<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04443673</url>
  </required_header>
  <id_info>
    <org_study_id>C40-20</org_study_id>
    <nct_id>NCT04443673</nct_id>
  </id_info>
  <brief_title>Glycine Supplement for Severe COVID-19</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Nacional de Enfermedades Respiratorias</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Instituto Nacional de Enfermedades Respiratorias</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will explore whether a daily supplement of glycine, a substance that has&#xD;
      antiinflammatory, cytoprotective, and endothelium-protecting effects, can improve mortality,&#xD;
      as well as clinical and biochemical parameters, in patients with severe COVID-19 who initiate&#xD;
      mechanical ventilatory support.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with severe forms of COVID-19 often develop acute respiratory distress syndrome&#xD;
      (ARDS) associated with high levels of proinflammatory cytokines and damage of lungs and other&#xD;
      organs. A special feature in these patients is thrombotic events in the micro- and&#xD;
      macro-vasculature. Owing to the lack of a specific and efficient treatment against COVID-19,&#xD;
      lowering of this &quot;cytokine storm&quot; is a further proposed strategy.&#xD;
&#xD;
      Glycine is the major agonist of glycine receptors (GlyR), which are chloride channels that&#xD;
      hyperpolarize cell membranes of inflammatory cells such as macrophages and neutrophils,&#xD;
      turning them less sensitive to proinflammatory stimuli. In addition, glycine possesses a&#xD;
      cytoprotective effect, improves endothelial function, and diminishes platelet aggregation.&#xD;
&#xD;
      In laboratory animals, in a rat model of endotoxic shock a 5% glycine-rich diet lowers&#xD;
      mortality, reduces pulmonary neutrophilic inflammation and hepatic lesions, and avoids&#xD;
      elevation of serum TNF-alpha. In animal models of ischemia-reperfusion injury, glycine&#xD;
      protects the gut and lungs.&#xD;
&#xD;
      In in vitro studies, glycine diminishes the expression and release of TNF-alpha and IL-6 from&#xD;
      adipose tissue, 3T3-L1 cells, and alveolar macrophages, probably through inhibition of&#xD;
      phosphorylation of NF-kappaB. Finally, glycine diminishes platelet aggregation.&#xD;
&#xD;
      In human beings, glycine has been used for many years for the management of some ailments. In&#xD;
      diabetic patients, oral glycine reduces glycosylated hemoglobin levels and serum TNF-alpha,&#xD;
      and in patients with cystic fibrosis glycine improves the clinical and spirometric status,&#xD;
      and tend to lower serum TNF-alpha, IL-6 and G-CSF.&#xD;
&#xD;
      Glycine is a white microcrystal powder soluble in water, with a sweet taste and relatively&#xD;
      low cost.&#xD;
&#xD;
      This controlled, randomized, two-branches clinical trial will recruit participants of any&#xD;
      sex, any age, with COVID-19 confirmed (or awaiting confirmation) by PCR, that are to initiate&#xD;
      (or with &lt;48 h of) mechanical ventilation. After obtaining an informed consent, participants&#xD;
      will be randomly assigned to two branches: 1) Experimental group, n=41 participants, that&#xD;
      along with habitual management for their condition will receive 0.5 g/kg/day glycine divided&#xD;
      in four doses every 6 h through nasogastric tube. 2) Control group, n=41 participants that&#xD;
      will only receive habitual management. Pregnant women and subjects already participating in&#xD;
      another study protocol will be excluded, and those with voluntary discharge or referenced to&#xD;
      another institution will be discarded.&#xD;
&#xD;
      Blood samples for measurements of serum cytokines (Bio-Plex Human Cytokine 17-Plex, Bio-Rad)&#xD;
      will be obtained at the beginning of the study and every 7 days thereafter.&#xD;
&#xD;
      The major outcome will be mortality. Secondary outcomes will be diminution of number of days&#xD;
      under mechanical ventilation and evolution of PaO2/FiO2, proinflammatory and metabolic&#xD;
      biomarkers, Sequence Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health&#xD;
      Evaluation II (APACHE II).&#xD;
&#xD;
      Routine test such as arterial blood gases, blood chemistry, blood count, coagulation test,&#xD;
      and ECG will also be analyzed by using the weighted average in certain time-periods (probably&#xD;
      7-days periods).&#xD;
&#xD;
      Group comparisons will be carried out by means of Fisher exact/chi-square tests and Student's&#xD;
      t-/Mann-Whitney U-tests. Feasibility of multivariate analysis will be evaluated.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    An interim analysis showed no difference in major outcomes (n=35 glycine and n=24 control&#xD;
    participants)&#xD;
  </why_stopped>
  <start_date type="Actual">June 15, 2020</start_date>
  <completion_date type="Actual">June 14, 2021</completion_date>
  <primary_completion_date type="Actual">June 14, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Controlled, randomized, two branches, clinical trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mortality</measure>
    <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_frame>
    <description>Number of participants who die divided by number of subjects enrolled in the that study group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Days under mechanical ventilation</measure>
    <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_frame>
    <description>Number of days spent under mechanical ventilation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PaO2/FiO2 ratio</measure>
    <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_frame>
    <description>Arterial pressure of oxygen divided by inspired fraction of oxygen.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arterial plasma lactate</measure>
    <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_frame>
    <description>Plasma concentration of lactate in arterial blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-1β</measure>
    <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_frame>
    <description>Serum concentration of interleukin 1β.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-2</measure>
