion day
Other outcomes:
Locations:
Study officials:
References: