Glycine Supplement for Severe COVID-19

• ClinicalTrials.gov Identifier: NCT04443673
• Recruitment Status: Recruiting
• First Posted: June 23, 2020
• Last Update Posted: August 24, 2020
• Sponsor: Instituto Nacional de Enfermedades Respiratorias
• Information provided by (Responsible Party): Mario H. Vargas, Instituto Nacional de Enfermedades Respiratorias

Study Description

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.

Condition or disease	Intervention/treatment	Phase
COVID-19; SARS-CoV Infection; SARS (Severe Acute Respiratory Syndrome); SARS Pneumonia; ARDS, Human; Pneumonia, Viral	Dietary Supplement: Glycine	Not Applicable

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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Controlled, randomized, two branches, clinical trial.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 20, 2020
• Estimated Primary Completion Date: February 28, 2021
• Estimated Study Completion Date: June 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	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.
No Intervention: Control; Participants will receive the habitual treatment for their severe condition.

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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. ]
   Number of days spent under mechanical ventilation.
2. 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 pressure of oxygen divided by inspired fraction of oxygen.
3. 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. ]
   Plasma concentration of lactate in arterial blood.
4. 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 concentration of interleukin 1β.
5. 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 concentration of interleukin 2.
6. 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 concentration of interleukin 4.
7. 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 concentration of interleukin 5.
8. 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 concentration of interleukin 6.
9. 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 concentration of interleukin 7.
10. 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 concentration of interleukin 8.
11. 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 concentration of interleukin 10.
12. 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 concentration of interleukin 12 (p70).
13. 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 concentration of interleukin 13.
14. 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 concentration of interleukin 17A.
15. 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 concentration of granulocyte colony stimulating factor.
16. 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 concentration of granulocyte monocyte colony stimulating factor.
17. 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 concentration of interferon gamma.
18. 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 concentration of monocyte chemoattractant protein 1 (MCAF).
19. 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 concentration of macrophage inflammatory protein 1β
20. 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 concentration of tumor necrosis factor alpha.
21. 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 concentration of creatinine.
22. 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 concentration of alanine aminotransferase.

    .

23. 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 concentration of aspartate aminotransferase.

    .

24. 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 concentration of alkaline phosphatase.
25. 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 concentration of total bilirubin.
26. 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 concentration of unconjugated bilirubin.
27. 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 concentration of conjugated bilirubin
28. 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. ]
    Serum concentration of C reactive protein.
29. 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. ]
    Blood concentration of hemoglobin.
30. 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. ]
    Number of white blood cells per µl blood.
31. 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. ]
    Number of neutrophils per µl blood.
32. 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. ]
    Number of lymphocytes per µl blood.
33. 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. ]
    Number of monocytes per µl blood.
34. 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. ]
    Number of eosinophils per µl blood.
35. 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. ]
    Number of basophils per µl blood.
36. 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. ]
    Number of platelets per µl blood.
37. 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. ]
    Time that blood takes to clot.
38. 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. ]
    Serum concentration of plasminogen activator inhibitor 1 (PAI-1).
39. 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. ]
    Sequence Organ Failure Assessment (SOFA) score, composed by assessment of PaO2/FiO2 ratio, Glasgow coma scale, mean arterial pressure, bilirubin, and platelets.
40. 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. ]
    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.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Mario H Vargas, MSc; 52+ 55 5666 5868; mhvargasb@yahoo.com.mx

Contact: David Ibarra-Villarreal, MD; 52+ 55 5487 1700 ext 5164; dibarrav@live.net.com

Locations

Mexico

Instituto Nacional de Enfermedades Respiratorias; Recruiting

Mexico DF, Mexico, 14080

Contact: Mario H Vargas, MSc 52+ 55 5666 5868 mhvargasb@yahoo.com.mx

Contact: David Ibarra-Villarreal, MD 52+ 55 5487 1700 ext 5164 dibarrav@live.net.com

Principal Investigator: Mario H. Vargas, MD, MSc

Sub-Investigator: David Ibarra-Villarreal, MD

Sub-Investigator: Cristóbal Guadarrama-Pérez, MD

Sub-Investigator: Alejandra R Báez-Saldaña, MD

Sub-Investigator: Justino Regalado-Pineda, MD

Sub-Investigator: Jaime Chávez-Alderete, PhD

Sponsors and Collaborators

Instituto Nacional de Enfermedades Respiratorias

Investigators

• Principal Investigator: Mario H Vargas, MSc; Instituto Nacional de Enfermedades Respiratorias

More Information

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• Responsible Party: Mario H. Vargas, Senior Researcher, Instituto Nacional de Enfermedades Respiratorias
• ClinicalTrials.gov Identifier: NCT04443673
• Other Study ID Numbers: C40-20
• First Posted: June 23, 2020
• Last Update Posted: August 24, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD can be shared on a reasonable basis and after authorization from the Instituto Nacional de Enfermedades Respiratorias' IRB.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: From publication of results in a scientific journal onward.
• Access Criteria: Reasonable request by E-mail (mhvargasb@yahoo.com.mx)

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mario H. Vargas, Instituto Nacional de Enfermedades Respiratorias:

Glycine; Aminoacetic Acid; Coronavirus Disease; COVID-19; Severe Acute Respiratory Syndrome; SARS

Additional relevant MeSH terms:

COVID-19; Pneumonia; Severe Acute Respiratory Syndrome; Pneumonia, Viral; Respiratory Distress Syndrome; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Glycine; Glycine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs