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Trial record 1 of 1 for:    NCT04343963
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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
Sponsor:
Information provided by (Responsible Party):
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

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.


Condition or disease Intervention/treatment Phase
COVID-19 SARS-CoV-2 Drug: Pyridostigmine Bromide Drug: Placebo Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 436 participants
Allocation: Randomized
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)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
Other Names:
  • Mestinon
  • Pyridostigmine

Placebo Comparator: Placebo
Placebo tablet (60mg P.O. once per day for 14 days)
Drug: Placebo
One tablet P.O. once per day for 14 days
Other Name: Starch (pharmaceutical grade)




Primary Outcome Measures :
  1. 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

  2. IL-6 [ Time Frame: 14 days in-hospital, hospital discharge, or death ]
    Kinetics of circulating IL-6



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

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


Contacts
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Contact: Sergio I Valdés-Ferrer, MD, PhD +525554870900 ext 4177 sergio.valdesf@incmnsz.mx
Contact: Juan Sierra-Madero, MD +525554870900 jsmadero@yahoo.com

Locations
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Mexico
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    sergio.valdesf@incmnsz.mx   
Contact: Juan Sierra-Madero, MD    +52(55)5487-0900    jsmadero@yahoo.com   
Sub-Investigator: José C Crispín, MD, PhD         
Sponsors and Collaborators
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Investigators
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Study Chair: Sergio I Valdés-Ferrer, MD, PhD Instituto Nacional De Ciencias Médicas y Nutrición
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier: NCT04343963    
Other Study ID Numbers: Inf-3323
First Posted: April 14, 2020    Key Record Dates
Last Update Posted: July 7, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Infection
Bromides
Pyridostigmine Bromide
Anticonvulsants
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs