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An interim analysis showed no difference in major outcomes (n=35 glycine and n=24 control participants)
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Glycine | Experimental | 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. |
|
| Control | No Intervention | Participants will receive the habitual treatment for their severe condition. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Glycine | Dietary Supplement | 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. |
| 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. |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
Elimination Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mario H Vargas, MSc | Instituto Nacional de Enfermedades Respiratorias | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Instituto Nacional de Enfermedades Respiratorias | Mexico City | 14080 | Mexico |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31986264 | Background | Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. | |
| 32360286 |
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IPD can be shared on a reasonable basis and after authorization from the Instituto Nacional de Enfermedades Respiratorias' IRB.
From publication of results in a scientific journal onward.
Reasonable request by E-mail (mhvargasb@yahoo.com.mx)
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D045169 | Severe Acute Respiratory Syndrome |
| D012128 | Respiratory Distress Syndrome |
| D011024 | Pneumonia, Viral |
| ID | Term |
|---|---|
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D014777 | Virus Diseases |
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| ID | Term |
|---|---|
| D005998 | Glycine |
| ID | Term |
|---|---|
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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Controlled, randomized, two branches, clinical trial.
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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. |
| Background |
| Yang Y, Shen C, Li J, Yuan J, Wei J, Huang F, Wang F, Li G, Li Y, Xing L, Peng L, Yang M, Cao M, Zheng H, Wu W, Zou R, Li D, Xu Z, Wang H, Zhang M, Zhang Z, Gao GF, Jiang C, Liu L, Liu Y. Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. J Allergy Clin Immunol. 2020 Jul;146(1):119-127.e4. doi: 10.1016/j.jaci.2020.04.027. Epub 2020 Apr 29. |
| 32291094 | Background | Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. Epub 2020 Apr 10. |
| 32486469 | Background | Marchandot B, Sattler L, Jesel L, Matsushita K, Schini-Kerth V, Grunebaum L, Morel O. COVID-19 Related Coagulopathy: A Distinct Entity? J Clin Med. 2020 May 31;9(6):1651. doi: 10.3390/jcm9061651. |
| 32056249 | Background | Liu J, Zheng X, Tong Q, Li W, Wang B, Sutter K, Trilling M, Lu M, Dittmer U, Yang D. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol. 2020 May;92(5):491-494. doi: 10.1002/jmv.25709. Epub 2020 Feb 21. |
| 32385712 | Background | Panigrahy D, Gilligan MM, Huang S, Gartung A, Cortes-Puch I, Sime PJ, Phipps RP, Serhan CN, Hammock BD. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Cancer Metastasis Rev. 2020 Jun;39(2):337-340. doi: 10.1007/s10555-020-09889-4. |
| 11917096 | Background | Jentsch TJ, Stein V, Weinreich F, Zdebik AA. Molecular structure and physiological function of chloride channels. Physiol Rev. 2002 Apr;82(2):503-68. doi: 10.1152/physrev.00029.2001. |
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| 27066896 | Background | Weinberg JM, Bienholz A, Venkatachalam MA. The role of glycine in regulated cell death. Cell Mol Life Sci. 2016 Jun;73(11-12):2285-308. doi: 10.1007/s00018-016-2201-6. Epub 2016 Apr 11. |
| 12589194 | Background | Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, Bunzendaul H, Bradford B, Lemasters JJ. L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):229-40. doi: 10.1097/00075197-200303000-00013. |
| 25988540 | Background | Gomez-Zamudio JH, Garcia-Macedo R, Lazaro-Suarez M, Ibarra-Barajas M, Kumate J, Cruz M. Vascular endothelial function is improved by oral glycine treatment in aged rats. Can J Physiol Pharmacol. 2015 Jun;93(6):465-73. doi: 10.1139/cjpp-2014-0393. Epub 2015 Mar 4. |
| 23135224 | Background | Schemmer P, Zhong Z, Galli U, Wheeler MD, Xiangli L, Bradford BU, Conzelmann LO, Forman D, Boyer J, Thurman RG. Glycine reduces platelet aggregation. Amino Acids. 2013 Mar;44(3):925-31. doi: 10.1007/s00726-012-1422-8. Epub 2012 Nov 8. |
| 8760112 | Background | Ikejima K, Iimuro Y, Forman DT, Thurman RG. A diet containing glycine improves survival in endotoxin shock in the rat. Am J Physiol. 1996 Jul;271(1 Pt 1):G97-103. doi: 10.1152/ajpgi.1996.271.1.G97. |
| 10926563 | Background | Wheeler MD, Rose ML, Yamashima S, Enomoto N, Seabra V, Madren J, Thurman RG. Dietary glycine blunts lung inflammatory cell influx following acute endotoxin. Am J Physiol Lung Cell Mol Physiol. 2000 Aug;279(2):L390-8. doi: 10.1152/ajplung.2000.279.2.L390. |
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| Background | Anonimous. New and nonofficial remedies. J Am Med Assoc 1935;104:1241 |
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| Background | 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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| 40234280 | Derived | Vargas MH, Chavez J, Del-Razo-Rodriguez R, Munoz-Perea C, Romo-Dominguez KJ, Baez-Saldana R, Rumbo-Nava U, Guerrero-Zuniga S. Lower Serum Magnesium Is Associated with Mortality in Severe COVID-19: A Secondary Analysis of a Randomized Trial. Biol Trace Elem Res. 2025 Nov;203(11):5987-5996. doi: 10.1007/s12011-025-04619-9. Epub 2025 Apr 15. |
| 38773199 | Derived | Vargas MH, Chavez J, Del-Razo-Rodriguez R, Munoz-Perea C, Romo-Dominguez KJ, Baez-Saldana R, Rumbo-Nava U, Guerrero-Zuniga S. Glycine by enteral route does not improve major clinical outcomes in severe COVID-19: a randomized clinical pilot trial. Sci Rep. 2024 May 21;14(1):11566. doi: 10.1038/s41598-024-62321-7. |
| D018352 |
| Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |