Pyridostigmine in Severe SARS-CoV-2 Infection

NCT04343963 | Unknown Phase 2 DMC

• 1 other identifier: Inf-3323
• Study Type: interventional
• Target: 436
• Locations: 1 country
• Sites: 1

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.

Conditions

COVID-19; SARS-CoV-2

Outcome Measures

Primary Outcomes (2)

• Critical condition or death

  Composite of death, Need for mechanical ventilation, or an increase of 2 or more points in the SOFA score

  28 days

• IL-6

  Kinetics of circulating IL-6

  14 days in-hospital, hospital discharge, or death

Study Arms (2)

Pyridostigmine

ACTIVE COMPARATOR

Pyridostigmine bromide tablet (60mg P.O. once per day for 14 days)

Drug: Pyridostigmine Bromide

Placebo

PLACEBO COMPARATOR

Placebo tablet (60mg P.O. once per day for 14 days)

Drug: Placebo

Interventions

Pyridostigmine Bromide DRUG

One 60mg tablet P.O. once per day for 14 days

Also known as: Mestinon, Pyridostigmine

Pyridostigmine

Placebo DRUG

One tablet P.O. once per day for 14 days

Also known as: Starch (pharmaceutical grade)

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (≥18 years old)
• Signed informed consent by the patient or designated legal representative
• Confirmatory laboratory test for SARS-CoV-2 / COVID-19 infection
• Pneumonia confirmed by imaging studies
• Agree to venous blood collection according to the protocol
• 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

You may not qualify if:

• Pyridostigmine allergy
• If female, pregnancy or breastfeeding
• Meet the following critical illness criteria before signing informed consent and taking the first dose of study medication:
• Need for mechanical ventilation
• Admission to the ICU for any reason
• Meet criteria for sepsis or septic shock
• Concomitant autoimmune diseases
• Known immunodeficiency (including HIV infection)
• Need for mechanical ventilation before signing informed consent and taking the first dose of study medication
• Inability to administer orally / enterally
• 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
• Participation in interventional clinical trials in the preceding 28 days (however, participation in observational trials or those with no therapeutic intervention, is allowed)

Sponsors & Collaborators

• Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran: lead

Study Sites (1)

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

Mexico City, Tlalpan, 14080, Mexico

RECRUITING

Related Publications (11)

• Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available.

  PMID: 32091533 BACKGROUND

• Chavan SS, Tracey KJ. Essential Neuroscience in Immunology. J Immunol. 2017 May 1;198(9):3389-3397. doi: 10.4049/jimmunol.1601613.

  PMID: 28416717 BACKGROUND

• Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA, Faltys M, Zitnik R, Tracey KJ, Tak PP. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):8284-9. doi: 10.1073/pnas.1605635113. Epub 2016 Jul 5.

  PMID: 27382171 BACKGROUND

• Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000 May 25;405(6785):458-62. doi: 10.1038/35013070.

  PMID: 10839541 BACKGROUND

• Rosas-Ballina M, Valdes-Ferrer SI, Dancho ME, Ochani M, Katz D, Cheng KF, Olofsson PS, Chavan SS, Al-Abed Y, Tracey KJ, Pavlov VA. Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. Brain Behav Immun. 2015 Feb;44:19-27. doi: 10.1016/j.bbi.2014.07.010. Epub 2014 Jul 23.

  PMID: 25063706 BACKGROUND

• Valdes-Ferrer SI, Crispin JC, Belaunzaran PF, Cantu-Brito CG, Sierra-Madero J, Alcocer-Varela J. Acetylcholine-esterase inhibitor pyridostigmine decreases T cell overactivation in patients infected by HIV. AIDS Res Hum Retroviruses. 2009 Aug;25(8):749-55. doi: 10.1089/aid.2008.0257.

  PMID: 19645607 BACKGROUND

• Robinson-Papp J, Nmashie A, Pedowitz E, George MC, Sharma S, Murray J, Benn EKT, Lawrence SA, Machac J, Heiba S, Kim-Schulze S, Navis A, Roland BC, Morgello S. The effect of pyridostigmine on small intestinal bacterial overgrowth (SIBO) and plasma inflammatory biomarkers in HIV-associated autonomic neuropathies. J Neurovirol. 2019 Aug;25(4):551-559. doi: 10.1007/s13365-019-00756-9. Epub 2019 May 16.

  PMID: 31098925 BACKGROUND

• Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.

  PMID: 32109013 BACKGROUND

• Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-481. doi: 10.1016/S2213-2600(20)30079-5. Epub 2020 Feb 24.

  PMID: 32105632 BACKGROUND

• Fragoso-Saavedra S, Nunez I, Audelo-Cruz BM, Arias-Martinez S, Manzur-Sandoval D, Quintero-Villegas A, Benjamin Garcia-Gonzalez H, Carbajal-Morelos SL, PoncedeLeon-Rosales S, Gotes-Palazuelos J, Maza-Larrea JA, Rosales-de la Rosa JJ, Diaz-Rivera D, Luna-Garcia E, Piten-Isidro E, Del Rio-Estrada PM, Fragoso-Saavedra M, Caro-Vega Y, Batina I, Islas-Weinstein L, Iruegas-Nunez DA, Calva JJ, Belaunzaran-Zamudio PF, Sierra-Madero J, Crispin JC, Valdes-Ferrer SI. Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial. Mol Med. 2022 Nov 8;28(1):131. doi: 10.1186/s10020-022-00553-x.

  PMID: 36348276 DERIVED

• Fragoso-Saavedra S, Iruegas-Nunez DA, Quintero-Villegas A, Garcia-Gonzalez HB, Nunez I, Carbajal-Morelos SL, Audelo-Cruz BM, Arias-Martinez S, Caro-Vega Y, Calva JJ, Luqueno-Martinez V, Gonzalez-Duarte A, Crabtree-Ramirez B, Crispin JC, Sierra-Madero J, Belaunzaran-Zamudio PF, Valdes-Ferrer SI. A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol. BMC Infect Dis. 2020 Oct 16;20(1):765. doi: 10.1186/s12879-020-05485-7.

  PMID: 33066761 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Pyridostigmine Bromide; Starch

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pyridinium Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Glucans; Biopolymers; Polymers; Macromolecular Substances; Dietary Carbohydrates; Carbohydrates; Polysaccharides

Study Officials

• Sergio I Valdés-Ferrer, MD, PhD

  Instituto Nacional De Ciencias Médicas y Nutrición

  STUDY CHAIR

Central Study Contacts

Sergio I Valdés-Ferrer, MD, PhD

CONTACT

+525554870900; sergio.valdesf@incmnsz.mx

Juan Sierra-Madero, MD

CONTACT

+525554870900; jsmadero@yahoo.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 9, 2020
• First Posted: April 14, 2020
• Study Start: April 4, 2020
• Primary Completion: September 30, 2020
• Study Completion: April 30, 2021
• Last Updated: July 7, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)