Clinical trial NCT04443673: Glycine Supplement for Severe COVID-19
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
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
Lead sponsor: Instituto Nacional de Enfermedades Respiratorias
Sponsor class: OTHER_GOV
First posted: 2020-06-23
Enrollment: 59
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Controlled, randomized, two branches, clinical trial.
Primary purpose: TREATMENT

Brief summary: This study will explore whether a daily supplement of glycine, a substance that has antiinflammatory, cytoprotective, and endothelium-protecting effects, can improve mortality, as well as clinical and biochemical parameters, in patients with severe COVID-19 who initiate mechanical ventilatory support.

Detailed description: Patients with severe forms of COVID-19 often develop acute respiratory distress syndrome (ARDS) associated with high levels of proinflammatory cytokines and damage of lungs and other organs. A special feature in these patients is thrombotic events in the micro- and macro-vasculature. Owing to the lack of a specific and efficient treatment against COVID-19, lowering of this "cytokine storm" is a further proposed strategy.

Glycine is the major agonist of glycine receptors (GlyR), which are chloride channels that hyperpolarize cell membranes of inflammatory cells such as macrophages and neutrophils, turning them less sensitive to proinflammatory stimuli. In addition, glycine possesses a cytoprotective effect, improves endothelial function, and diminishes platelet aggregation.

In laboratory animals, in a rat model of endotoxic shock a 5% glycine-rich diet lowers mortality, reduces pulmonary neutrophilic inflammation and hepatic lesions, and avoids elevation of serum TNF-alpha. In animal models of ischemia-reperfusion injury, glycine protects the gut and lungs.

In in vitro studies, glycine diminishes the expression and release of TNF-alpha and IL-6 from adipose tissue, 3T3-L1 cells, and alveolar macrophages, probably through inhibition of phosphorylation of NF-kappaB. Finally, glycine diminishes platelet aggregation.

In human beings, glycine has been used for many years for the management of some ailments. In diabetic patients, oral glycine reduces glycosylated hemoglobin levels and serum TNF-alpha, and in patients with cystic fibrosis glycine improves the clinical and spirometric status, and tend to lower serum TNF-alpha, IL-6 and G-CSF.

Glycine is a white microcrystal powder soluble in water, with a sweet taste and relatively low cost.

This controlled, randomized, two-branches clinical trial will recruit participants of any sex, any age, with COVID-19 confirmed (or awaiting confirmation) by PCR, that are to initiate (or with \<48 h of) mechanical ventilation. After obtaining an informed consent, participants will be randomly assigned to two branches: 1) Experimental group, n=41 participants, that along with habitual management for their condition will receive 0.5 g/kg/day glycine divided in four doses every 6 h through nasogastric tube. 2) Control group, n=41 participants that will only receive habitual management. Pregnant women and subjects already participating in another study protocol will be excluded, and those with voluntary discharge or referenced to another institution will be discarded.

Blood samples for measurements of serum cytokines (Bio-Plex Human Cytokine 17-Plex, Bio-Rad) will be obtained at the beginning of the study and every 7 days thereafter.

The major outcome will be mortality. Secondary outcomes will be diminution of number of days under mechanical ventilation and evolution of PaO2/FiO2, proinflammatory and metabolic biomarkers, Sequence Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II).

Routine test such as arterial blood gases, blood chemistry, blood count, coagulation test, and ECG will also be analyzed by using the weighted average in certain time-periods (probably 7-days periods).

Group comparisons will be carried out by means of Fisher exact/chi-square tests and Student's t-/Mann-Whitney U-tests. Feasibility of multivariate analysis will be evaluated.

Eligibility 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.

Primary outcomes:
measure: Mortality
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Secondary outcomes:
measure: Days under mechanical ventilation
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: PaO2/FiO2 ratio
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Arterial plasma lactate
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-1β
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-2
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-4
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-5
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-6
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-7
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-8
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-10
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-12
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-13
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IL-17
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum G-CSF
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum GM-CSF
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum IFN-γ
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum MCP-1
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum MIP-1β
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum TNF-α
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum creatinine
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum alanine aminotransferase
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum aspartate aminotransferase
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum alkaline phosphatase
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum total bilirubin
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum unconjugated bilirubin
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum conjugated bilirubin
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum C reactive protein
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Hemoglobin
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Total leukocytes
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Neutrophils
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Lymphocytes
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Monocytes
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Eosinophils
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Basophils
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Platelets
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Prothrombin time
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: Serum PAI-1
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: SOFA score
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
measure: APACHE II score
timeFrame: From date of enrollment and until the date of weaning from ventilator or death, whichever came first, assessed up to 12 months.
Other outcomes:
Locations:
city: Mexico DF
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias
Study officials:
affiliation: Instituto Nacional de Enfermedades Respiratorias
name: Mario H Vargas, MSc
role: PRINCIPAL_INVESTIGATOR
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