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.
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.
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.
Instituto Nacional de Enfermedades Respiratorias
Mexico City, Mexico
Mortality
Number of participants who die divided by number of subjects enrolled in the that study group.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Days under mechanical ventilation
Number of days spent 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.
PaO2/FiO2 ratio
Arterial pressure of oxygen divided by inspired fraction of oxygen.
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 plasma lactate
Plasma concentration of lactate in arterial blood.
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 IL-1β
Serum concentration of interleukin 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 IL-2
Serum concentration of interleukin 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 IL-4
Serum concentration of interleukin 4.
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
59
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 IL-5
Serum concentration of interleukin 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 IL-6
Serum concentration of interleukin 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 IL-7
Serum concentration of interleukin 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 IL-8
Serum concentration of interleukin 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 IL-10
Serum concentration of interleukin 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 IL-12
Serum concentration of interleukin 12 (p70).
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 IL-13
Serum concentration of interleukin 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 IL-17
Serum concentration of interleukin 17A.
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 G-CSF
Serum concentration of granulocyte colony stimulating factor.
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 GM-CSF
Serum concentration of granulocyte monocyte colony stimulating factor.
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 IFN-γ
Serum concentration of interferon gamma.
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 MCP-1
Serum concentration of monocyte chemoattractant protein 1 (MCAF).
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 MIP-1β
Serum concentration of macrophage inflammatory protein 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 TNF-α
Serum concentration of tumor necrosis factor alpha.
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 creatinine
Serum concentration of 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 alanine aminotransferase
Serum concentration of 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 aspartate aminotransferase
Serum concentration of 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 alkaline phosphatase
Serum concentration of 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 total bilirubin
Serum concentration of 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 unconjugated bilirubin
Serum concentration of 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 conjugated bilirubin
Serum concentration of 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 C reactive protein
Serum concentration of 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.
Hemoglobin
Blood concentration of 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.
Total leukocytes
Number of white blood cells per µl blood.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Neutrophils
Number of neutrophils per µl blood.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Lymphocytes
Number of lymphocytes per µl blood.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Monocytes
Number of monocytes per µl blood.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Eosinophils
Number of eosinophils per µl blood.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Basophils
Number of basophils per µl blood.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Platelets
Number of platelets per µl blood.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Prothrombin time
Time that blood takes to clot.
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 PAI-1
Serum concentration of plasminogen activator inhibitor 1 (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.
SOFA score
Sequence Organ Failure Assessment (SOFA) score, composed by assessment of PaO2/FiO2 ratio, Glasgow coma scale, mean arterial pressure, bilirubin, and 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.
APACHE II score
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.
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.