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Glycine Supplement for Severe COVID-19

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ClinicalTrials.gov Identifier: NCT04443673
Recruitment Status : Recruiting
First Posted : June 23, 2020
Last Update Posted : August 24, 2020
Sponsor:
Information provided by (Responsible Party):
Mario H. Vargas, Instituto Nacional de Enfermedades Respiratorias

Brief Summary:
This study will explore whether a daily supplement of glycine, a substance that has antiinflammatory, cytoprotective, and endothelium-protecting effects, can improve mortality, as well as clinical and biochemical parameters, in patients with severe COVID-19 who initiate mechanical ventilatory support.

Condition or disease Intervention/treatment Phase
COVID-19 SARS-CoV Infection SARS (Severe Acute Respiratory Syndrome) SARS Pneumonia ARDS, Human Pneumonia, Viral Dietary Supplement: Glycine Not Applicable

Detailed Description:

Patients with severe forms of COVID-19 often develop acute respiratory distress syndrome (ARDS) associated with high levels of proinflammatory cytokines and damage of lungs and other organs. A special feature in these patients is thrombotic events in the micro- and macro-vasculature. Owing to the lack of a specific and efficient treatment against COVID-19, lowering of this "cytokine storm" is a further proposed strategy.

Glycine is the major agonist of glycine receptors (GlyR), which are chloride channels that hyperpolarize cell membranes of inflammatory cells such as macrophages and neutrophils, turning them less sensitive to proinflammatory stimuli. In addition, glycine possesses a cytoprotective effect, improves endothelial function, and diminishes platelet aggregation.

In laboratory animals, in a rat model of endotoxic shock a 5% glycine-rich diet lowers mortality, reduces pulmonary neutrophilic inflammation and hepatic lesions, and avoids elevation of serum TNF-alpha. In animal models of ischemia-reperfusion injury, glycine protects the gut and lungs.

In in vitro studies, glycine diminishes the expression and release of TNF-alpha and IL-6 from adipose tissue, 3T3-L1 cells, and alveolar macrophages, probably through inhibition of phosphorylation of NF-kappaB. Finally, glycine diminishes platelet aggregation.

In human beings, glycine has been used for many years for the management of some ailments. In diabetic patients, oral glycine reduces glycosylated hemoglobin levels and serum TNF-alpha, and in patients with cystic fibrosis glycine improves the clinical and spirometric status, and tend to lower serum TNF-alpha, IL-6 and G-CSF.

Glycine is a white microcrystal powder soluble in water, with a sweet taste and relatively low cost.

This controlled, randomized, two-branches clinical trial will recruit participants of any sex, any age, with COVID-19 confirmed (or awaiting confirmation) by PCR, that are to initiate (or with <48 h of) mechanical ventilation. After obtaining an informed consent, participants will be randomly assigned to two branches: 1) Experimental group, n=41 participants, that along with habitual management for their condition will receive 0.5 g/kg/day glycine divided in four doses every 6 h through nasogastric tube. 2) Control group, n=41 participants that will only receive habitual management. Pregnant women and subjects already participating in another study protocol will be excluded, and those with voluntary discharge or referenced to another institution will be discarded.

Blood samples for measurements of serum cytokines (Bio-Plex Human Cytokine 17-Plex, Bio-Rad) will be obtained at the beginning of the study and every 7 days thereafter.

The major outcome will be mortality. Secondary outcomes will be diminution of number of days under mechanical ventilation and evolution of PaO2/FiO2, proinflammatory and metabolic biomarkers, Sequence Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II).

Routine test such as arterial blood gases, blood chemistry, blood count, coagulation test, and ECG will also be analyzed by using the weighted average in certain time-periods (probably 7-days periods).

Group comparisons will be carried out by means of Fisher exact/chi-square tests and Student's t-/Mann-Whitney U-tests. Feasibility of multivariate analysis will be evaluated.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 82 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Controlled, randomized, two branches, clinical trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Controlled and Randomized Clinical Trial for Evaluating the Effect of a Supplement of Glycine as Adjuvant in the Treatment of COVID-19 Pneumonia in Patients Initiating Mechanical Ventilation
Actual Study Start Date : August 20, 2020
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : June 30, 2021


Arm Intervention/treatment
Experimental: Glycine
Along with habitual treatment for their severe condition, participants will receive 0.5 g/kg/day glycine by nasogastric tube, divided in four equal doses in a day, since their enrollment and until they are weaned from mechanical ventilator or die.
Dietary Supplement: Glycine
Along with habitual treatment for their severe condition, participants will receive 0.5 g/kg/day glycine by nasogastric tube, divided in four equal doses in a day, since their enrollment and until they are weaned from mechanical ventilator or die.

No Intervention: Control
Participants will receive the habitual treatment for their severe condition.



Primary Outcome Measures :
  1. Mortality [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of participants who die divided by number of subjects enrolled in the that study group.


Secondary Outcome Measures :
  1. Days under mechanical ventilation [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of days spent under mechanical ventilation.

  2. PaO2/FiO2 ratio [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Arterial pressure of oxygen divided by inspired fraction of oxygen.

  3. Arterial plasma lactate [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Plasma concentration of lactate in arterial blood.

