COVID-19NCT04443673
Glycine Supplement for Severe COVID-19
A study testing Glycine in people with COVID-19 and SARS-CoV Infection, run by Instituto Nacional de Enfermedades Respiratorias at 1 site in Mexico.
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- COVID-19, SARS-CoV Infection, SARS (Severe Acute Respiratory Syndrome)
- What is being tested?
- Glycine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 59 participants
- Where
- 1 siteMexico
- Study dates
- 15 Jun 2020to 14 Jun 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- Pregnant women.
- Already participating in another research protocol.
- Elimination Criteria:
- Voluntary hospital discharge or referenced to another institution.
Trial locations and contacts
1 site in 1 country.
Mexico1 site
Instituto Nacional de Enfermedades Respiratorias
Mexico City, 14080
About this study
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
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.
Read the 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.
- Conditions
- COVID-19, SARS-CoV Infection, SARS (Severe Acute Respiratory Syndrome), SARS Pneumonia, ARDS, Human, Pneumonia, Viral
- Being tested
- Glycine
- Keywords
- Glycine, Aminoacetic Acid, Coronavirus Disease, COVID-19, Severe Acute Respiratory Syndrome, SARS
- Medical subject headings
- COVID-19, Severe Acute Respiratory Syndrome, Respiratory Distress Syndrome, Pneumonia, Viral
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GlycineDietary 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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Dietary Supplement: Glycine |
| Control | No intervention | Participants will receive the habitual treatment for their severe condition. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Number of participants who die divided by number of subjects enrolled in the that study group.
Measured: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Secondary outcomes (40)
Days under mechanical ventilation
Number of days spent under mechanical ventilation.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
.
Measured: 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.
.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jun 2020
- Study start15 Jun 2020
- Primary completion14 Jun 2021
- Study completion14 Jun 2021
Why it stopped: An interim analysis showed no difference in major outcomes (n=35 glycine and n=24 control participants)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (31)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Controlled, randomized, two branches, clinical trial.
- Masking
- None (open label)
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- Instituto Nacional de Enfermedades Respiratorias
- Sponsor type
- Other government
- Responsible party
- Principal investigator, Mario H. Vargas, Instituto Nacional de Enfermedades Respiratorias
- Investigators
- Mario H Vargas, MSc, Principal investigator, Instituto Nacional de Enfermedades Respiratorias
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04443673
- Sponsor's protocol ID
- C40-20
- Status last verified
- Aug 2022
- First submitted
- 18 Jun 2020
- Last updated
- 4 Aug 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD can be shared on a reasonable basis and after authorization from the Instituto Nacional de Enfermedades Respiratorias' IRB.
Publications
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.
PubMed 31986264Yang 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.
PubMed 32360286Klok 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.
PubMed 32291094Marchandot 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.
PubMed 32486469Liu 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.
PubMed 32056249Panigrahy 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.
PubMed 32385712Jentsch 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.
PubMed 11917096Petrat 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.
PubMed 22044190Weinberg 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.
PubMed 27066896Zhong 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.
PubMed 12589194Gomez-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.
PubMed 25988540Schemmer 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.
PubMed 23135224Ikejima 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.
PubMed 8760112Wheeler 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.
PubMed 10926563Iijima 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. doi: 10.1007/s11605-006-0011-0.
PubMed 9834470
Study at a glance
From the registry record, last updated by the sponsor on 4 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04443673
- Acronym / sponsor ID
- C40-20
- Conditions
- COVID-19, SARS-CoV Infection, SARS (Severe Acute Respiratory Syndrome), SARS Pneumonia, ARDS, Human, Pneumonia, Viral
- Keywords
- Glycine, Aminoacetic Acid, Coronavirus Disease, COVID-19, Severe Acute Respiratory Syndrome, SARS
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: An interim analysis showed no difference in major outcomes (n=35 glycine and n=24 control participants)
- Enrolment
- 59 participants (actual)
- Lead sponsor
- Instituto Nacional de Enfermedades RespiratoriasOther government
- Study start
- 15 Jun 2020 (actual)
- Primary completion
- 14 Jun 2021 (actual)
- Study completion
- 14 Jun 2021 (actual)
- First posted
- 23 Jun 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Controlled, randomized, two branches, clinical trial.
| Arm | Type | Receives |
|---|---|---|
| Glycine | Experimental | Dietary Supplement: GlycineAlong 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (4 listed)
- Pregnant women.
- Already participating in another research protocol.
- Voluntary hospital discharge or referenced to another institution.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GlycineAlong 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 |
Primary outcome
Mortality
Time frame: 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.
40 secondary outcomes
Days 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 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
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
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
Time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Results and safety
The study was stopped early (reason given: An interim analysis showed no difference in major outcomes (n=35 glycine and n=24 control participants)). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Aug 2022.
- Background: PubMed 31986264Huang 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.
- Background: PubMed 32360286Yang 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.
- Background: PubMed 32291094Klok 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.
- Background: PubMed 32486469Marchandot 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.
- Background: PubMed 32056249Liu 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.
- Background: PubMed 32385712Panigrahy 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.
- Background: PubMed 11917096Jentsch 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.
- Background: PubMed 22044190Petrat 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.
- Background: PubMed 27066896Weinberg 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.
- Background: PubMed 12589194Zhong 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.
- Background: PubMed 25988540Gomez-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.
- Background: PubMed 23135224Schemmer 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.
- Individual participant dataSharing planned: Yes. IPD can be shared on a reasonable basis and after authorization from the Instituto Nacional de Enfermedades Respiratorias' IRB.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mario H Vargas, MSc principal investigator
Instituto Nacional de Enfermedades Respiratorias
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Glycine in people with COVID-19 and SARS-CoV Infection, run by Instituto Nacional de Enfermedades Respiratorias at 1 site in Mexico.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Mexico. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: An interim analysis showed no difference in major outcomes (n=35 glycine and n=24 control participants)). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04443673, which also lists 31 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Aug 2022.