Glycine Supplement for Severe COVID-19

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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COVID-19, SARS-CoV Infection, SARS (Severe Acute Respiratory Syndrome), SARS Pneumonia, ARDS, Human, Pneumonia, Viral

Intervention / Treatment
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* Dietary Supplement: Glycine


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Controlled, randomized, two branches, clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glycine<br>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<br>* 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.<br>|
| No Intervention: Control<br>Participants will receive the habitual treatment for their severe condition. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Number of participants who die divided by number of subjects enrolled in the that study group. | From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days under mechanical ventilation | Number of days spent under mechanical ventilation. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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. | 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. | 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. | 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. | 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. | 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). | 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 | 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. | 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. | 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. . | 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. . | 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. | 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. | 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. | 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 | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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. | 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. | From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glycine, Aminoacetic Acid, Coronavirus Disease, COVID-19, Severe Acute Respiratory Syndrome, SARS