Pyridostigmine in Severe SARS-CoV-2 Infection (PISCO)
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|ClinicalTrials.gov Identifier: NCT04343963|
Recruitment Status : Recruiting
First Posted : April 14, 2020
Last Update Posted : July 7, 2020
We will evaluate low-dose pyridostigmine as add-on therapy to best medical care in patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and its related Coronavirus Disease 2019 (COVID-19) who require hospitalization. Our hypothesis is that, in comparison to the placebo, pyridostigmine will reduce in at least 10% a composite outcome [death; mechanical ventilation; >2 point-increase in the SOFA score) by day 28. We will also evaluate interleukin (IL)-6 kinetics during the first 14 days of in-hospital stay.
It is estimated that 25-33% of patients hospitalized for COVID-19 are admitted to intensive care units (ICU) for severe hypoxemia. The reported mortality in those with severe disease ranges between 38% and 49%. So far, there is no pharmacological therapeutic (or else) strategy known to reduce morbidity and mortality in these patients. Mortality in COVID-19 appears to be mediated not necessarily by the direct effect of the infection, but by the disproportionate inflammatory response of the host.
Pyridostigmine is an old drug that, by inhibiting acetylcholine-esterase, the enzymatic machinery that degrades acetylcholine (ACh), results in increased ACh bioavailability. ACh, in turn, ligates to nicotinic-alpha7 receptors in macrophages and T cells, resulting in reduced overactivation of these immune cells. In experimental murine sepsis, this family of drugs has resulted in reduced inflammation and mortality. Human evidence is scarce for severe inflammatory conditions. However, recent evidence from our group and others indicates that pyridostigmine has an immunomodulatory effect in people living with HIV, resulting in elevation of CD4+ T cell counts, decreased immune activation, and reduction in inflammatory mediators. Altogether, this suggests that ACh-esterase inhibitors may act as immunomodulators during viral infections, potentially reducing the inflammatory cascade (the so-called "cytokine storm") observed in critically ill COVID-19 patients.
At the proposed dose (60mg/d), the rate of minor adverse events is less than 5% with no reported serious adverse effects. From that perspective, we consider that pyridostigmine can function as an immuno-modulator and reduce morbidity and mortality in COVID-19-stricken patients, with the added value of a safe pharmacological profile. Moreover, as an old drug, re-purposing it for a novel indication may be a simpler, more efficient approach than developing a novel one from the ground up.
|Condition or disease||Intervention/treatment||Phase|
|COVID-19 SARS-CoV-2||Drug: Pyridostigmine Bromide Drug: Placebo||Phase 2 Phase 3|
The study will be divided into two phases, each with different variables to evaluate, as described below:
The primary objective of the first phase (proof-of-concept) will be to evaluate the effect of pyridostigmine on the serum level of interleukin (IL)-6 as an indicator of severe inflammation, as well as its kinetics throughout the days that the patient is hospitalized.
In the first phase, we will evaluate the safety and feasibility of the study in a representative sample and we will explore in a preliminary way the magnitude of the effect of the intervention. Safety will be evaluated according to the adverse effects reported in patients with acute intoxication (accidental or in suicide attempt) with pyridostigmine:
- Abdominal pain/cramps
- Vomiting, nausea, or both
- Urinary incontinence
- Fasciculations or muscle weakness
- Blurred vision
In the second phase (to be carried out only if the results of the first phase justify it), the primary outcome to be evaluated is mortality, the requirement of invasive or non-invasive mechanical ventilation, or an increase in the SOFA scale ≥2 points.
The following secondary outcomes were evaluated: changes in the total SOFA score between study entry and evaluation at 3, 7, and 14 days; the number of days of hospital stay, days of hospitalization in the intensive care unit, and the need (and if applicable, the number of days required) for invasive or non-invasive mechanical ventilation.
The variables to measure are sex, age at hospitalization, date of COVID-19 diagnosis, date and SOFA scale measurement, date of hospitalization, date of transfer to the intensive care unit, date of initiation of mechanical ventilation. , date and reason for leaving the intensive care unit.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||436 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||
Participants will receive pyridostigmine at a dose of 60 mg / day (or matching placebo), P.O. during a period of up to 14 days, until hospital discharge, death, mechanical ventilation, or increase in the SOFA scale ≥2 points.
The proposed dose is a safe dose according to the experience in myasthenia gravis and healthy people, as well as in at least three clinical studies in people living with HIV.
Participants will be double-blind 1: 1 randomized to receive pyridostigmine or placebo for up to 14 days.
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Pyridostigmine in Patients With Severe Acute Respiratory Syndrome Secondary to SARS-CoV-2 Infection|
|Actual Study Start Date :||April 4, 2020|
|Estimated Primary Completion Date :||September 30, 2020|
|Estimated Study Completion Date :||April 30, 2021|
Active Comparator: Pyridostigmine
Pyridostigmine bromide tablet (60mg P.O. once per day for 14 days)
Drug: Pyridostigmine Bromide
One 60mg tablet P.O. once per day for 14 days
Placebo Comparator: Placebo
Placebo tablet (60mg P.O. once per day for 14 days)
One tablet P.O. once per day for 14 days
Other Name: Starch (pharmaceutical grade)
- Critical condition or death [ Time Frame: 28 days ]Composite of death, Need for mechanical ventilation, or an increase of 2 or more points in the SOFA score
- IL-6 [ Time Frame: 14 days in-hospital, hospital discharge, or death ]Kinetics of circulating IL-6
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04343963
|Contact: Sergio I Valdés-Ferrer, MD, PhD||+525554870900 ext firstname.lastname@example.org|
|Contact: Juan Sierra-Madero, MDemail@example.com|
|Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán||Recruiting|
|Ciudad de México, Tlalpan, Mexico, 14080|
|Contact: Sergio I Valdés-Ferrer, MD, PhD +52(55)5487-0900 ext 4177 firstname.lastname@example.org|
|Contact: Juan Sierra-Madero, MD +52(55)5487-0900 email@example.com|
|Sub-Investigator: José C Crispín, MD, PhD|
|Study Chair:||Sergio I Valdés-Ferrer, MD, PhD||Instituto Nacional De Ciencias Médicas y Nutrición|