    <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_frame>
    <description>Serum concentration of interleukin 2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-4</measure>
    <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_frame>
    <description>Serum concentration of interleukin 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-5</measure>
    <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_frame>
    <description>Serum concentration of interleukin 5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-6</measure>
    <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_frame>
    <description>Serum concentration of interleukin 6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-7</measure>
    <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_frame>
    <description>Serum concentration of interleukin 7.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-8</measure>
    <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_frame>
    <description>Serum concentration of interleukin 8.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-10</measure>
    <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_frame>
    <description>Serum concentration of interleukin 10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-12</measure>
    <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_frame>
    <description>Serum concentration of interleukin 12 (p70).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-13</measure>
    <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_frame>
    <description>Serum concentration of interleukin 13.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-17</measure>
    <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_frame>
    <description>Serum concentration of interleukin 17A.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum G-CSF</measure>
    <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_frame>
    <description>Serum concentration of granulocyte colony stimulating factor.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum GM-CSF</measure>
    <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_frame>
    <description>Serum concentration of granulocyte monocyte colony stimulating factor.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IFN-γ</measure>
    <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_frame>
    <description>Serum concentration of interferon gamma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum MCP-1</measure>
    <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_frame>
    <description>Serum concentration of monocyte chemoattractant protein 1 (MCAF).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum MIP-1β</measure>
    <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_frame>
    <description>Serum concentration of macrophage inflammatory protein 1β</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum TNF-α</measure>
    <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_frame>
    <description>Serum concentration of tumor necrosis factor alpha.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum creatinine</measure>
    <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_frame>
    <description>Serum concentration of creatinine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum alanine aminotransferase</measure>
    <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_frame>
    <description>Serum concentration of alanine aminotransferase.&#xD;
.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum aspartate aminotransferase</measure>
    <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_frame>
    <description>Serum concentration of aspartate aminotransferase.&#xD;
.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum alkaline phosphatase</measure>
    <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_frame>
    <description>Serum concentration of alkaline phosphatase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum total bilirubin</measure>
    <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_frame>
    <description>Serum concentration of total bilirubin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum unconjugated bilirubin</measure>
    <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_frame>
    <description>Serum concentration of unconjugated bilirubin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum conjugated bilirubin</measure>
    <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_frame>
    <description>Serum concentration of conjugated bilirubin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum C reactive protein</measure>
    <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_frame>
    <description>Serum concentration of C reactive protein.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hemoglobin</measure>
    <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_frame>
    <description>Blood concentration of hemoglobin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total leukocytes</measure>
    <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_frame>
    <description>Number of white blood cells per µl blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neutrophils</measure>
    <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_frame>
    <description>Number of neutrophils per µl blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lymphocytes</measure>
    <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_frame>
    <description>Number of lymphocytes per µl blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monocytes</measure>
    <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_frame>
    <description>Number of monocytes per µl blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Eosinophils</measure>
    <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_frame>
    <description>Number of eosinophils per µl blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Basophils</measure>
    <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_frame>
    <description>Number of basophils per µl blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelets</measure>
    <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_frame>
    <description>Number of platelets per µl blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prothrombin time</measure>