  4. Serum IL-1β [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 1β.

  5. Serum IL-2 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 2.

  6. Serum IL-4 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 4.

  7. Serum IL-5 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 5.

  8. Serum IL-6 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 6.

  9. Serum IL-7 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 7.

  10. Serum IL-8 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 8.

  11. Serum IL-10 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 10.

  12. Serum IL-12 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 12 (p70).

  13. Serum IL-13 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 13.

  14. Serum IL-17 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interleukin 17A.

  15. Serum G-CSF [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of granulocyte colony stimulating factor.

  16. Serum GM-CSF [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of granulocyte monocyte colony stimulating factor.

  17. Serum IFN-γ [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of interferon gamma.

  18. Serum MCP-1 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of monocyte chemoattractant protein 1 (MCAF).

  19. Serum MIP-1β [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of macrophage inflammatory protein 1β

  20. Serum TNF-α [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of tumor necrosis factor alpha.

  21. Serum creatinine [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of creatinine.

  22. Serum alanine aminotransferase [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]

    Serum concentration of alanine aminotransferase.

    .


  23. Serum aspartate aminotransferase [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]

    Serum concentration of aspartate aminotransferase.

    .


  24. Serum alkaline phosphatase [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of alkaline phosphatase.

  25. Serum total bilirubin [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of total bilirubin.

  26. Serum unconjugated bilirubin [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of unconjugated bilirubin.

  27. Serum conjugated bilirubin [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of conjugated bilirubin

  28. Serum C reactive protein [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of C reactive protein.

  29. Hemoglobin [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Blood concentration of hemoglobin.

  30. Total leukocytes [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of white blood cells per µl blood.

  31. Neutrophils [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of neutrophils per µl blood.

  32. Lymphocytes [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of lymphocytes per µl blood.

  33. Monocytes [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of monocytes per µl blood.

  34. Eosinophils [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of eosinophils per µl blood.

  35. Basophils [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of basophils per µl blood.

  36. Platelets [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Number of platelets per µl blood.

  37. Prothrombin time [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Time that blood takes to clot.

  38. Serum PAI-1 [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Serum concentration of plasminogen activator inhibitor 1 (PAI-1).

  39. SOFA score [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Sequence Organ Failure Assessment (SOFA) score, composed by assessment of PaO2/FiO2 ratio, Glasgow coma scale, mean arterial pressure, bilirubin, and platelets.

  40. APACHE II score [ Time Frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. ]
    Acute Physiology And Chronic Health Evaluation II (APACHE II) score, composed by assessment of AaDO2 or PaO2, temperature, mean arterial pressure, pH arterial, heart rate, respiratory rate, sodium, potassium, creatinine, hematocrit, white blood cell count, Glasgow coma scale.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Any age.
  • Any sex.
  • With COVID-19 confirmed (or awaiting confirmation) by PCR.
  • With a clinical decision of initiation of mechanical ventilation or with <48 h under mechanical ventilation.
  • Informed consent signed by the participant's responsible.

Exclusion Criteria:

  • Pregnant women.
  • Already participating in another research protocol.

Elimination Criteria:

  • Voluntary hospital discharge or referenced to another institution.

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): NCT04443673


Contacts
Layout table for location contacts
Contact: Mario H Vargas, MSc 52+ 55 5666 5868 mhvargasb@yahoo.com.mx
Contact: David Ibarra-Villarreal, MD 52+ 55 5487 1700 ext 5164 dibarrav@live.net.com

Locations
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Mexico
Instituto Nacional de Enfermedades Respiratorias Recruiting
Mexico DF, Mexico, 14080
Contact: Mario H Vargas, MSc    52+ 55 5666 5868    mhvargasb@yahoo.com.mx   
Contact: David Ibarra-Villarreal, MD    52+ 55 5487 1700 ext 5164    dibarrav@live.net.com   
Principal Investigator: Mario H. Vargas, MD, MSc         
Sub-Investigator: David Ibarra-Villarreal, MD         
Sub-Investigator: Cristóbal Guadarrama-Pérez, MD         
Sub-Investigator: Alejandra R Báez-Saldaña, MD         
Sub-Investigator: Justino Regalado-Pineda, MD         
Sub-Investigator: Jaime Chávez-Alderete, PhD         
Sponsors and Collaborators
Instituto Nacional de Enfermedades Respiratorias
Investigators
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Principal Investigator: Mario H Vargas, MSc Instituto Nacional de Enfermedades Respiratorias
Publications:
Anonimous. New and nonofficial remedies. J Am Med Assoc 1935;104:1241
Carvajal, G., et al., Inhibición de la glicosilación no enzimática de la hemoglobina en la diabetes mellitus. Rev Inst Nal Enf Resp 1995;8:185-188.

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Responsible Party: Mario H. Vargas, Senior Researcher, Instituto Nacional de Enfermedades Respiratorias
ClinicalTrials.gov Identifier: NCT04443673    
Other Study ID Numbers: C40-20
First Posted: June 23, 2020    Key Record Dates
Last Update Posted: August 24, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD can be shared on a reasonable basis and after authorization from the Instituto Nacional de Enfermedades Respiratorias' IRB.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: From publication of results in a scientific journal onward.
Access Criteria: Reasonable request by E-mail (mhvargasb@yahoo.com.mx)

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mario H. Vargas, Instituto Nacional de Enfermedades Respiratorias:
Glycine
Aminoacetic Acid
Coronavirus Disease
COVID-19
Severe Acute Respiratory Syndrome
SARS
Additional relevant MeSH terms:
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Severe Acute Respiratory Syndrome
Coronavirus Infections
Pneumonia, Viral
Pneumonia
Respiratory Distress Syndrome, Adult
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiration Disorders
Glycine
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs