ARDS, Human, COVID-19, Pneumonia, Viral, SARS-CoV Infection, SARS Pneumonia, SARS (Severe Acute Respiratory Syndrome)
Conditions
Keywords
Glycine, Aminoacetic Acid, Coronavirus Disease, COVID-19, Severe Acute Respiratory Syndrome, SARS
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.
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.
Interventions
DIETARY_SUPPLEMENTGlycine
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.
Sponsors
Instituto Nacional de Enfermedades Respiratorias
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Controlled, randomized, two branches, clinical trial.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 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
| Measure | Time frame | Description |
|---|---|---|
| PaO2/FiO2 ratio | 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. |
| Arterial plasma lactate | 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. |
| Serum IL-1β | 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. |
| Serum IL-2 | 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. |
| Serum IL-4 | 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. |
| Serum IL-5 | 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. |
| Serum IL-6 | 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. |
| Serum IL-7 | 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. |
| Serum IL-8 | 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. |
| Serum IL-10 | 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. |
| Serum IL-12 | 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). |
| Serum IL-13 | 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. |
| Serum IL-17 | 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. |
| Serum G-CSF | 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. |
| Serum GM-CSF | 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. |
| Serum IFN-γ | 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. |
| Serum MCP-1 | 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). |
| Serum MIP-1β | 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 |
| Serum TNF-α | 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. |
| Serum creatinine | 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. |
| Serum 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 concentration of alanine aminotransferase. . |
| Serum 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 concentration of aspartate aminotransferase. . |
| Serum 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 concentration of alkaline phosphatase. |
| Serum 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 concentration of total bilirubin. |
| Serum 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 concentration of unconjugated bilirubin. |
| Serum 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 concentration of conjugated bilirubin |
| Serum 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. | Serum concentration of C reactive protein. |
| Hemoglobin | 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. |
| Total leukocytes | 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. |
| Neutrophils | 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. |
| Lymphocytes | 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. |
| Monocytes | 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. |
| Eosinophils | 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. |
| Basophils | 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. |
| Days 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. | Number of days spent under mechanical ventilation. |
| Prothrombin time | 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. |
| Serum PAI-1 | 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). |
| SOFA score | 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. |
| APACHE II score | 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. |
| Platelets | 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. |
Countries
Mexico
Outcome results
None listed