    <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_frame>
    <description>Time that blood takes to clot.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum PAI-1</measure>
    <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_frame>
    <description>Serum concentration of plasminogen activator inhibitor 1 (PAI-1).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SOFA score</measure>
    <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_frame>
    <description>Sequence Organ Failure Assessment (SOFA) score, composed by assessment of PaO2/FiO2 ratio, Glasgow coma scale, mean arterial pressure, bilirubin, and platelets.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>APACHE II score</measure>
    <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_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">59</enrollment>
  <condition>COVID-19</condition>
  <condition>SARS-CoV Infection</condition>
  <condition>SARS (Severe Acute Respiratory Syndrome)</condition>
  <condition>SARS Pneumonia</condition>
  <condition>ARDS, Human</condition>
  <condition>Pneumonia, Viral</condition>
  <arm_group>
    <arm_group_label>Glycine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants will receive the habitual treatment for their severe condition.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Glycine</intervention_name>
    <description>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.</description>
    <arm_group_label>Glycine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Any age.&#xD;
&#xD;
          -  Any sex.&#xD;
&#xD;
          -  With COVID-19 confirmed (or awaiting confirmation) by PCR.&#xD;
&#xD;
          -  With a clinical decision of initiation of mechanical ventilation or with &lt;48 h under&#xD;
             mechanical ventilation.&#xD;
&#xD;
          -  Informed consent signed by the participant's responsible.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant women.&#xD;
&#xD;
          -  Already participating in another research protocol.&#xD;
&#xD;
        Elimination Criteria:&#xD;
&#xD;
          -  Voluntary hospital discharge or referenced to another institution.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mario H Vargas, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto Nacional de Enfermedades Respiratorias</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Instituto Nacional de Enfermedades Respiratorias</name>
      <address>
        <city>Mexico DF</city>
        <zip>14080</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
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    <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. doi: 10.1007/s11605-006-0011-0.</citation>
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    <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. doi: 10.1097/01.TP.0000053200.98125.14.</citation>
    <PMID>12640295</PMID>
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  <reference>
    <citation>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.</citation>
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    <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.</citation>
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    <citation>Garcia-Macedo R, Sanchez-Munoz 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.</citation>
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    <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.</citation>
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    <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. doi: 10.1080/14628840600643383.</citation>
    <PMID>16720430</PMID>
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  </reference>
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    <citation>Cruz M, Maldonado-Bernal C, Mondragon-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. doi: 10.1007/BF03346417.</citation>
    <PMID>18852529</PMID>
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    <citation>Vargas MH, Del-Razo-Rodriguez R, Lopez-Garcia A, Lezana-Fernandez JL, Chavez J, Furuya MEY, Marin-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.</citation>
    <PMID>29246256</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>August 2, 2022</last_update_submitted>
  <last_update_submitted_qc>August 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Instituto Nacional de Enfermedades Respiratorias</investigator_affiliation>
    <investigator_full_name>Mario H. Vargas</investigator_full_name>
    <investigator_title>Senior Researcher</investigator_title>
  </responsible_party>
  <keyword>Glycine</keyword>
  <keyword>Aminoacetic Acid</keyword>
  <keyword>Coronavirus Disease</keyword>
  <keyword>COVID-19</keyword>
  <keyword>Severe Acute Respiratory Syndrome</keyword>
  <keyword>SARS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Pneumonia</mesh_term>
    <mesh_term>Severe Acute Respiratory Syndrome</mesh_term>
    <mesh_term>Pneumonia, Viral</mesh_term>
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glycine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>IPD can be shared on a reasonable basis and after authorization from the Instituto Nacional de Enfermedades Respiratorias' IRB.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>From publication of results in a scientific journal onward.</ipd_time_frame>
    <ipd_access_criteria>Reasonable request by E-mail (mhvargasb@yahoo.com.mx)</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04443673
org study id: C40-20
nct id: NCT04443673
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study will explore whether a daily supplement of glycine, a substance that has
      antiinflammatory, cytoprotective, and endothelium-protecting effects, can improve mortality,
      as well as clinical and biochemical parameters, in patients with severe COVID-19 who initiate
      mechanical ventilatory support.
Patients with severe forms of COVID-19 often develop acute respiratory distress syndrome
      (ARDS) associated with high levels of proinflammatory cytokines and damage of lungs and other
      organs. A special feature in these patients is thrombotic events in the micro- and
      macro-vasculature. Owing to the lack of a specific and efficient treatment against COVID-19,
      lowering of this "cytokine storm" is a further proposed strategy.

