Glycine Supplement for Severe COVID-19

COVID-19 Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04443673
• Other study ID #: C40-20
• Status: Terminated
• Phase: N/A
• Start date: June 15, 2020
• Est. completion date: June 14, 2021

Study information

• Verified date: August 2022
• Source: Instituto Nacional de Enfermedades Respiratorias
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 59
• Est. completion date: June 14, 2021
• Est. primary completion date: June 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

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.

Locations

Country	Name	City	State
Mexico	Instituto Nacional de Enfermedades Respiratorias	Mexico DF

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Enfermedades Respiratorias

Country where clinical trial is conducted

Mexico, 

References & Publications (29)

Alarcon-Aguilar FJ, Almanza-Perez J, Blancas G, Angeles S, Garcia-Macedo R, Roman R, Cruz M. Glycine regulates the production of pro-inflammatory cytokines in lean and monosodium glutamate-obese mice. Eur J Pharmacol. 2008 Dec 3;599(1-3):152-8. doi: 10.1016/j.ejphar.2008.09.047. Epub 2008 Oct 9. — View Citation

Almanza-Perez JC, Alarcon-Aguilar FJ, Blancas-Flores G, Campos-Sepulveda AE, Roman-Ramos R, Garcia-Macedo R, Cruz M. Glycine regulates inflammatory markers modifying the energetic balance through PPAR and UCP-2. Biomed Pharmacother. 2010 Oct;64(8):534-40. doi: 10.1016/j.biopha.2009.04.047. Epub 2009 Oct 17. — View Citation

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.

Cruz M, Maldonado-Bernal C, Mondragón-Gonzalez R, Sanchez-Barrera R, Wacher NH, Carvajal-Sandoval G, Kumate J. Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes. J Endocrinol Invest. 2008 Aug;31(8):694-9. — View Citation

File SE, Fluck E, Fernandes C. Beneficial effects of glycine (bioglycin) on memory and attention in young and middle-aged adults. J Clin Psychopharmacol. 1999 Dec;19(6):506-12. — View Citation

Fries MH, Rinaldo P, Schmidt-Sommerfeld E, Jurecki E, Packman S. Isovaleric acidemia: response to a leucine load after three weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy. J Pediatr. 1996 Sep;129(3):449-52. — View Citation

Garcia-Macedo R, Sanchez-Muñoz F, Almanza-Perez JC, Duran-Reyes G, Alarcon-Aguilar F, Cruz M. Glycine increases mRNA adiponectin and diminishes pro-inflammatory adipokines expression in 3T3-L1 cells. Eur J Pharmacol. 2008 Jun 10;587(1-3):317-21. doi: 10.1016/j.ejphar.2008.03.051. Epub 2008 Apr 8. — View Citation

Gómez-Zamudio JH, García-Macedo R, Lázaro-Suárez 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. — View Citation

Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D. Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry. 1996 Nov;169(5):610-7. — View Citation

Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry. 1999 Jan;56(1):29-36. — View Citation

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. Erratum in: Lancet. 2020 Jan 30;:. — View Citation

Iijima S, Shou J, Naama H, Calvano SE, Daly JM. Beneficial effect of enteral glycine in intestinal ischemia/reperfusion injury. J Gastrointest Surg. 1997 Jan-Feb;1(1):61-7; discussion 67-8. — View Citation

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. — View Citation

Jentsch TJ, Stein V, Weinreich F, Zdebik AA. Molecular structure and physiological function of chloride channels. Physiol Rev. 2002 Apr;82(2):503-68. Review. Erratum in: Physiol Rev. 2003 Apr;83(2):following table of contents. — View Citation

Khan M, Ron Van Der Wieken L, Riezebos RK, Tijssen JG, Kiemeneij F, Slagboom T, Laarman GJ. Oral administration of glycine in the prevention of restenosis after coronary angioplasty. A double blind placebo controlled randomized feasibility trial evaluating safety and efficacy of glycine in the prevention of restenosis after angioplasty. Acute Card Care. 2006;8(1):58-64. — View Citation

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. — View Citation

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. Review. — View Citation

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). pii: E1651. doi: 10.3390/jcm9061651. Review. — View Citation

Omasa M, Fukuse T, Toyokuni S, Mizutani Y, Yoshida H, Ikeyama K, Hasegawa S, Wada H. Glycine ameliorates lung reperfusion injury after cold preservation in an ex vivo rat lung model. Transplantation. 2003 Mar 15;75(5):591-8. — View Citation

Panigrahy D, Gilligan MM, Huang S, Gartung A, Cortés-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. — View Citation

Petrat F, Boengler K, Schulz R, de Groot H. Glycine, a simple physiological compound protecting by yet puzzling mechanism(s) against ischaemia-reperfusion injury: current knowledge. Br J Pharmacol. 2012 Apr;165(7):2059-72. doi: 10.1111/j.1476-5381.2011.01711.x. Review. — View Citation

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. — View Citation

Vargas MH, Del-Razo-Rodríguez R, López-García A, Lezana-Fernández JL, Chávez J, Furuya MEY, Marín-Santana JC. Effect of oral glycine on the clinical, spirometric and inflammatory status in subjects with cystic fibrosis: a pilot randomized trial. BMC Pulm Med. 2017 Dec 15;17(1):206. doi: 10.1186/s12890-017-0528-x. — View Citation

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. Review. — View Citation

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. — View Citation

Wheeler MD, Thurman RG. Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. Am J Physiol. 1999 Nov;277(5):L952-9. doi: 10.1152/ajplung.1999.277.5.L952. — View Citation

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. — View Citation

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. Review. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	Serum IL-1ß	Serum concentration of interleukin 1ß.	From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Serum IFN-?	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.
Secondary	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.
Secondary	Serum MIP-1ß	Serum concentration of macrophage inflammatory protein 1ß	From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Secondary	Serum TNF-a	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.