Clinical trial NCT04343963: Pyridostigmine in Severe SARS-CoV-2 Infection
Official title: Pyridostigmine in Patients With Severe Acute Respiratory Syndrome Secondary to SARS-CoV-2 Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: COVID-19
SARS-CoV-2
Lead sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Sponsor class: OTHER
First posted: 2020-04-14
Enrollment: 436
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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:

1. Abdominal pain/cramps
2. Diarrhea
3. Vomiting, nausea, or both
4. Hypersalivation
5. Urinary incontinence
6. Fasciculations or muscle weakness
7. 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.

Eligibility criteria: Inclusion Criteria:

1. Adult patients (≥18 years old)
2. Signed informed consent by the patient or designated legal representative
3. Confirmatory laboratory test for SARS-CoV-2 / COVID-19 infection
4. Pneumonia confirmed by imaging studies
5. Agree to venous blood collection according to the protocol
6. Need for hospitalization with increased mortality criteria according to published observations, including one or more of the following severity criteria according to the treating medical team:

   * a. Dyspnoea
   * b. Lung infiltrates\> 50% of lung fields by CT
   * c. A ratio of partial pressure arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) \<300 mmHg
   * d. Pulse oximetry \<90% to ambient air, or a 3% drop in baseline oximetry, or need to increase supplemental oxygen due to chronic hypoxia, as well as the need for supplemental oxygen according to medical judgment

And, alteration of one or more of the following laboratory studies at the time of hospital admission:

* i. D-dimer \>1 ug/mL
* ii. Ferritin level \>300 ng/mL
* iii. C-reactive protein (CRP) \>3mg/L
* iv. Lactate dehydrogenase (LDH) \>245 U/L
* v. Lymphopenia \<800 cells/uL
* vi. Creatine kinase (CK) level \>800 IU/L

Exclusion Criteria:

1. Pyridostigmine allergy
2. If female, pregnancy or breastfeeding
3. Meet the following critical illness criteria before signing informed consent and taking the first dose of study medication:

   1. . Need for mechanical ventilation
   2. . Admission to the ICU for any reason
   3. . Meet criteria for sepsis or septic shock
4. Concomitant autoimmune diseases
5. Known immunodeficiency (including HIV infection)
6. Need for mechanical ventilation before signing informed consent and taking the first dose of study medication
7. Inability to administer orally / enterally
8. Use of immunosuppressants or immuno-modulators in the preceding 28 days, including chemotherapeutics and steroids, unless recommended by the treatment medical team as part of the therapeutic approach for SARS-CoV-2 infection
9. Participation in interventional clinical trials in the preceding 28 days (however, participation in observational trials or those with no therapeutic intervention, is allowed)

Primary outcomes:
measure: Critical condition or death
timeFrame: 28 days
measure: IL-6
timeFrame: 14 days in-hospital, hospital discharge, or death
Secondary outcomes:
Other outcomes:
Locations:
city: Ciudad de México
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
state: Tlalpan
Study officials:
affiliation: Instituto Nacional De Ciencias Médicas y Nutrición
name: Sergio I Valdés-Ferrer, MD, PhD
role: STUDY_CHAIR
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