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

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

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

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

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

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

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

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

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

      Group comparisons will be carried out by means of Fisher exact/chi-square tests and Student's
      t-/Mann-Whitney U-tests. Feasibility of multivariate analysis will be evaluated.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Controlled, randomized, two branches, clinical trial.
primary purpose: Treatment
masking: None (Open Label)
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.
description: Number of participants who die divided by number of subjects enrolled in the that study group.
measure: 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.
description: Number of days spent under mechanical ventilation.
measure: 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.
description: Arterial pressure of oxygen divided by inspired fraction of oxygen.
measure: 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.
description: Plasma concentration of lactate in arterial blood.
measure: 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.
description: Serum concentration of interleukin 1β.
measure: 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.
description: Serum concentration of interleukin 2.
measure: 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.
description: Serum concentration of interleukin 4.
measure: 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.
description: Serum concentration of interleukin 5.
measure: 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.
description: Serum concentration of interleukin 6.
measure: 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.
description: Serum concentration of interleukin 7.
measure: 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.
description: Serum concentration of interleukin 8.
measure: 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.
description: Serum concentration of interleukin 10.
measure: 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.
description: Serum concentration of interleukin 12 (p70).
measure: 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.
description: Serum concentration of interleukin 13.
measure: 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.
description: Serum concentration of interleukin 17A.
measure: 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.
description: Serum concentration of granulocyte colony stimulating factor.
measure: 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.
description: Serum concentration of granulocyte monocyte colony stimulating factor.
measure: 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.
description: Serum concentration of interferon gamma.
measure: 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.
description: Serum concentration of monocyte chemoattractant protein 1 (MCAF).
measure: 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.
description: Serum concentration of macrophage inflammatory protein 1β
measure: 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.
description: Serum concentration of tumor necrosis factor alpha.
measure: 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.
description: Serum concentration of creatinine.
measure: 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.
description: Serum concentration of alanine aminotransferase.
.
measure: 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.
description: Serum concentration of aspartate aminotransferase.
.
measure: 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.
description: Serum concentration of alkaline phosphatase.
measure: 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.
description: Serum concentration of total bilirubin.
measure: 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.
description: Serum concentration of unconjugated bilirubin.
measure: 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.
description: Serum concentration of conjugated bilirubin
measure: 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.
description: Serum concentration of C reactive protein.
measure: 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.
description: Blood concentration of hemoglobin.
measure: 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.
description: Number of white blood cells per µl blood.
measure: 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.
description: Number of neutrophils per µl blood.
measure: 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.
description: Number of lymphocytes per µl blood.
measure: 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.
description: Number of monocytes per µl blood.
measure: 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.
description: Number of eosinophils per µl blood.
measure: 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.
description: Number of basophils per µl blood.
measure: 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.
description: Number of platelets per µl blood.
measure: 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.
description: Time that blood takes to clot.
measure: 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.
description: Serum concentration of plasminogen activator inhibitor 1 (PAI-1).
measure: 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.
description: Sequence Organ Failure Assessment (SOFA) score, composed by assessment of PaO2/FiO2 ratio, Glasgow coma scale, mean arterial pressure, bilirubin, and platelets.
measure: 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.
description: 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.
arm group label: Glycine
arm group type: Experimental
description: 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.
arm group label: Control
arm group type: No Intervention
description: Participants will receive the habitual treatment for their severe condition.
intervention type: Dietary Supplement
intervention name: Glycine
description: 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.
arm group label: Glycine
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Mario H Vargas, MSc
role: Principal Investigator
affiliation: Instituto Nacional de Enfermedades Respiratorias
facility: 
country: Mexico
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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. doi: 10.1152/ajpgi.1996.271.1.G97.
PMID: 8760112
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. doi: 10.1152/ajplung.2000.279.2.L390.
PMID: 10926563
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. doi: 10.1007/s11605-006-0011-0.
PMID: 9834470
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. doi: 10.1097/01.TP.0000053200.98125.14.
PMID: 12640295
citation: 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.
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PMID: 29246256
responsible party type: Principal Investigator
investigator affiliation: Instituto Nacional de Enfermedades Respiratorias
investigator full name: Mario H. Vargas
investigator title: Senior Researcher
mesh term: COVID-19
mesh term: Pneumonia
mesh term: Severe Acute Respiratory Syndrome
mesh term: Pneumonia, Viral
mesh term: Respiratory Distress Syndrome
mesh term: Glycine
sharing ipd: Yes
ipd description: IPD can be shared on a reasonable basis and after authorization from the Instituto Nacional de Enfermedades Respiratorias' IRB.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: From publication of results in a scientific journal onward.
ipd access criteria: Reasonable request by E-mail (mhvargasb@yahoo.com.mx)